Author: "Les Laboratoires SERVIER" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Les Laboratoires SERVIER"' showing total 40 results

Start Over Author "Les Laboratoires SERVIER"

40 results on '"Les Laboratoires SERVIER"'

1. A Roll-over Study to Provide Continued Treatment With Lyophilized Pegaspargase (S95014) in Pediatric Patients With Acute Lymphoblastic Leukemia (ALL) (ALL)

Author: ADIR, a Servier Group company and Les Laboratoires Servier (L.L.S), Russia
Published: 2023

2. A Study Comparing the Blood Levels of Both Pegaspargase (S95014) Formulations (Liquid vs Lyophilized) in the Treatment of Paediatric Patients With Acute Lymphoblastic Leukemia (ALL) (ALL)

Author: ADIR, a Servier Group company and Les Laboratoires Servier (L.L.S), Russia
Published: 2023

3. Clinical Trial Assessing the HERV-W Env Antagonist GNbAC1 for Efficacy in MS (CHANGE-MS)

Author: Les Laboratoires Servier (LLS), Institut de Recherches Internationales Servier, and Worldwide Clinical Trials
Published: 2020

4. Assessing the HERV-W Env ANtagonist GNbAC1 for Evaluation in an Open Label Long-term Safety Study in Patients With Multiple Sclerosis (ANGEL-MS)

Author: Les Laboratoires Servier, Worldwide Clinical Trials, and Institut de Recherches Internationales Servier
Published: 2020

5. ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

Author: Oussama Abla, Stephen Peeke, Irem Eldem, Marianne D. van de Wetering, Jennifer Picarsic, Kseniya Petrova-Drus, Robert B. Lorsbach, Jan A M van Laar, Paul Geraeds Kemps, Sylvie Fraitag, Sébastien Héritier, Kristian T. Schafernak, Amy A. Swanson, Eli L. Diamond, Raf Sciot, Karen Ernestus, Mariko Suchi, Nabeel R. Yaseen, Sanda Alexandrescu, Laura Sophia Hiemcke-Jiwa, Matthew Collin, Ingrid S Tam, Sabrina Rossi, Benjamin H. Durham, F J Sherida H Woei-A-Jin, James A. Whitlock, Brianna Empringham, Laura Munoz-Arcos, Falko Fend, Olga Gryniewicz-Kwiatkowska, Majid Madni, Verena Wiegering, Kerry Turner, Dina El Demellawy, Gianpiero Tamburrini, Aditya Raghunathan, Lucas R. Massoth, Carel J. M. van Noesel, Robert Möhle, Cor van den Bos, Jacinthe Bonneau-Lagacherie, Somak Roy, Pasquale M Barbaro, Andreas Beilken, Stefania Gaspari, Jean-François Emile, David D. Grier, Claire Lamaison, Kee Kiat Yeo, Jean Donadieu, Jon M Brandt, Laure Farnault, Friedrich Feuerhake, Marie-Laure Jullie, Uta Flucke, Pancras C.W. Hogendoorn, Astrid G. S. van Halteren, Antje Bornemann, Bryan A. Sisk, Tina Méry, Joanna Weinstein, Ashish R Kumar, Robert M. Verdijk, V. Baykov, Alysa A Poulin, Mandy M Atkinson, VG Potapenko, Vaish Sridhar, Julien Haroche, Zofia Hélias-Rodzewicz, Shipra Garg, Susan Picton, Michael M. Henry, Jackie Allotey, Daniel Leino, Nishant Tiwari, Martin Ebinger, Jason L Hornick, Bożenna Dembowska-Bagińska, Marco Gessi, Dmitry A Evseev, Paediatric Oncology, CCA - Cancer biology and immunology, Pathology, CCA - Cancer Treatment and Quality of Life, Leiden University Medical Center (LUMC), Universiteit Leiden, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Ambroise Paré [AP-HP], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pontchaillou [Rennes], CHU Marseille, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux], CHU Pitié-Salpêtrière [AP-HP], National Institutes of Health, NIH, National Cancer Institute, NCI: P30 CA008748, R37 CA259260-01, Cincinnati Children's Hospital Medical Center, University of Saskatchewan, Leids Universitair Medisch Centrum, LUMC, Institut National Du Cancer, INCa: PRT-K19-143, P.G.K. received a grant from Leiden University Medical Center. A.G.S.v.H. is supported by Stichting 1000 kaarsjes voor Juultje. E.L.D. is supported by the National Institutes of Health/National Cancer Institute Core Grant (P30 CA008748), National Cancer Institute (R37 CA259260-01), the Frame Fund, Applebaum Foundation, and Joy Family West Foundation. J.-F.E. is supported by the Programme de Recherche Translationnelle sur le Cancer from the French National Cancer Institute (PRT-K19-143)., and The authors acknowledge the International Rare Histiocytic Disorders Registry (IRHDR, ClinicalTrial.gov number NCT02285582), which included some patients described in this study. The authors thank Chris Woods (Lead Analyst, Imaging Informatics) and the Research Pathology Laboratory at Cincinnati Children's Hospital Medical Center, John DeCoteau (molecular pathologist) at University of Saskatchewan, Sven van Kempen (senior laboratory technician) and Lennart Kester (clinical molecular biologist in pathology in training) at Princess M?xima Center for Pediatric Oncology, and Demi van Egmond (laboratory technician), Tom van Wezel (clinical molecular biologist in pathology), and Arjen Cleven (pathologist) at Leiden University Medical Center for technical assistance. The authors thank Els Wauters (pulmonologist and respiratory oncologist) at University Hospitals Leuven, Andreas Rosenwald (pathologist) at the Institute of Pathology of the University of W?rzburg, and Bipin Mathew (pathologist) at Leeds Teaching Hospitals for clinical care and/or diagnostics of patients described in this study. The authors thank Les Laboratoires Servier for allowing the use of their medical illustrations (Servier Medical Art, https://smart.servier.com) in the visual abstract. Figure 6 was created with BioRender.com. P.G.K. received a grant from Leiden University Medical Center. A.G.S.v.H. is supported by Stichting 1000 kaarsjes voor Juultje. E.L.D. is supported by the National Institutes of Health/National Cancer Institute Core Grant (P30 CA008748), National Cancer Institute (R37 CA259260-01), the Frame Fund, Applebaum Foundation, and Joy Family West Foundation. J.-F.E. is supported by the Programme de Recherche Translationnelle sur le Cancer from the French National Cancer Institute (PRT-K19-143).
Subjects: Adult, Histiocytic Disorders, Malignant, Male, Pathology, medicine.medical_specialty, Adolescent, Oncogene Proteins, Fusion, [SDV]Life Sciences [q-bio], BLOOD COMMENTARY, Immunology, Disease, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Biochemistry, Young Adult, hemic and lymphatic diseases, medicine, Humans, Anaplastic Lymphoma Kinase, Child, Protein Kinase Inhibitors, Histiocyte, Retrospective Studies, business.industry, Infant, Histology, Cell Biology, Hematology, medicine.disease, Phenotype, Histiocytosis, Histiocytic neoplasm, Child, Preschool, Female, Nervous System Diseases, business
Abstract: Contains fulltext : 249882.pdf (Publisher’s version ) (Closed access) ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.
Published: 2022
Full Text: View/download PDF

6. On-line 2D-RPLC x RPLC – HRMS to assess wastewater treatment in a pharmaceutical plant

Author: Jean-Michel Lerestif, Karine Faure, Fleur Marie Saint Germain, Estelle Saunier, Sabine Heinisch, Oril Industrie, Chromatography & Hyphenated Techniques - Chromatographie et techniques couplées, Institut des Sciences Analytiques (ISA), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and This work was financially supported by ORIL Industrie, affiliated to Les Laboratoires Servier, the University of Lyon and the Centre National de la Recherche Scientifique (CNRS).
Subjects: Clinical Biochemistry, Relative standard deviation, Pharmaceutical Science, 010501 environmental sciences, 01 natural sciences, Mass Spectrometry, Water Purification, Analytical Chemistry, Industrial wastewater treatment, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Drug Discovery, Neutral ph, Effluent, Spectroscopy, ComputingMilieux_MISCELLANEOUS, 0105 earth and related environmental sciences, Active ingredient, Chromatography, Reverse-Phase, Plants, Medicinal, Chromatography, Chemistry, 010401 analytical chemistry, Water, Reversed-phase chromatography, 6. Clean water, 0104 chemical sciences, Pharmaceutical Preparations, Sewage treatment, Quantitative analysis (chemistry)
Abstract: Pharmaceutical effluents are complex media containing hundreds of compounds including active ingredients, intermediate products and unknown impurities. Bringing an industrial wastewater treatment plant (WWTP) into compliance with European directives requires a thorough analysis of the effluent. In this study, we demonstrate how online comprehensive two-dimensional liquid chromatography (on-line LC × LC) hyphenated to high resolution mass spectrometry (HRMS) can be a powerful analytical methodology to monitoring the outlet water, by analysing the content of known molecules while characterising unknown compounds. Reversed phase liquid chromatography (RPLC) was used in both dimensions, with a penta-fluoro-phenyl silica-based column at neutral pH in the first dimension (1D) and a C18 column at acidic pH in the second one (2D). The conditions were optimized for a total analysis time of 60 min. The variability of both retention times and peak areas was evaluated. The average standard deviation on retention times was found to be less than 0.1 s in 2D. The relative standard deviation on peak area was about 7% for run-to-run analysis. This analytical approach, applied to the pharmaceutical effluents before (inlet) and after (outlet) wastewater treatment permitted to detect 240 compounds. These included 27 priority pharmaceutical products, 8 of which were of very high priority and their concentrations could be compared to target values. The comparison of 2D-LC and 1D-LC approaches clearly highlights the power of on-line RPLC x RPLC technique, which allows both targeted quantitative analysis and non-targeted qualitative analysis of pharmaceutical effluents.
Published: 2022
Full Text: View/download PDF

7. Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: a study in three European data sources

Author: Miguel Cainzos-Achirica, Nicolas Deltour, Beatriz Poblador-Plou, Alexandra Prados-Torres, Susana Perez-Gutthann, Jordi Castellsague, Joan Forns, Maria Giner-Soriano, Maja Hellfritzsch, Anton Pottegård, Rosa Morros, Manel Pladevall, Jordi Cortés, Jesper Hallas, Emmanuelle Jacquot, Universitat Politècnica de Catalunya. Doctorat en Estadística i Investigació Operativa, Universitat Politècnica de Catalunya. GRBIO - Grup de Recerca en Bioestadística i Bioinformàtica, Institut Català de la Salut, [Forns J, Cainzos-Achirica M, Castellsagué J, Perez-Gutthann S] Epidemiology, RTI Health Solutions, Barcelona, Spain. [Hellfritzsch M, Hallas J, Pottegård A] Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark. [Morros R, Giner-Soriano M] Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra (Cerdanyola del Vallès), Barcelona, Spain. Institut Català de la Salut, Barcelona, Spain. [Poblador-Plou B, Prados-Torres A] EpiChron, Instituto Aragonés de Ciencias de la Salud, (IACS), IIS Aragón, REDISSEC ISCIII, Zaragoza, Spain. [Cortés J] Departament d'Estadística i Investigació Operativa, Universitat Politècnica de Catalunya, Barcelona, Spain. [Jacquot E, Deltour N] Pharmacoepidemiology Department, Les Laboratoires Servier, Paris, France. [Pladevall M] Epidemiology, RTI Health Solutions, Barcelona, Spain. The Center for Health Policy and Health Services Research, Henry Ford Health System, Detroit, MI, USA., and IDIAP Jordi Gol
Subjects: Male, pharmacoepidemiology, Databases, Factual, Epidemiology, Denmark, Digestive System Diseases::Liver Diseases::Hepatic Insufficiency::Liver Failure::Liver Failure, Acute [DISEASES], acute liver injury, acciones y usos químicos::acciones farmacológicas::usos terapéuticos::fármacos del sistema nervioso central::fármacos psicotrópicos::antidepresivos [COMPUESTOS QUÍMICOS Y DROGAS], 030226 pharmacology & pharmacy, Liver disease, 0302 clinical medicine, Health Occupations::Medicine::Public Health::Epidemiology::Health Occupations::Pharmacoepidemiology [DISCIPLINES AND OCCUPATIONS], profesiones sanitarias::medicina::salud pública::epidemiología::profesiones sanitarias::farmacoepidemiología [DISCIPLINAS Y OCUPACIONES], Validation, Original Report, Pharmacology (medical), 030212 general & internal medicine, Aged, 80 and over, validation, Medical record, 92 Biology and other natural sciences::92B Mathematical biology in general [Classificació AMS], ICD-10, Antidepressius, Middle Aged, Pharmacoepidemiology, Jaundice, respiratory system, Registres mèdics, antidepressants, language, Other subheadings::Other subheadings::/utilization [Other subheadings], Female, Chemical and Drug Induced Liver Injury, medicine.symptom, Adult, medicine.medical_specialty, Biomatemàtica, Adolescent, injury, epidemiología y bioestadística::bioestadística::clasificaciones en salud::Clasificación Internacional de Enfermedades [SALUD PÚBLICA], Epidemiology and Biostatistics::Biostatistics::Health Classifications::International Classification of Diseases [PUBLIC HEALTH], 62 Statistics::62D05 Sampling theory, sample surveys [Classificació AMS], Insuficiència hepàtica - Diagnòstic, pharmacoepidemiology validation, Danish, Young Adult, 03 medical and health sciences, Internal medicine, Original Reports, medicine, Hospital discharge, Acute liver injury, Humans, Matemàtiques i estadística::Estadística matemàtica::Anàlisi multivariant [Àrees temàtiques de la UPC], Sampling (Statistics), Diagnosis-Related Groups, Aged, Biomathematics, Matemàtiques i estadística::Estadística aplicada::Estadística biosanitària [Àrees temàtiques de la UPC], business.industry, Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Central Nervous System Agents::Psychotropic Drugs::Antidepressive Agents [CHEMICALS AND DRUGS], enfermedades del sistema digestivo::enfermedades hepáticas::insuficiencia hepática::fracaso hepático::fracaso hepático agudo [ENFERMEDADES], acute liver, Otros calificadores::Otros calificadores::/utilización [Otros calificadores], Reproducibility of Results, medicine.disease, language.human_language, respiratory tract diseases, Spain, business, Mostreig (Estadística), Farmacoepidemiologia
Abstract: This is the peer reviewed version of the following article: Forns, J. [et al.]. Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: a study in three European data sources. "Pharmacoepidemiology and drug safety", 6 Juny 2019, vol. 28, núm. 7, p. 965-975, which has been published in final form at 10.1002/pds.4803. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving." Purpose Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs). Methods Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers. Three ALI definitions were evaluated: primary (specific hospital discharge codes), secondary (specific and nonspecific hospital discharge codes), and tertiary (specific and nonspecific hospital and outpatient codes). The validation included review of patient profiles (EpiChron and SIDIAP) and of clinical data from medical records (EpiChron and Denmark). ALI cases were confirmed when liver enzyme values met a definition by an international working group. Results Overall PPVs (95% CIs) for the study ALI definitions were, for the primary ALI definition, 84% (60%-97%) (EpiChron), 60% (26%-88%) (SIDIAP), and 74% (60%-85%) (Denmark); for the secondary ALI definition, 65% (45%-81%) (EpiChron), 40% (19%-64%) (SIDIAP), and 70% (64%-77%) (Denmark); and for the tertiary ALI definition, 25% (18%-34%) (EpiChron), 8% (7%-9%) (SIDIAP), and 47% (42%-52%) (Denmark). The overall PPVs were higher for specific than for nonspecific codes and for hospital discharge than for outpatient codes. The nonspecific code “unspecified jaundice” had high PPVs in Denmark. Conclusions PPVs obtained apply to patients using antidepressants without preexisting liver disease or ALI risk factors. To maximize validity, studies on ALI should prioritize hospital specific discharge codes and should include hospital codes for unspecified jaundice. Case validation is required when ALI outpatient cases are considered.
Published: 2019
Full Text: View/download PDF

8. Structure–activity relationships of urotensin II and URP

Author: Hubert Vaudry, David Chatenet, Daniel Davoust, Pierre Pacaud, Christophe Dubessy, Laure Guilhaudis, Alain Fournier, Bruno Pfeiffer, Hassan Oulyadi, Marie-Christine Tonon, Jérôme Leprince, Pierre Renard, Elizabeth Scalbert, Isabelle Ségalas-Milazzo, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Montreal Heart Institute (MONTREAL HEART INSTITUTE), Les Laboratoires SERVIER, Institut de Recherche Servier, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), and Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)
Subjects: Protein Conformation, Physiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Peptide Hormones, Peptide, Endogeny, MESH: Amino Acid Sequence, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biochemistry, MESH: Tyrosine, chemistry.chemical_compound, MESH: Protein Conformation, MESH: Structure-Activity Relationship, 0302 clinical medicine, Endocrinology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Animals, Disulfides, MESH: Peptide Fragments, Receptor, chemistry.chemical_classification, 0303 health sciences, Alanine, Molecular Structure, Biological activity, 3. Good health, Amino acid, MESH: Alanine, Urotensins, MESH: Molecular Structure, Molecular Sequence Data, MESH: Sequence Alignment, Structure-Activity Relationship, 03 medical and health sciences, Cellular and Molecular Neuroscience, Animals, Humans, Structure–activity relationship, MESH: Disulfides, Amino Acid Sequence, Cysteine, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, MESH: Urotensins, Rational design, MESH: Cysteine, Peptide Fragments, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Peptide Hormones, Tyrosine, Urotensin-II, Sequence Alignment, 030217 neurology & neurosurgery
Abstract: International audience; Urotensin II (U-II) and urotensin II-related peptide (URP) are the endogenous ligands for the orphan G-protein-coupled receptor GPR14 now renamed UT. At the periphery, U-II and/or URP exert a wide range of biological effects on cardiovascular tissues, airway smooth muscles, kidney and endocrine glands, while central administration of U-II elicits various behavioral and cardiovascular responses. There is also evidence that U-II and/or URP may be involved in a number of pathological conditions including heart failure, atherosclerosis, renal dysfunction and diabetes. Because of the potential involvement of the urotensinergic system in various physiopathological processes, there is need for the rational design of potent and selective ligands for the UT receptor. Structure-activity relationship studies have shown that the minimal sequence required to retain full biological activity is the conserved U-II(4-11) domain, in particular the Cys5 and Cys10 residues involved in the disulfide bridge, and the Phe6, Lys8 and Tyr9 residues. Free alpha-amino group and C-terminal COOH group are not necessary for the biological activity, and modifications of these radicals may even increase the stability of the analogs. Punctual substitution of native amino acids, notably Phe6 and Trp7, by particular residues generates analogs with antagonistic properties. These studies, which provide crucial information regarding the structural and conformational requirements for ligand-receptor interactions, will be of considerable importance for the design of novel UT ligands with increased selectivity, potency and stability, that may eventually lead to the development of innovative drugs.
Published: 2008
Full Text: View/download PDF

9. Structure–Activity Relationships of Human Urotensin II and Related Analogues on Rat Aortic Ring Contraction

Author: Gervaise Loirand, Pierre Renard, Pierre Pacaud, Jérôme Leprince, David Chatenet, Hubert Vaudry, Marie-Christine Tonon, Christophe Dubessy, Elizabeth Scalbert, Bernard Calas, Céline Marionneau, Bruno Pfeiffer, Patricia Labarrère, Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, and Institut de Recherche Servier
Subjects: Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Aorta, Thoracic, Peptide, MESH: Amino Acid Sequence, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Dose-Response Relationship, Drug, chemistry.chemical_compound, MESH: Structure-Activity Relationship, 0302 clinical medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Drug Discovery, Vasoconstrictor Agents, MESH: Animals, MESH: Peptide Fragments, Receptor, chemistry.chemical_classification, Alanine, 0303 health sciences, Biological activity, General Medicine, Amino acid, Biochemistry, MESH: Rats, Stereochemistry, Urotensins, MESH: Aorta, Thoracic, Molecular Sequence Data, In Vitro Techniques, Structure-Activity Relationship, MESH: Vasoconstrictor Agents, 03 medical and health sciences, Animals, Humans, Amino Acid Sequence, Rats, Wistar, 030304 developmental biology, MESH: In Vitro Techniques, Pharmacology, MESH: Humans, MESH: Molecular Sequence Data, MESH: Urotensins, Dose-Response Relationship, Drug, MESH: Rats, Wistar, Peptide Fragments, MESH: Male, In vitro, Rats, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Urotensin-II, 030217 neurology & neurosurgery, Cysteine
Abstract: International audience; The sequence of human urotensin II (UII) has been recently established as H-Glu-Thr-Pro-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH, and it has been reported that UII is the most potent mammalian vasoconstrictor peptide identified so far. A series of UII analogues was synthesized, and the contractile activity of each compound was studied in vitro using de-endothelialised rat aortic rings. Replacement of each amino acid by an L-alanine or by a D-isomer showed that the N- and C-terminal residues flanking the cyclic region of the amidated peptide were relatively tolerant to substitution. Conversely, replacement of any residue of the cyclic region significantly reduced the contractile activity of the molecule. The octapeptide UII(4-11) was 4 times more potent than UII, indicating that the C-terminal region of the molecule possesses full biological activity. Alanine or D-isomer substitutions in UII(4-11) or in UII(4-11)-NH2, respectively, showed a good correlation with the results obtained for UII-NH2. Disulfide bridge disruption or replacement of the cysteine residues by their D-enantiomers markedly reduced the vasoconstrictor effect of UII and its analogues. In contrast, acetylation of the N-terminal residue of UII and UII-NH2 enhanced the potency of the peptide. Finally, monoiodination of the Tyr6 residue in UII(4-11) increased by 5 fold the potency of the peptide in the aortic ring bioassay. This structure-activity relationship study should provide useful information for the rational design of selective and potent UII receptor agonists and antagonists.
Published: 2003
Full Text: View/download PDF

10. A convenient extension of the Wessely–Moser rearrangement for the synthesis of substituted alkylaminoflavones as neuroprotective agents in vitro

Author: Ronan Larget, Pierre Renard, Martine Largeron, Lockhart Brian, Institut de Recherches Servier, Les Laboratoires SERVIER, Institut de Recherche Servier, Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Radical scavengers, Stereochemistry, [SDV]Life Sciences [q-bio], education, Clinical Biochemistry, Pharmaceutical Science, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, In Vitro Techniques, 010402 general chemistry, 01 natural sciences, Biochemistry, Chemical synthesis, Neuroprotection, Antioxidants, Neuroprotective agents, Structure-Activity Relationship, Drug Discovery, Substituent effects, [CHIM]Chemical Sciences, Structure–activity relationship, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Flavonoids, Bicyclic molecule, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Chemistry, Organic Chemistry, In vitro, 0104 chemical sciences, Molecular Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Abstract: International audience; A series of 8-alkylamino-5,7-dihydroxyflavones was prepared from chrysine via a seven step sequence. The synthesis of their 6-alkylamino isomers could be subsequently accomplished through a convenient extension of the Wessely-Moser rearrangement. These compounds were found to be efficient neuroprotective agents in vitro.
Published: 2000
Full Text: View/download PDF

11. Acute food deprivation reduces expression of diazepam-binding inhibitor, the precursor of the anorexigenic octadecaneuropeptide ODN, in mouse glial cells

Author: Schouft, Marie-Thérèse, Fontaine, Marc, Scalbert, Elisabeth, Malagon, Maria, Gandolfo, Pierrick, Desrues, Laurence, Cellier, Eric, Decker, Annick, Clerens, Stefan, Vandesande, Frans, Do-Rego, C., Beauvillain, C., Baroncini, Marc, Balment, Richard, Dujardin, Cynthia, Tollemer, Helene, BRUZZONE, FEDERICA, Tollemer, Hélène, Do-Régo, Jean, Simonnet, Guy, VALLARINO, MAURO, Beauvillain, Jean, Costentin, Jean, Do-Régo, Jean-Claude, Beauvillain, Jean-Claude, Chartrel, C, Alvear-Perez, P, Iturrioz, X., Reaux-Le Goazigo, A., Audinot, V., Chomarat, C, Coge, C, Nosjean, O., Rodriguez, M., Galizzi, J., Goazigo, R., Chomarat, P., Coge, F., Chartrel, Nicolas, Alonzeau, Jessy, Alexandre, David, Jeandel, Jean, Alvear-Perez, Rodrigo, Boutin, Jean, Anouar, Youssef, Llorens-Cortes, Catherine, Jeandel, Lydie, Carlier, Ludovic, Ségalas-Milazzo, Isabelle, Guilhaudis, Laure, Oulyadi, Hassan, Davoust, Daniel, Dubessy, Christophe, Scalbert, Elizabeth, Pfeiffer, Bruno, Renard, Pierre, Lihrmann, Isabelle, Pacaud, Pierre, Chevrier, Lucie, De Brevern, Alexandre, Hernandez, Eva, Guedj, Anne Marie, de Roux, Nicolas, Cholez, V, Debuysscher, V, Bourgeais, B, Boudot, B, Tron, F., Brassart, B., Regnier, A., Bissac, E, Pecnard, E, Gouilleux, F., Lassoued, K, Gouilleux-Gruart, V, Cholez, E, Bourgeais, J, Boudot, C., Gouilleux, V, Chuquet, Julien, Lecrux, Clotilde, Chatenet, David, Chazalviel, Laurent, Roussel, Simon, MacKenzie, Eric, Touzani, Omar, Tonon, M.C, Li, S., Leprince, J�r�me, Tonon, M.C., Compère, M, Lanfray, D, Castel, Hélène, Morin, M., Leprince, Jérôme, Dureuil, B, Vaudry, Hubert, Pelletier, G., Tonon, Marie-Christine, Compère, V., Morin, F., Dureuil, D, Vaudry, V, inconnu, Inconnu, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Chercheur indépendant, Laboratoire de l'intégration, du matériau au système (IMS), Centre National de la Recherche Scientifique (CNRS)-Institut Polytechnique de Bordeaux-Université Sciences et Technologies - Bordeaux 1, University of Córdoba [Córdoba], Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, UMR 5287, Homéostasie-Allostasie-Pathologie-Réhabilitation, Centre National de la Recherche Scientifique (CNRS), Neuropsycho-pharmacologie expérimentale, Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique et Physiologie Intégratives de l'Arbre Fruitier et Forestier (PIAF), Institut National de la Recherche Agronomique (INRA)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropeptides centraux et régulations hydrique et cardiovasculaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherches Servier, Centre de Recherches de Croissy, ESPE de l'Académie d'Amiens, Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Université Henri Poincaré - Nancy 1 (UHP), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatique génomique et moléculaire ((U 726)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Service des Maladies Métaboliques et Endocriniennes, Hôpital Universitaire Carémeau [Nîmes], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Henri Becquerel-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), STMicroelectronics, Génétique, immunothérapie, chimie et cancer (GICC), UMR 6239 CNRS [2008-2011] (GICC UMR 6239 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Matrice extracellulaire et régulations cellulaires (MERC), Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Neurodégénérescence : modèles et stratégies thérapeutiques (NMST), Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Aix-Marseille Université - Faculté de pharmacie (AMU PHARM), Aix Marseille Université (AMU), IRCELYON-Ingéniérie, du matériau au réacteur (ING), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Télécom SudParis (TSP), Université Sciences et Technologies - Bordeaux 1-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille 2 - Faculté de Médecine -Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], CHU Rouen, Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-CRLCC Henri Becquerel-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre interdisciplinaire de recherche en biologie (CIRB), Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie Organique Fine (IRCOF), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université Le Havre Normandie (ULH), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Leptin, Male, Transcription, Genetic, MESH: Sequence Homology, Amino Acid, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Receptors, G-Protein-Coupled, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Neuropeptides, Energy homeostasis, MESH: Down-Regulation, MESH: Ependyma, Mice, 0302 clinical medicine, Endocrinology, Lateral Ventricles, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Insulin, MESH: Animals, MESH: Proline-Rich Protein Domains, MESH: Peptide Fragments, MESH: Lateral Ventricles, Diazepam Binding Inhibitor, 2. Zero hunger, 0303 health sciences, MESH: Ranidae, MESH: Receptors, Kisspeptin-1, Fasting, medicine.anatomical_structure, Hypothalamus, Neuroglia, MESH: Neuroglia, Ependyma, Diazepam binding inhibitor, Injections, Intraperitoneal, MESH: Injections, Intraperitoneal, Protein Binding, MESH: Protein Transport, medicine.medical_specialty, MESH: Rats, Central nervous system, Down-Regulation, Neuropeptide, MESH: Fasting, MESH: Insulin, Biology, 03 medical and health sciences, Internal medicine, medicine, Animals, MESH: Protein Binding, Molecular Biology, MESH: Mice, Third Ventricle, MESH: RNA, Messenger, 030304 developmental biology, MESH: Transcription, Genetic, Neuropeptides, MESH: Time Factors, MESH: Rats, Wistar, MESH: Leptin, MESH: Hypothalamus, Peptide Fragments, MESH: Male, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Diazepam Binding Inhibitor, 030217 neurology & neurosurgery, MESH: Third Ventricle
Abstract: In the central nervous system of mammals, the gene encoding diazepam-binding inhibitor (DBI) is exclusively expressed in glial cells. Previous studies have shown that central administration of a DBI processing product, the octadecaneuropeptide ODN, causes a marked inhibition of food consumption in rodents. Paradoxically, however, the effect of food restriction on DBI gene expression has never been investigated. Here, we show that in mice, acute fasting dramatically reduces DBI mRNA levels in the hypothalamus and the ependyma bordering the third and lateral ventricles. I.p. injection of insulin, but not of leptin, selectively stimulated DBI expression in the lateral ventricle area. These data support the notion that glial cells, through the production of endozepines, may relay peripheral signals to neurons involved in the central regulation of energy homeostasis.
Published: 2010
Full Text: View/download PDF

12. Receptor- and Ligand-Based Study on Novel 2,2′-Bithienyl Derivatives as Non-Peptidic AANAT Inhibitors

Author: Stephane Lemaitre, Jana Sopkova-de Oliveira Santos, Ronan Bureau, Pierre Renard, Philippe Delagrange, Sylvain Rault, Jean A. Boutin, Alban Lepailleur, Xiao Feng, Cailly, Thomas, Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Chongqing Jiaotong University, Neuroscience et Pharmacologie, Institut de Recherches Servier, Centre de Recherches de Croissy, Les Laboratoires SERVIER, and Institut de Recherche Servier
Subjects: Models, Molecular, Stereochemistry, AANAT, General Chemical Engineering, Thiophenes, Library and Information Sciences, Crystallography, X-Ray, Ligands, 01 natural sciences, Arylalkylamine N-Acetyltransferase, 03 medical and health sciences, Structure-Activity Relationship, [CHIM.CHEM] Chemical Sciences/Cheminformatics, Transferase, Structure–activity relationship, Animals, Enzyme Inhibitors, Receptor, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Virtual screening, Sheep, 010405 organic chemistry, Chemistry, Ligand, General Chemistry, 0104 chemical sciences, Computer Science Applications, Docking (molecular), Arylalkylamine, [CHIM.CHEM]Chemical Sciences/Cheminformatics
Abstract: Arylalkylamine N-acetyl transferase (serotonin N-acetyl transferase, AANAT) is a critical enzyme in the light-mediated regulation of melatonin production and circadian rythm. With the objective of discovering new chemical entities with inhibitory potencies against AANAT, a medium-throughput screening campaign was performed on a chemolibrary. We found a class of molecules based on a 2,2'-bithienyl scaffold, and compound 1 emerged as a first hit. Herein, we describe our progress from hit discovery and to optimization of this new class of compounds. To complete the study, computational approaches were carried out: a docking study which provided insights into the plausible binding modes of these new AANAT inhibitors and a three-dimensional quantitative structure-activity relationship study that applied comparative molecular field analysis (CoMFA) methodology. Several CoMFA models were developed (variable alignments and options), and the best predictive one yields good statistical results (q(2) = 0.744, r(2) = 0.891, and s = 0.273). The resulting CoMFA contour maps were used to illustrate the pharmacomodulations relevant to the biological activities in this series of analogs and to design new active inhibitors. This novel series of 2,2'-bithienyl derivatives gives new insights into the design of AANAT inhibitors.
Published: 2010

13. Rebeccamycin derivatives as dual DNA damaging agents and potent checkpoint kinase 1 inhibitors

Author: Marie -Paule Hildebrand, Olivier Lozach, Laurent Meijer, Michelle Prudhomme, Christelle Marminon, Roy M. Golsteyn, Pascale Moreau, Marie-Hélène David-Cordonnier, Fabrice Anizon, Bruno Pfeiffer, Alain Pierré, Paul Peixoto, Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Association EURATOM-CEA (CEA/DSM/DRFC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherches Paul Pascal (CRPP), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biogenèse membranaire (LBM), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Botanique, Faculté des Sciences Pharmaceutiques et Biologiques, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Matériaux Catalytiques et Catalyse en Chimie Organique (LMCCCO), Université Montpellier 1 (UM1)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS), Institut des Matériaux Jean Rouxel (IMN), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN), Département de Recherche sur la Fusion Contrôlée (DRFC), Service de Recherche en Hémato-Immunologie (SRHI - UMR_E 05), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7), Service d'hématologie clinique, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Institut de Recherches Servier, SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Division Recherche et Cancérologie, Institut de recherches sur la catalyse (IRC), Centre National de la Recherche Scientifique (CNRS), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Maladies a Prions et Systeme Immunitaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Molécules et cibles thérapeutiques (MCT), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes (UN)-Université de Nantes (UN)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), and Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: DNA damage, Rebeccamycin, Stereochemistry, Carbazoles, Antineoplastic Agents, Topoisomerase-I Inhibitor, Indolocarbazole, 03 medical and health sciences, chemistry.chemical_compound, Mice, Structure-Activity Relationship, 0302 clinical medicine, medicine, Structure–activity relationship, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, CHEK1, DNA Cleavage, Protein Kinase Inhibitors, 030304 developmental biology, Cell Proliferation, Pharmacology, 0303 health sciences, biology, Topoisomerase, DNA, 3. Good health, chemistry, Biochemistry, 030220 oncology & carcinogenesis, Checkpoint Kinase 1, biology.protein, Molecular Medicine, Drug Screening Assays, Antitumor, Topoisomerase I Inhibitors, Protein Kinases, medicine.drug, DNA Damage
Abstract: Rebeccamycin is an indolocarbazole class inhibitor of topoisomerase I. In the course of structure-activity relationship studies on rebeccamycin derivatives, we have synthesized analogues with the sugar moiety attached to either one or both indole nitrogens. Some analogues, especially those with substitutions at the 6' position of the carbohydrate moiety exhibit potent inhibitory activity toward Checkpoint kinase 1 (Chk1), a kinase that has a major role in the G2/M checkpoint in response to DNA damage. Some of these compounds retained a genotoxic activity either through intercalation into the DNA and/or by topoisomerase I-mediated DNA cleavage. We explored the structure-activity relationship between these compounds and their multiple targets. These rebeccamycin derivatives represent a novel class of potential antitumor agents that have a dual effect and might selectively induce the death of cancer cells.
Published: 2008
Full Text: View/download PDF

14. Structure−Activity Relationships of a Novel Series of Urotensin II Analogues: Identification of a Urotensin II Antagonist

Author: Cédric Boularan, Christophe Dubessy, Bruno Pfeiffer, Hubert Vaudry, Pierre Pacaud, Isabelle Lihrmann, David Chatenet, Elizabeth Scalbert, Marie-Christine Tonon, Pierre Renard, Jérôme Leprince, Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Rats, Stereochemistry, Urotensins, Vasodilator Agents, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Cricetinae, Peptide, CHO Cells, MESH: Receptors, G-Protein-Coupled, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, In Vitro Techniques, MESH: Radioligand Assay, Receptors, G-Protein-Coupled, Radioligand Assay, Structure-Activity Relationship, 03 medical and health sciences, chemistry.chemical_compound, Cricetulus, 0302 clinical medicine, MESH: Structure-Activity Relationship, MESH: Cricetulus, MESH: CHO Cells, Cricetinae, Drug Discovery, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Animals, Humans, Structure–activity relationship, MESH: Animals, Receptor, MESH: Peptide Fragments, 030304 developmental biology, chemistry.chemical_classification, MESH: In Vitro Techniques, 0303 health sciences, MESH: Humans, MESH: Urotensins, Rational design, Antagonist, Biological activity, Peptide Fragments, Cyclic peptide, Rats, MESH: Vasodilator Agents, chemistry, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Molecular Medicine, Urotensin-II, 030217 neurology & neurosurgery
Abstract: International audience; Urotensin II (U-II) is a potent vasoconstrictor peptide which has been identified as the endogenous ligand for the orphan G protein-coupled receptor GPR14 now renamed UT receptor. As the C-terminal cyclic hexapeptide of U-II (U-II(4-11), H-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH) possesses full biological activity, we have synthesized a series of U-II(4-11) analogues and measured their binding affinity on hGPR14-transfected CHO cells and their contractile activity on de-endothelialized rat aortic rings. The data indicate that a free amino group and a functionalized side-chain at the N-terminal extremity of the peptide are not required for biological activity. In addition, the minimal chemical requirement at position 9 of U-II(4-11) is the presence of an aromatic moiety. Most importantly, replacement of the Phe6 residue by cyclohexyl-Ala (Cha) led to an analogue, [Cha6]U-II(4-11), that was devoid of agonistic activity but was able to dose-dependently suppress the vasoconstrictor effect of U-II on rat aortic rings. These new pharmacological data, by providing further information regarding the structure-activity relationships of U-II analogues, should prove useful for the rational design of potent and nonpeptidic UT receptor agonists and antagonists.
Published: 2006
Full Text: View/download PDF

15. Structure-activity relationships and structural conformation of a novel urotensin II-related peptide. Peptides 2004. Proceedings of the 3rd International and 28th European Symposium, pp 804-805

Author: Chatenet, David, Leprince, Jérôme, Dubessy, Christophe, Carlier, Ludovic, Boularan, Cedric, Milazzo-Segalas, Isabelle, Guilhaudis, Laure, Oulyadi, Hassan, Davoust, Daniel, Scalbert, Elisabeth, Pfeiffer, Bruno, Renard, Pierre, Pacaud, Pierre, Lihrmann, Isabelle, Tonon, Marie Christine, Vaudry, Hubert, Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Physiopathologie et pharmacologie cellulaires et moléculaires, and Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2005

16. Structure–activity relationships and structural conformation of a novel urotensin II-related peptide

Author: Hassan Oulyadi, Cédric Boularan, Pierre Renard, Pierre Pacaud, Isabelle Ségalas-Milazzo, Laure Guilhaudis, Isabelle Lihrmann, David Chatenet, Jérôme Leprince, Christophe Dubessy, Bruno Pfeiffer, Hubert Vaudry, Daniel Davoust, Ludovic Carlier, Elizabeth Scalbert, Marie-Christine Tonon, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, Université de Nantes (UN), Université de Picardie Jules Verne (UPJV), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Equipe de Chimie Organique et Biologie Structurale (ECOBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut du thorax, and Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Models, Molecular, Protein Conformation, Physiology, Stereochemistry, Peptide Hormones, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Molecular Sequence Data, Peptide, MESH: Amino Acid Sequence, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Urotensin-II receptor, Biochemistry, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, MESH: Protein Conformation, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Animals, Humans, MESH: Animals, Amino Acid Sequence, Receptor, MESH: Peptide Fragments, MESH: Organ Specificity, 030304 developmental biology, chemistry.chemical_classification, Alanine, 0303 health sciences, MESH: Humans, MESH: Molecular Sequence Data, Intracellular Signaling Peptides and Proteins, Rational design, Antagonist, Biological activity, Peptide Fragments, 3. Good health, chemistry, Organ Specificity, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Peptide Hormones, Urotensin-II, 030217 neurology & neurosurgery, MESH: Models, Molecular
Abstract: Urotensin II (UII) has been described as the most potent vasoconstrictor peptide and recognized as the endogenous ligand of the orphan G protein-coupled receptor GPR14. Recently, a UII-related peptide (URP) has been isolated from the rat brain and its sequence has been established as H-Ala- Cys-Phe-Trp-Lys-Tyr-Cys- Val-OH. In order to study the structure–function relationships of URP, we have synthesized a series of URP analogs and measured their binding affinity on h GPR14-transfected cells and their contractile activity in a rat aortic ring bioassay. Alanine substitution of each residue of URP significantly reduced the binding affinity and the contractile activity of the peptides, except for the Ala 8 -substituted analog that retained biological activity. Most importantly, d -scan of URP revealed that [ d -Trp 4 ]URP abrogated and [ d -Tyr 6 ]URP partially suppressed the UII-evoked contractile response. [Orn 5 ]URP, which had very low agonistic efficacy, was the most potent antagonist in this series. The solution structure of URP has been determined by 1 H NMR spectroscopy and molecular dynamics. URP exhibited a single conformation characterized by an inverse γ-turn comprising residues Trp-Lys-Tyr which plays a crucial role in the biological activity of URP. These pharmacological and structural data should prove useful for the rational design of non-peptide ligands as potential GPR14 agonists and antagonists.
Published: 2004
Full Text: View/download PDF

17. Analogues of tjipanazoles from rebeccamycin: synthesis, in vitro antiproliferative activities, and inhibitory properties toward topoisomerase I

Author: Prudhomme, Michelle, Moreau, Pascale, Dias, N., Bailly, Christian, Leonce, Stéphane, Pierré, Alain, Hickman, John, Peiffer, Bruno, Renard, Pierre, Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Division Recherche et Cancérologie, Institut de Recherches Servier, Les Laboratoires SERVIER, Institut de Recherche Servier, and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Published: 2004

18. Analogues of antifungal tjipanazoles from rebeccamycin

Author: Michelle Prudhomme, Pascale Moreau, Alain Pierré, Aline Voldoire, Pierre Renard, Martine Sancelme, John A. Hickman, Mária Matulová, Christian Bailly, Bruno Pfeiffer, Nathalie Dias, Stéphane Léonce, Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Division Recherche et Cancérologie, Institut de Recherches Servier, Les Laboratoires SERVIER, Institut de Recherche Servier, Génétique moléculaire et approches thérapeutiques des hémopathies malignes, IRCL-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)
Subjects: Antifungal Agents, Indoles, Gram-negative bacteria, Rebeccamycin, Antimicrobial activities, Gram-positive bacteria, Clinical Biochemistry, Carbazoles, Pharmaceutical Science, 010402 general chemistry, Indolocarbazole, 01 natural sciences, Biochemistry, Microbiology, Mice, chemistry.chemical_compound, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, Indolocarbazoles, Molecular Biology, Antibacterial agent, biology, 010405 organic chemistry, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Topoisomerase, Organic Chemistry, Antiproliferative activities, Antimicrobial, biology.organism_classification, Growth Inhibitors, 3. Good health, 0104 chemical sciences, chemistry, biology.protein, Molecular Medicine, Tjipanazoles, Actinomycetales, medicine.drug
Abstract: Analogues of antifungal tjipanazoles were obtained by semi-synthesis from rebeccamycin, an antitumor antibiotic isolated from cultures of Saccharothrix aerocolonigenes. The antiproliferative activities of the new compounds were evaluated in vitro against nine tumor cell lines. The effect on the cell cycle of murine leukemia L1210 cells was examined and the antimicrobial activities against two Gram positive bacteria, a Gram negative bacterium and a yeast were determined. The inhibitory properties toward four kinases and toward topoisomerase I were evaluated. The most cytotoxic compound in the series was a dinitro derivative characterized as a potent topoisomerase I inhibitor.
Published: 2004
Full Text: View/download PDF

19. Cancer chemotherapy: A SN-38 (7-Ethyl-10-hydroxycamptothecin) glucuronide prodrug for treatment by a PMT (Prodrug monoTherapy) strategy

Author: Bruno Pfeiffer, Pierre Renard, Sylvie Thirot, Frédéric Schmidt, Stéphane Angenault, Claude Monneret, Conception, synthèse et vectorisation de biomolécules. (CSVB), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris], Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Les Laboratoires SERVIER, Institut de Recherche Servier, Institut Curie-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Drug, Stereochemistry, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Pharmaceutical Science, Antineoplastic Agents, SN-38, Pharmacology, Irinotecan, Biochemistry, Inhibitory Concentration 50, 03 medical and health sciences, chemistry.chemical_compound, Glucuronides, 0302 clinical medicine, Drug Discovery, medicine, Humans, [CHIM]Chemical Sciences, Prodrugs, Cytotoxicity, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Glucuronidase, 030304 developmental biology, media_common, 0303 health sciences, Organic Chemistry, Biological activity, Prodrug, 3. Good health, chemistry, 030220 oncology & carcinogenesis, Molecular Medicine, Camptothecin, Glucuronide, HT29 Cells, medicine.drug
Abstract: A glucuronide-based prodrug of SN-38 (7-ethyl-10-hydroxycamptothecin) has been synthesized for use in a Prodrug MonoTherapy Strategy (PMT). Since this prodrug is significantly less cytotoxic than SN-38 itself and efficiently releases the drug in vitro in the presence of beta-D-glucuronidase, it can be considered as an appropriate candidate for cancer treatment by a PMT strategy.
Published: 2003
Full Text: View/download PDF

20. Nouveaux dérivés de [3,4-a:3,4-c]carbazole, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Author: Prudhomme, Michelle, Hugon, Bernadette, Anizon, Fabrice, Hickman, John, Pierré, Alain, Renard, Pierre, Pfeiffer, Bruno, Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Division Recherche et Cancérologie, Institut de Recherches Servier, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Published: 2002

21. Nouveaux dérivés de [3,4-c]carbazole et de pyrido[2,3-b]pyrrolo[3,4-e]indole, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Author: Prudhomme, Michelle, Hugon, Bernadette, Anizon, Fabrice, Hickman, John, Pierré, Alain, Renard, Pierre, Pfeiffer, Bruno, Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Division Recherche et Cancérologie, Institut de Recherches Servier, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)
Published: 2002

22. Structure-activity relationship of human urotensin II. Peptides 2002, Proceedings of the 27th European Peptide Symposium, pp176-177

Author: Labarrère, Patricia, Chatenet, David, Marionneau, Clémence, Leprince, Jérôme, Scalbert, Elisabeth, Chavanieu, Alain, Pfeiffer, Bruno, Renard, Pierre, Pacaud, Pierre, Vaudry, Hubert, Calas, Bernard, Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut du thorax, and Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2002

23. Nouveaux dérivés d'hydroxyalkyle indolocarbazole, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Author: Prudhomme, Michelle, Marminon, Christelle, Moreau, Pascale, Hickman, John, Pierré, Alain, Pfeiffer, Bruno, Renard, Pierre, G. Bizot-Espiart, J., Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Division Recherche et Cancérologie, Institut de Recherches Servier, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Published: 2001

24. Nouveaux dérivés de pyrido-pyrido-pyrrolo[3,2-g]pyrrolo[3,4-e]-indole et pyrido-pyrrolo[2,3-a]pyrrolo[3,4-c]carbazole, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent

Author: Prudhomme, Michelle, Marminon, Christelle, Routier, S., Coudert, G., Merour, J.-Y., Hickman, John, Pierré, Alain, Renard, Pierre, Pfeiffer, Bruno, Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Division Recherche et Cancérologie, Institut de Recherches Servier, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut de recherches Servier (INSTITUT DE RECHERCHES SERVIER), INSTITUT SERVIER, and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)
Published: 2001

25. Substituted 3-amino and/or 3-aminomethyl-3,4-dihydro-2 H -1-benzopyrans: synthesis and biological activity

Author: Marie-Claire Rettori, Bruno Pfeiffer, Pierre Renard, Virginie Guérin, Gérald Guillaumet, Corinne Comoy, Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Synthèse et étude de systèmes à intêret biologique (SEESIB), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Les Laboratoires SERVIER, Institut de Recherche Servier, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.drug_class, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Ligands, Biochemistry, Chemical synthesis, Aminoketone, 03 medical and health sciences, chemistry.chemical_compound, Inhibitory Concentration 50, Structure-Activity Relationship, 0302 clinical medicine, Drug Discovery, medicine, Humans, Benzopyrans, Receptor, Serotonin, 5-HT2A, Binding site, Amines, Imide, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Binding Sites, Bicyclic molecule, Ligand, Receptors, Dopamine D2, [CHIM.ORGA]Chemical Sciences/Organic chemistry, Organic Chemistry, Haloketone, 3. Good health, chemistry, Receptors, Serotonin, Molecular Medicine, Receptors, Serotonin, 5-HT1, 030217 neurology & neurosurgery
Abstract: A series of new 3-amino, 3-aminomethyl-5-alkoxy-3,4-dihydro-2H-1-benzopyran and 5′-alkoxy-3′,4′-dihydrospiro[piperazine-2,3′(2′H)-benzopyran] derivatives was prepared and evaluated for affinity at 5-HT1A, 5-HT2A and D2 receptors. Two of the compounds ( Figure 3 , Scheme 3 , Figure 4 , Scheme 4 ) can be considered as potent and selective 5-HT2A ligands. One compound ( Figure 3 , Scheme 3 ) demonstrated high affinity for 5-HT1A and D2 receptor binding sites and one compound ( Figure 3 , Scheme 2 ) proved to be a mixed 5-HT1A/5-HT2A ligand.
Published: 2000
Full Text: View/download PDF

26. Effect of the new imidazoline derivative S-22068 (PMS 847) on insulin secretion in vitro and glucose turnover in vivo in rats

Author: Beatrice Guardiola-Lemaitre, Susan L.F. Chan, Agnès Pelé-Tounian, Dominique Manechez, Frédéric Rondu, Noel G. Morgan, Azzdine Lamouri, Estera Touboul, Alain Ktorza, Marie-Hélène Giroix, Luc Pénicaud, Jean-Jacques Godfroid, Bruno Pfeiffer, Pierre Renard, Gaëlle Le Bihan, Institut de Recherches Servier, SERVIER, Les Laboratoires SERVIER, Institut de Recherche Servier, Institut de Recherches Internationales Servier (IRIS-Servier), Centre National de la Recherche Scientifique (CNRS), Neurobiologie, plasticité tissulaire et métabolisme énergétique (NPTME), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Laboratoire de physiopathologie de la nutrition (LPN), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, Imidazoline receptor, In Vitro Techniques, Carbohydrate metabolism, Biology, Piperazines, Diabetes Mellitus, Experimental, Islets of Langerhans, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Insulin Secretion, medicine, Diazoxide, Animals, Hypoglycemic Agents, Insulin, Rats, Wistar, Antihypertensive Agents, Pancreatic hormone, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Pharmacology, 0303 health sciences, Imidazoles, medicine.disease, Rats, Rats, Zucker, Glucose, Endocrinology, Liver, L-Glucose, chemistry, Basal (medicine), Glucose Clamp Technique, Rubidium Radioisotopes, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, medicine.drug
Abstract: We have investigated the possible mechanisms underlying the antihyperglycaemic effect of the imidazoline derivative S-22068. In vitro, in the presence of 5 mmol/l glucose, S-22068 (100 micromol/l) induced a significant and sustained increase in insulin secretion from isolated, perifused, rat islets and a marked sensitization to a subsequent glucose challenge (10 mmol/l). S-22068 (100 micromol/l was able to antagonize the stimulatory effect of diazoxide on 86Rb efflux from preloaded islets incubated in the presence of 20 mmol/l glucose. Experiments were also performed to investigate whether S-22068 can alter glucose turnover and peripheral insulin sensitivity in vivo in mildly diabetic rats and obese, insulin resistant, Zucker rats. Neither glucose production nor individual tissue glucose utilization was modified by S-22068 in either group of rats. Similar results were obtained whether the studies were performed under basal conditions or during euglycaemic/hyperinsulinemic clamps. The results suggest that S-22068 exerts part of its antihyperglycaemic effect by promoting insulin secretion without alteration of peripheral insulin sensitivity.
Published: 1999

27. Antidepressant use in Denmark, Germany, Spain, and Sweden between 2009 and 2014: incidence and comorbidities of antidepressant initiators

Author: Rosa Morros, Anton Pottegård, Tammo Reinders, Joan Forns, Susana Perez-Gutthann, Jordi Cortés, Maja Hellfritzsch, Nicolas Deltour, Maria Giner-Soriano, David Hägg, Manel Pladevall, Tania Schink, Emmanuelle Jacquot, Miguel Cainzos-Achirica, Beatriz Poblador-Plou, Alexandra Prados-Torres, Lena Brandt, Johan Reutfors, Jesper Hallas, [Forns J, Perez-Gutthann S, Pladevall M, Cainzos-Achirica M] Epidemiology, RTI Health Solutions, Barcelona, Spain. [Pottegård A, Hellfritzsch M, Hallas J] Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark. [Reinders T, Schink T] Leibniz Institute for Prevention Research and Epidemiology–BIPS, Bremen, Germany. [Poblador-Plou B, Prados-Torres A] EpiChron Research Group on Chronic Diseases, Aragon Health Sciences Institute (IACS), IIS Aragón, REDISSEC ISCIII, Miguel Servet University Hospital, Zaragoza, Spain. [Morros R, Giner-Soriano M] Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Institut Català de la Salut, Barcelona, Spain. [Brandt L, Reutfors J, Hägg D] Centre for Pharmacoepidemiology, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. [Cortés J] Departament d'Estadística i Investigació Operativa, Universitat Politècnica de Catalunya, Barcelona, Spain. [Jacquot E, Deltour N] Pharmacoepidemiology Department, Les Laboratoires Servier, Suresnes, France, IDIAP Jordi Gol, Universitat Politècnica de Catalunya. Departament d'Estadística i Investigació Operativa, and Universitat Politècnica de Catalunya. GRBIO - Grup de Recerca en Bioestadística i Bioinformàtica
Subjects: Male, Biologia, Drug utilization study, Comorbidity, Antidepressants, Europe, Environment and Public Health::Public Health::Epidemiologic Factors::Comorbidity [HEALTH CARE], Matemàtiques i estadística::Matemàtica aplicada a les ciències [Àrees temàtiques de la UPC], Venlafaxine, 0302 clinical medicine, Health Services Administration::Organization and Administration::Pharmacy Administration::Drug Utilization [HEALTH CARE], Registries, Practice Patterns, Physicians', ambiente y salud pública::salud pública::factores epidemiológicos::comorbilidad [ATENCIÓN DE SALUD], Sertraline, Administración de los Servicios de Salud::Organización y Administración::Administración Farmacéutica::Utilización de Medicamentos [ATENCIÓN DE SALUD], Age Factors, Middle Aged, Antidepressive Agents, Psychiatry and Mental health, Clinical Psychology, Antidepressant, Female, medicine.drug, Adult, medicine.medical_specialty, Mirtazapine, Citalopram, Medicaments - Ús, 62 Statistics::62D05 Sampling theory, sample surveys [Classificació AMS], 03 medical and health sciences, Sex Factors, Comorbiditat, medicine, Humans, Escitalopram, Agomelatine, Matemàtiques i estadística::Estadística matemàtica::Anàlisi multivariant [Àrees temàtiques de la UPC], Sampling (Statistics), Psychiatry, Biology, 92 Biology and other natural sciences::92C Physiological, cellular and medical topics [Classificació AMS], Aged, Depressive Disorder, Fluoxetine, business.industry, Pharmacoepidemiology, Medio Ambiente y Salud Pública::Salud Pública::Factores Epidemiológicos::Comorbilidad [ATENCIÓN DE SALUD], farmacoepidemiología, Drug Utilization, 030227 psychiatry, administración de los servicios de salud::organización y administración::administración farmacéutica::utilización de medicamentos [ATENCIÓN DE SALUD], business, Mostreig (Estadística), 030217 neurology & neurosurgery, Farmacoepidemiologia
Abstract: Antidepressants; Comorbidity; Drug utilization study; Europe Antidepresivos; Comorbilidad; Estudio de utilización de medicamentos; Europa Antidepressius; Comorbiditat; Estudi d'utilització de medicaments; Europa Background We aimed to describe patterns of use and characteristics of 10 commonly used antidepressants for the period 2009–2014 in Denmark, Germany, Spain, and Sweden. Methods Adult initiators from 2009 to 2014 of each study antidepressant were identified in four countries using five data sources: the Danish National registers, GePaRD (Germany), EpiChron (Aragon, Spain), SIDIAP (Catalonia, Spain), and the Swedish National Registers. The study included 10 study antidepressants: citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, amitriptyline, mirtazapine, and agomelatine. Results Citalopram was the most prescribed study antidepressant, followed by mirtazapine. Paroxetine and agomelatine were the least prescribed antidepressants. Mirtazapine was widely used among older antidepressant initiators with higher percentages of comorbidities at baseline, and fluoxetine was used among young patients. Citalopram and amitriptyline had the lowest percentage of multiple antidepressant use in the 12 months prior to the current treatment episode, while agomelatine, duloxetine, and venlafaxine had the highest percentage of multiple antidepressant use in the year prior to the current treatment episode. Limitations The most important limitations are exposure information based on filled prescriptions, focus on antidepressant initiators only, lack of information on the indication, and heterogeneity of the type of data across data sources. Conclusions Results of this study including 4.8 million study antidepressant initiators of study antidepressants suggest that citalopram and mirtazapine are the most commonly prescribed antidepressants. Agomelatine and paroxetine were the least used antidepressants in the participating populations. Mirtazapine was the antidepressant most commonly prescribed among older antidepressant initiators with high percentage of comorbidities at baseline, whereas fluoxetine was commonly used among young patients.
Full Text: View/download PDF

28. Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells.

Author: Cecon E, Oishi A, Luka M, Ndiaye-Lobry D, François A, Lescuyer M, Panayi F, Dam J, Machado P, and Jockers R
Subjects: Mice, Animals, tau Proteins genetics, tau Proteins metabolism, Microtubules metabolism, Neurons physiology, Brain metabolism, Alzheimer Disease metabolism, Tauopathies pathology
Abstract: Aggregates of the tau protein are a well-known hallmark of several neurodegenerative diseases, collectively referred to as tauopathies, including frontal temporal dementia and Alzheimer's disease (AD). Monitoring the transformation process of tau from physiological monomers into pathological oligomers or aggregates in a high-throughput, quantitative manner and in a cellular context is still a major challenge in the field. Identifying molecules able to interfere with those processes is of high therapeutic interest. Here, we developed a series of inter- and intramolecular tau biosensors based on the highly sensitive Nanoluciferase (Nluc) binary technology (NanoBiT) able to monitor the pathological conformational change and self-interaction of tau in living cells. Our repertoire of tau biosensors reliably reports i. molecular proximity of physiological full-length tau at microtubules; ii. changes in tau conformation and self-interaction associated with tau phosphorylation, as well as iii. tau interaction induced by seeds of recombinant tau or from mouse brain lysates of a mouse model of tau pathology. By comparing biosensors comprising different tau forms ( i.e . full-length or short fragments, wild-type, or the disease-associated tau(P301L) variant) further insights into the tau transformation process are obtained. Proof-of-concept data for the high-throughput suitability and identification of molecules interfering with the pathological tau transformation processes are presented. This novel repertoire of tau biosensors is aimed to boost the disclosure of molecular mechanisms underlying pathological tau transformation in living cells and to discover new drug candidates for tau-related neurodegenerative diseases., Competing Interests: EC, AO, ML, DN, AF, ML, FP, JD, PM, RJ No competing interests declared, (© 2023, Cecon et al.)
Published: 2023
Full Text: View/download PDF

29. A UK cost-effectiveness analysis of trifluridine/tipiracil for heavily pretreated metastatic gastroesophageal cancers.

Author: Hamerton L, Gomes K, Fougeray R, Hook ES, Gomes MV, Hauch O, and Bullement A
Subjects: Humans, Trifluridine therapeutic use, Uracil therapeutic use, Cost-Effectiveness Analysis, Cost-Benefit Analysis, Thymine therapeutic use, Pyrrolidines therapeutic use, United Kingdom epidemiology, Antineoplastic Combined Chemotherapy Protocols adverse effects, Stomach Neoplasms drug therapy, Stomach Neoplasms secondary, Esophageal Neoplasms drug therapy, Neoplasms, Second Primary, Colorectal Neoplasms pathology
Abstract: Background: The current work was designed to estimate the cost-effectiveness of trifluridine/tipiracil (T/T) versus best supportive care (BSC) for patients with advanced stage or metastatic gastroesophageal cancer (mGC) from a UK perspective. Materials & methods: A partitioned survival analysis was undertaken using data from the phase III TAGS trial. A jointly fitted lognormal model was selected for overall survival and individual generalized gamma models were chosen for progression-free survival and time-to-treatment-discontinuation. The primary outcome was the cost per quality-adjusted life year (QALY) gained. Sensitivity analyses were undertaken to investigate uncertainty. Results: Compared with BSC, T/T was associated with a cost per QALY gained of £37,907. Conclusion: T/T provides a cost-effective treatment option for mGC in the UK setting.
Published: 2023
Full Text: View/download PDF

30. Meeting report of the 3rd European Biotransformation Workshop.

Author: Walles M, Pähler A, Isin EM, and Ahlqvist MM
Subjects: Humans, Mass Spectrometry methods, Biotransformation, Drug Discovery
Abstract: Challenges, strategies and new technologies in the field of biotransformation were presented and discussed at the 3rd European Biotransformation Workshop which was held in collaboration with the DMDG on 5-6 October 2022 in Amsterdam. In this meeting report we summarise the presentations and discussions from this workshop. The topics covered are listed below:Accelerator mass spectrometry (AMS) for the support of microtracer studiesBiotransformation of the novel myeloperoxidase inhibitor AZD4831 in preclinical species and humansAMS in biotransformation studies: unusual case studiesDiscussion on new FDA draft guidance and AMSMultimodal molecular imaging and ion mobility applications in drug discovery and developmentMetabolites in Safety Testing considerations for large molecules.
Published: 2023
Full Text: View/download PDF

31. Trifluridine/tipiracil versus placebo for third or later lines of treatment in metastatic gastric cancer: an exploratory subgroup analysis from the TAGS study.

Author: Tabernero J, Shitara K, Zaanan A, Doi T, Lorenzen S, Van Cutsem E, Fornaro L, Catenacci DVT, Fougeray R, Moreno SR, Azcue P, Arkenau HT, Alsina M, and Ilson DH
Subjects: Humans, Pyrrolidines, Thymine, Trifluridine therapeutic use, Uracil, Colorectal Neoplasms, Stomach Neoplasms drug therapy
Abstract: Background: Metastatic gastric cancer and cancer of the esophagogastric junction (GC/EGJ) is an aggressive disease with poor prognosis. In the TAGS study, trifluridine/tipiracil (FTD/TPI) improved overall survival (OS) compared with placebo in heavily pre-treated patients. This unplanned, exploratory subgroup analysis of the TAGS study aimed to clarify outcomes when FTD/TPI was used as third-line (3L) treatment and fourth- or later-line (4L+) treatment., Patients and Methods: Patients were divided into a 3L group (126 and 64 in FTD/TPI and placebo arms, respectively) and 4L+ group (211 and 106 in FTD/TPI and placebo arms, respectively). Endpoints included OS, progression-free survival (PFS), time to Eastern Cooperative Oncology Group performance status (ECOG PS) deterioration to ≥2, and safety., Results: Baseline characteristics were generally well balanced between FTD/TPI and placebo for 3L and 4L+ treatment. Median OS (mOS) for FTD/TPI versus placebo was: 6.8 versus 3.2 months {hazard ratio (HR) [95% confidence interval (CI)] = 0.68 (0.47-0.97), P = 0.0318} in the 3L group; and 5.2 versus 3.7 months [0.73 (0.55-0.95), P = 0.0192] in the 4L+ group. Median PFS for FTD/TPI versus placebo was 3.1 versus 1.9 months [0.54 (0.38-0.77), P = 0.0004] in the 3L group; and 1.9 versus 1.8 months [0.57 (0.44-0.74), P < 0.0001] in the 4L+ group. Time to deterioration of ECOG PS to ≥2 for FTD/TPI versus placebo was 4.8 versus 2.0 months [HR (95% CI) = 0.60 (0.42-0.86), P = 0.0049] in the 3L group; and 4.0 versus 2.5 months [0.75 (0.57-0.98), P = 0.0329] in the 4L+ group. The safety of FTD/TPI was consistent in all subgroups., Conclusions: This analysis confirms the efficacy and safety of FTD/TPI in patients with GC/EGJ in third and later lines with a survival benefit that seems slightly superior in 3L treatment. When FTD/TPI is taken in 3L as recommended in the international guidelines, physicians can expect to provide patients with an mOS of 6.8 months., Competing Interests: Disclosure JT: Consulting: Array BioPharma, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Chugai Pharma, Foundation Medicine, Genentech, Genmab, HalioDx, Halozyme, Imugene, Inflection Biosciences, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign, Rafael Pharmaceuticals, Roche, Roche Diagnostics, Sanofi, Seattle Genetics, Servier, Symphogen, Taiho Pharmaceutical, VCN Biosciences. KS: Consulting/honoraria/research funding: Abbvie, Astellas Pharma, BMS, Chugai Pharma, Daiichi Sankyo, GSK, Lilly, Mediscience Planning, MSD, Novartis, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, Takeda, Yakult Pharmaceutical. AZ: Consulting/honoraria/expenses/research funding: Amgen, Baxter, Lilly, Merck Serono, MSD, Roche, Sanofi, Servier, Pierre Fabre, Havas Life, Alira Health, Zymeworks. TD: Consulting/honoraria/research funding: Abbvie, Amgen, Astellas Pharma, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Eisai, Lilly Japan, Merck Serono, MSD, Novartis, Oncolys BioPharma, Ono Pharmaceutical, Otsuka, Pfizer, Quintiles, Rakuten Medical, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, Takeda. SL: Consulting/expenses/speaker: Amgen, BMS, Lilly, MSD Oncology, Roche, Sanofi-Aventis, Servier. EVC: Consulting/research funding: Amgen, Array BioPharma, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, BMS, Celgene, Daiichi Sankyo, GSK, Halozyme, Incyte, Ipsen, Lilly, MSD, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex Medical, Taiho Pharmaceutical. LF: Consulting/honoraria/expenses/research funding: Celgene, Gilead Sciences, Lilly, MSD. DVTC: Consulting/honoraria/speaker: Amgen, Astella Pharma, BMS, Five Prime Therapeutics, Foundation Medicine, Genentech/Roche, Guardant Health, Lilly, Merck, Seattle Genetics, Taiho Pharmaceutical, Tempus. RF, SRM, and PA: Employees of Servier. H-TA: Consulting/honoraria/research funding: Bayer, BeiGene, Bicycle Therapeutics, Guardant Health, iOncologi, Merck KGaA, Roche, Sarah Cannon Research institute, Servier. MA: Consulting/expenses/speaker: Amgen, BMS, Lilly, MSD Oncology, Roche/Genentech, Servier. DHI: Consulting: Astellas Pharma, AstraZeneca, Bayer, BMS, Lilly/ImClone, Merck, Pieris Pharmaceuticals, Roche/Genentech, Taiho Pharmaceutical., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2021
Full Text: View/download PDF

32. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies.

Author: Benjamin R, Graham C, Yallop D, Jozwik A, Mirci-Danicar OC, Lucchini G, Pinner D, Jain N, Kantarjian H, Boissel N, Maus MV, Frigault MJ, Baruchel A, Mohty M, Gianella-Borradori A, Binlich F, Balandraud S, Vitry F, Thomas E, Philippe A, Fouliard S, Dupouy S, Marchiq I, Almena-Carrasco M, Ferry N, Arnould S, Konto C, Veys P, and Qasim W
Subjects: Adult, Child, Preschool, Cytokine Release Syndrome etiology, Feasibility Studies, Female, Gene Editing, Humans, Immunotherapy, Adoptive adverse effects, Male, Antigens, CD19 immunology, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Receptors, Chimeric Antigen therapeutic use
Abstract: Background: Genome-edited donor-derived allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia., Methods: We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1-2·3 × 10 6 cells per kg and adults received UCART19 doses of 6 × 10 6 cells, 6-8 × 10 7 cells, or 1·8-2·4 × 10 8 cells in a dose-escalation study. The primary outcome measure was adverse events in the period between first infusion and data cutoff. These studies were registered at ClinicalTrials.gov, NCT02808442 and NCT02746952., Findings: Between June 3, 2016, and Oct 23, 2018, seven children and 14 adults were enrolled in the two studies and received UCART19. Cytokine release syndrome was the most common adverse event and was observed in 19 patients (91%); three (14%) had grade 3-4 cytokine release syndrome. Other adverse events were grade 1 or 2 neurotoxicity in eight patients (38%), grade 1 acute skin graft-versus-host disease in two patients (10%), and grade 4 prolonged cytopenia in six patients (32%). Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent cytokine release syndrome and one from pulmonary haemorrhage in a patient with persistent cytopenia. 14 (67%) of 21 patients had a complete response or complete response with incomplete haematological recovery 28 days after infusion. Patients not receiving alemtuzumab (n=4) showed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%., Interpretation: These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable., Funding: Servier., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
Published: 2020
Full Text: View/download PDF

33. Identification of catalytic and non-catalytic activity inhibitors against PRC2-EZH2 complex through multiple high-throughput screening campaigns.

Author: Zhou Y, Du DH, Wang J, Cai XQ, Deng AX, Nosjean O, Boutin JA, Renard P, Yang DH, Luo C, and Wang MW
Subjects: Catalysis, Dose-Response Relationship, Drug, Enhancer of Zeste Homolog 2 Protein chemistry, Enhancer of Zeste Homolog 2 Protein genetics, Fluorescence Polarization, Polycomb Repressive Complex 2 chemistry, Small Molecule Libraries administration & dosage, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, High-Throughput Screening Assays methods, Polycomb Repressive Complex 2 antagonists & inhibitors, Small Molecule Libraries pharmacology
Abstract: Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) along with embryonic ectoderm development (EED) and suppressor of zeste 12 (SUZ12), which implements transcriptional repression mainly by depositing trimethylation marks at lysine 27 of histone H3 (H3K27me3). Its catalytic activity is closely correlated with the stability of PRC2, and somatic activating mutation of EZH2 Y641F within the catalytic SET domain drives tumor aggressiveness, drug resistance, and poor prognosis. Here, we report two high-throughput screening (HTS) campaigns targeting EZH2 Y641F and EZH2-EED interaction, respectively. For the EZH2 Y641F mutant, the HTS campaign involved a library of 250,000 compounds using a homogenous time-resolved fluorescence (HTRF) assay and identified 162 hits, while 60,160 compounds were screened against EZH2-EED interaction with a fluorescence polarization (FP) assay resulting in 97 hits. Among the 162 EZH2 Y641F inhibitors, 38 also suppressed EZH2-EED interaction and 80 showed inhibitory effects on the wide-type (WT) EZH2. Meanwhile, 10 of the 97 EZH2-EED interaction inhibitors were active against WT EZH2. These hit compounds provide useful tools for the development of novel PRC2-EZH2 inhibitors targeting its catalytic and non-catalytic activities., (© 2020 John Wiley & Sons A/S.)
Published: 2020
Full Text: View/download PDF

34. Effect of trifluridine/tipiracil in patients treated in RECOURSE by prognostic factors at baseline: an exploratory analysis.

Author: Tabernero J, Argiles G, Sobrero AF, Borg C, Ohtsu A, Mayer RJ, Vidot L, Moreno Vera SR, and Van Cutsem E
Subjects: Drug Combinations, Female, Humans, Male, Middle Aged, Prognosis, Pyrrolidines, Quality of Life, Thymine, Trifluridine, Colorectal Neoplasms
Abstract: Background: The choice of treatment in patients with metastatic colorectal cancer (mCRC) is generally influenced by tumour and patient characteristics, treatment efficacy and tolerability, and quality of life. Better patient selection might lead to improved outcomes., Methods: This post hoc exploratory analysis examined the effect of prognostic factors on outcomes in the Randomized, Double-blind, Phase 3 Study of trifluridine tipiracil (FTD/TPI) plus Best Supportive Care (BSC) versus Placebo plus BSC in Patients with mCRC Refractory to Standard Chemotherapies (RECOURSE) trial. Patients were redivided by prognosis into two subgroups: those with <3 metastatic sites at randomisation (low tumour burden) and ≥18 months from diagnosis of metastatic disease to randomisation (indolent disease) were included in the good prognostic characteristics (GPC) subgroup; the remaining patients were considered to have poor prognostic characteristics (PPC)., Results: GPC patients (n=386) had improved outcome versus PPC patients (n=414) in both the trifluridine/tipiracil and placebo arms. GPC patients receiving trifluridine/tipiracil (n=261) had an improved median overall survival (9.3 vs 5.3 months; HR (95% CI) 0.46 (0.37 to 0.57), p<0.0001) and progression-free survival (3.3 vs 1.9 months; HR (95% CI) 0.56 (0.46 to 0.67), p<0.0001) than PPC patients receiving trifluridine/tipiracil (n=273). Improvements in survival were irrespective of age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), KRAS mutational status, and site of metastases at randomisation. In the trifluridine/tipiracil arm, time to deterioration of ECOG PS to ≥2 and proportion of patients with PS=0-1 discontinuing treatment were longer for GPC than for PPC patients (7.8 vs 4.2 months and 89.1% vs 78.4%, respectively)., Conclusion: Low tumour burden and indolent disease were factors of good prognosis in late-line mCRC, with patients experiencing longer progression-free survival and greater overall survival., Competing Interests: Competing interests: JT has received personal fees from Array Biopharma, AstraZeneca, Bayer AG, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Eli Lilly and Company, Merck, Menarini, Merck Serono, Merrimack Pharmaceuticals, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche, Sanofi, Seattle Genetics, Servier, Symphogen, Taiho Pharmaceutical, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX, SAS Pharmaceuticals and Roche Diagnostics. GA has had an advisory role, or received honoraria or travel grants from Hoffmann-La Roche, Merck Serono, Amgen, Sanofi, Bayer, Servier and Bristol-Myers Squibb. AFS has had an advisory role for Amgen, Bayer, Celgene, Roche, Merck Serono, Sanofi, and Servier, and has attended a speakers’ bureau for Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Lilly, Merck Serono, Roche, Sanofi and Takeda. EVC has received research funding from Amgen, Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck, Merck KgA, Novartis, Roche, Sanofi and Servier, and has attended advisory boards for Astellas, Astrazeneca, Bayer, Bristol-Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, and Servier. CB has attended advisory boards for Roche, Servier and Sanofi, and has received a research grant from Roche. AO has received honoraria from Ono, BMS, Chugai, Taiho, Eisai and Amgen, and has received research funding from Bristol-Myers Squibb. An immediate family member of AO has been employed by Celgene. RJM declares no conflicts of interest. LV and SRMV are employees of Servier., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)
Published: 2020
Full Text: View/download PDF

35. Ivabradine drug utilization study in five European countries: A multinational, retrospective, observational study to assess effectiveness of risk-minimization measures.

Author: Salem L, Malouvier A, Blatchford J, Rivero-Ferrer E, Deltour N, and Jacquot E
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, Cardiovascular Agents adverse effects, Cohort Studies, Drug Utilization, Europe, Female, Guideline Adherence, Humans, Ivabradine adverse effects, Male, Middle Aged, Retrospective Studies, Risk Management, Young Adult, Angina, Stable drug therapy, Cardiovascular Agents administration & dosage, Ivabradine administration & dosage, Practice Guidelines as Topic
Abstract: Purpose: This drug utilization study of ivabradine evaluated prescriber compliance with the new risk minimization measures (RMMs), communicated starting 2014 following preliminary results from the SIGNIFY study., Methods: This was a multinational (five European countries) chart review study with two study periods: pre-RMM and post-RMM. Patients initiating ivabradine for chronic stable angina pectoris in routine clinical practice were identified across general practitioners and specialists. The primary outcome analysis evaluated the compliance with the new RMMs, ie, use in patients with a heart rate greater than or equal to 70 bpm at initiation, no doses higher than those recommended in the summary of product characteristics (SmPC) at initiation and during 6 months of follow-up, and no concomitant use of verapamil or diltiazem., Results: Overall, 711 and 506 eligible patients were included in the pre-RMM and post-RMM periods, respectively. The percentage of patients prescribed ivabradine according to the new RMMs increased significantly in the post-RMM period (70.6% and 78.4% in the pre- and post-RMM periods respectively; P value = .0035). The compliance to RMMs increased for all the criteria assessed independently: the proportions of patients with (a) heart rate ≥ 70 bpm at initiation (79.4% and 85.2%, respectively; P value = .0141), (b) no dose higher than the SmPC doses at initiation and during follow-up (92.8% and 94.1%, respectively; P value = .3957), and (c) no concomitance with verapamil or diltiazem (96.1% and 99.2%, respectively; P value = .0007)., Conclusions: The RMMs for ivabradine were well implemented across the five participating European countries confirming a favorable benefit-risk balance of ivabradine in chronic stable angina pectoris., (© 2019 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.)
Published: 2019
Full Text: View/download PDF

36. Validity of ICD-9 and ICD-10 codes used to identify acute liver injury: A study in three European data sources.

Author: Forns J, Cainzos-Achirica M, Hellfritzsch M, Morros R, Poblador-Plou B, Hallas J, Giner-Soriano M, Prados-Torres A, Pottegård A, Cortés J, Castellsagué J, Jacquot E, Deltour N, Perez-Gutthann S, and Pladevall M
Subjects: Adolescent, Adult, Aged, Aged, 80 and over, Chemical and Drug Induced Liver Injury diagnosis, Denmark epidemiology, Female, Humans, Male, Middle Aged, Pharmacoepidemiology, Reproducibility of Results, Spain epidemiology, Young Adult, Chemical and Drug Induced Liver Injury epidemiology, Databases, Factual, Diagnosis-Related Groups standards
Abstract: Purpose: Validating cases of acute liver injury (ALI) in health care data sources is challenging. Previous validation studies reported low positive predictive values (PPVs)., Methods: Case validation was undertaken in a study conducted from 2009 to 2014 assessing the risk of ALI in antidepressants users in databases in Spain (EpiChron and SIDIAP) and the Danish National Health Registers. Three ALI definitions were evaluated: primary (specific hospital discharge codes), secondary (specific and nonspecific hospital discharge codes), and tertiary (specific and nonspecific hospital and outpatient codes). The validation included review of patient profiles (EpiChron and SIDIAP) and of clinical data from medical records (EpiChron and Denmark). ALI cases were confirmed when liver enzyme values met a definition by an international working group., Results: Overall PPVs (95% CIs) for the study ALI definitions were, for the primary ALI definition, 84% (60%-97%) (EpiChron), 60% (26%-88%) (SIDIAP), and 74% (60%-85%) (Denmark); for the secondary ALI definition, 65% (45%-81%) (EpiChron), 40% (19%-64%) (SIDIAP), and 70% (64%-77%) (Denmark); and for the tertiary ALI definition, 25% (18%-34%) (EpiChron), 8% (7%-9%) (SIDIAP), and 47% (42%-52%) (Denmark). The overall PPVs were higher for specific than for nonspecific codes and for hospital discharge than for outpatient codes. The nonspecific code "unspecified jaundice" had high PPVs in Denmark., Conclusions: PPVs obtained apply to patients using antidepressants without preexisting liver disease or ALI risk factors. To maximize validity, studies on ALI should prioritize hospital specific discharge codes and should include hospital codes for unspecified jaundice. Case validation is required when ALI outpatient cases are considered., (© 2019 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.)
Published: 2019
Full Text: View/download PDF

37. Antidepressant use in Denmark, Germany, Spain, and Sweden between 2009 and 2014: Incidence and comorbidities of antidepressant initiators.

Author: Forns J, Pottegård A, Reinders T, Poblador-Plou B, Morros R, Brandt L, Cainzos-Achirica M, Hellfritzsch M, Schink T, Prados-Torres A, Giner-Soriano M, Hägg D, Hallas J, Cortés J, Jacquot E, Deltour N, Perez-Gutthann S, Pladevall M, and Reutfors J
Subjects: Adult, Age Factors, Aged, Comorbidity, Depressive Disorder epidemiology, Europe epidemiology, Female, Humans, Male, Middle Aged, Practice Patterns, Physicians' statistics & numerical data, Registries, Sex Factors, Antidepressive Agents therapeutic use, Depressive Disorder drug therapy, Drug Utilization statistics & numerical data
Abstract: Background: We aimed to describe patterns of use and characteristics of 10 commonly used antidepressants for the period 2009-2014 in Denmark, Germany, Spain, and Sweden., Methods: Adult initiators from 2009 to 2014 of each study antidepressant were identified in four countries using five data sources: the Danish National registers, GePaRD (Germany), EpiChron (Aragon, Spain), SIDIAP (Catalonia, Spain), and the Swedish National Registers. The study included 10 study antidepressants: citalopram, escitalopram, fluoxetine, paroxetine, sertraline, duloxetine, venlafaxine, amitriptyline, mirtazapine, and agomelatine., Results: Citalopram was the most prescribed study antidepressant, followed by mirtazapine. Paroxetine and agomelatine were the least prescribed antidepressants. Mirtazapine was widely used among older antidepressant initiators with higher percentages of comorbidities at baseline, and fluoxetine was used among young patients. Citalopram and amitriptyline had the lowest percentage of multiple antidepressant use in the 12 months prior to the current treatment episode, while agomelatine, duloxetine, and venlafaxine had the highest percentage of multiple antidepressant use in the year prior to the current treatment episode., Limitations: The most important limitations are exposure information based on filled prescriptions, focus on antidepressant initiators only, lack of information on the indication, and heterogeneity of the type of data across data sources., Conclusions: Results of this study including 4.8 million study antidepressant initiators of study antidepressants suggest that citalopram and mirtazapine are the most commonly prescribed antidepressants. Agomelatine and paroxetine were the least used antidepressants in the participating populations. Mirtazapine was the antidepressant most commonly prescribed among older antidepressant initiators with high percentage of comorbidities at baseline, whereas fluoxetine was commonly used among young patients., (Copyright © 2019. Published by Elsevier B.V.)
Published: 2019
Full Text: View/download PDF

38. Substituted tetrahydroisoquinolines: synthesis, characterization, antitumor activity and other biological properties.

Author: Capilla AS, Soucek R, Grau L, Romero M, Rubio-Martínez J, Caignard DH, and Pujol MD
Subjects: Angiogenesis Inhibitors chemical synthesis, Angiogenesis Inhibitors chemistry, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Cycle drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Mice, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins p21(ras) metabolism, Structure-Activity Relationship, Tetrahydroisoquinolines chemical synthesis, Tetrahydroisoquinolines chemistry, Angiogenesis Inhibitors pharmacology, Antineoplastic Agents pharmacology, Osteoporosis drug therapy, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors, Tetrahydroisoquinolines pharmacology
Abstract: This work deals with the molecular design, synthesis and biological activity of a series of tetrahydro[1,4]dioxanisoquinolines and dimethoxyisoquinoline analogues. This study describes the synthesis strategy of these potential antitumor compounds, their multi-step synthesis and their optimization. A series of tetrahydroisoquinolines was synthesized and their cytotoxicity evaluated. Some of these tetrahydroisoquinolines showed promising KRas inhibition, antiangiogenesis activity and antiosteoporosis properties. Molecular modeling studies showed that compound 12 bind in the p1 pocket of the KRas protein making interactions with the hydrophobic residues Leu56, Tyr64, Tyr71 and Thr74 and hydrogen bonds with residues Glu37 and Asp38., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
Published: 2018
Full Text: View/download PDF

39. Amyotrophic lateral sclerosis and denervation alter sphingolipids and up-regulate glucosylceramide synthase.

Author: Henriques A, Croixmarie V, Priestman DA, Rosenbohm A, Dirrig-Grosch S, D'Ambra E, Huebecker M, Hussain G, Boursier-Neyret C, Echaniz-Laguna A, Ludolph AC, Platt FM, Walther B, Spedding M, Loeffler JP, and Gonzalez De Aguilar JL
Subjects: Amyotrophic Lateral Sclerosis genetics, Animals, Blotting, Western, Chromatography, High Pressure Liquid, Electromyography, Glucosyltransferases genetics, Humans, Male, Mice, Retrospective Studies, Reverse Transcriptase Polymerase Chain Reaction, Amyotrophic Lateral Sclerosis metabolism, Glucosyltransferases metabolism, Sphingolipids metabolism
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. Growing evidence suggests a link between changes in lipid metabolism and ALS. Here, we used UPLC/TOF-MS to survey the lipidome in SOD1(G86R) mice, a model of ALS. Significant changes in lipid expression were evident in spinal cord and skeletal muscle before overt neuropathology. In silico analysis also revealed appreciable changes in sphingolipids including ceramides and glucosylceramides (GlcCer). HPLC analysis showed increased amounts of GlcCer and downstream glycosphingolipids (GSLs) in SOD1(G86R) muscle compared with wild-type littermates. Glucosylceramide synthase (GCS), the enzyme responsible for GlcCer biosynthesis, was up-regulated in muscle of SOD1(G86R) mice and ALS patients, and in muscle of wild-type mice after surgically induced denervation. Conversely, inhibition of GCS in wild-type mice, following transient peripheral nerve injury, reversed the overexpression of genes in muscle involved in oxidative metabolism and delayed motor recovery. GCS inhibition in SOD1(G86R) mice also affected the expression of metabolic genes and induced a loss of muscle strength and morphological deterioration of the motor endplates. These findings suggest that GSLs may play a critical role in ALS muscle pathology and could lead to the identification of new therapeutic targets., (© The Author 2015. Published by Oxford University Press.)
Published: 2015
Full Text: View/download PDF

40. A proposal for an updated neuropsychopharmacological nomenclature.

Author: Zohar J, Nutt DJ, Kupfer DJ, Moller HJ, Yamawaki S, Spedding M, and Stahl SM
Subjects: Humans, Mental Disorders drug therapy, Psychotropic Drugs therapeutic use, Terminology as Topic
Abstract: Current psychopharmacological nomenclature remains wedded in an earlier period of scientific understanding, failing to reflect contemporary developments and knowledge, does not aid clinicians in selecting the best medication for a given patient, and tends to confuse patients by prescribing a drug that does not reflect their identified diagnosis (e.g. prescribe "antipsychotics" to depression). Four major colleges of Neuropsychopharmacology (ECNP, ACNP, Asian CNP, and CINP) proposed a new template comprising a multi-axial pharmacologically-driven nomenclature tested by four surveys. The template has five axes: 1-class (primary pharmacological target and relevant mechanism); 2-family (reflecting the relevant neurotransmitter and mechanism); 3-neurobiological activities; 4-efficacy and major side effects; and 5-approved indications. The results of the surveys suggest that the clinicians found the available indication-based nomenclature system dissatisfactory, non-intuitive, confusing, and doubt-inducing for them and the patients. The proposed five-axis template seeks to upend current usage by placing pharmacology rather than indication as the primary axes, with the proposed nomenclature relating primarily to Axis 1-the class, and usage of the other axes would largely depend upon the extent to which the clinician seeks to deepen the scientific and clinical base of his involvement. A significant proportion of the participants in the four surveys were in favour of the proposed system, a similar number wanted to consider the idea further, and only a small proportion (8.6%) were against it. The proposed five-axis pharmacology based nomenclature template is a system which might refresh and reflect the current scientific concepts of neuropsychopharmacology., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)
Published: 2014
Full Text: View/download PDF

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Region

Database

Publisher

40 results on '"Les Laboratoires SERVIER"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources