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Start Over Descriptor "MESH: Benzodiazepinones" Topic 0302 clinical medicine
4 results on '"MESH: Benzodiazepinones"'

1. A Phase 1–2 Study of Rovalpituzumab Tesirine in Combination With Nivolumab Plus or Minus Ipilimumab in Patients With Previously Treated Extensive-Stage SCLC

Author

John Wrangle, Ticiana Leal, Gilles Robinet, Neal Ready, David Maag, Jyoti Malhotra, Melissa Lynne Johnson, Satwant Lally, Petros Nikolinakos, Jyoti D. Patel, Daniel Morgensztern, Benjamin Besse, Vincent Blot, Giuseppe Curigliano, Ricardo Valenzuela, Laurent Greillier, Jonathan M. Lehman, Rutgers cancer institute of New Jersey [Newark, NJ], University Cancer and Blood Center (UCBC), University of Wisconsin-Madison, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Feinberg School of Medicine, Northwestern University [Evanston], Medical University of South Carolina [Charleston] (MUSC), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sarah Cannon Research Institute [Nashville, Tennessee], Duke University Medical Center, Hôpital Morvan - CHRU de Brest (CHU - BREST ), Abbvie Inc. [North Chicago], Institut Gustave Roussy (IGR), Université Paris-Saclay, and Département de médecine oncologique [Gustave Roussy]

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Immunoconjugates, Lung Neoplasms, Combination therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Ipilimumab, Antibodies, Monoclonal, Humanized, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Gastroenterology, MESH: Benzodiazepinones, MESH: Ipilimumab, 03 medical and health sciences, Clinical trials, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, MESH: Immunoconjugates, medicine, Humans, Antibody-drug conjugates, Adverse effect, Benzodiazepinones, MESH: Humans, business.industry, Rovalpituzumab tesirine, respiratory tract diseases, MESH: Lung Neoplasms, MESH: Antineoplastic Combined Chemotherapy Protocols, Nivolumab, 030104 developmental biology, Oncology, Tolerability, MESH: Antibodies, Monoclonal, Humanized, Response Evaluation Criteria in Solid Tumors, 030220 oncology & carcinogenesis, Cohort, Small-molecule agents, MESH: Nivolumab, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunotherapy, Lung cancer, business, medicine.drug
Abstract

Introduction This open-label, phase 1–2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC). Methods Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data. Results A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses. Conclusions Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.

Published
2021

2. Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation During Human Terminal Erythropoiesis

Author

Naomi Taylor, Claude Hattab, Suella Martino, Mariano A. Ostuni, Sophie D. Lefevre, Martina Moras, Pedro Gonzalez-Menendez, Jérôme Larghero, Sandrina Kinet, Caroline Le Van Kim, KARLI, Mélanie, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hematopoïèse et Immunothérapie, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CIC - Biotherapie - Saint Louis ((CIC-BT 301)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)

Subjects
Mitochondrion, MESH: Benzodiazepinones, MESH: Down-Regulation, lcsh:Chemistry, 0302 clinical medicine, MESH: RNA, Small Interfering, Mitophagy, Erythropoiesis, RNA, Small Interfering, lcsh:QH301-705.5, Spectroscopy, 0303 health sciences, Benzodiazepinones, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Kinetics, biology, VDAC, Chemistry, Cell Differentiation, General Medicine, Computer Science Applications, Cell biology, Mitochondria, Phenotype, MESH: Receptors, GABA, 030220 oncology & carcinogenesis, enucleation, MESH: Cell Differentiation, MESH: Cell Nucleus, Voltage-dependent anion channel, MESH: Mitochondria, MESH: Mitophagy, Down-Regulation, PINK1, MESH: Phenotype, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Downregulation and upregulation, Receptors, GABA, Erythroblast, Translocator protein, Humans, Physical and Theoretical Chemistry, Molecular Biology, 030304 developmental biology, Cell Nucleus, MESH: Humans, MESH: Erythropoiesis, Organic Chemistry, Kinetics, lcsh:Biology (General), lcsh:QD1-999, biology.protein, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, TSPO1
Abstract

International audience; Translocator protein (TSPO) and voltage dependent anion channels (VDAC) are two proteins forming a macromolecular complex in the outer mitochondrial membrane that is involved in pleiotropic functions. Specifically, these proteins were described to regulate the clearance of damaged mitochondria by selective mitophagy in non-erythroid immortalized cell lines. Although it is well established that erythroblast maturation in mammals depends on organelle clearance, less is known about mechanisms regulating this clearance throughout terminal erythropoiesis. Here, we studied the effect of TSPO1 downregulation and the action of Ro5-4864, a drug ligand known to bind to the TSPO/VDAC complex interface, in ex vivo human terminal erythropoiesis. We found that both treatments delay mitochondrial clearance, a process associated with reduced levels of the PINK1 protein, which is a key protein triggering canonical mitophagy. We also observed that TSPO1 downregulation blocks erythroblast maturation at the orthochromatic stage, decreases the enucleation rate, and increases cell death. Interestingly, TSPO1 downregulation does not modify reactive oxygen species (ROS) production nor intracellular adenosine triphosphate (ATP) levels. Ro5-4864 treatment recapitulates these phenotypes, strongly suggesting an active role of the TSPO/VDAC complex in selective mitophagy throughout human erythropoiesis. The present study links the function of the TSPO/VDAC complex to the PINK1/Parkin-dependent mitophagy induction during terminal erythropoiesis, leading to the proper completion of erythroid maturation.

Published
2020

3. Cardioprotection by the TSPO ligand 4'-chlorodiazepam is associated with inhibition of mitochondrial accumulation of cholesterol at reperfusion.: mitochondrial cholesterol, TSPO and cardioprotection

Author

Claudio Caccia, Alain Berdeaux, Stéphanie Paradis, Didier Morin, Valerio Leoni, INSERM U955, équipe 3, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratory of Clinical Pathology and Medical Genetics, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', S. Paradis was supported by a doctoral grant from the Ministère de la Recherche et de la Technologie and by a grant from Trophos. V. Leoni was supported by Italian Mini ster of Health, Fondi per giovani Ricercatori 2008 (GR-2008-1145270). This work was supported by grants of the Fondation de France (grant numbers 2009-002496, 2012- 00029514)., Paradis, S, Leoni, V, Caccia, C, Berdeaux, A, and Morin, D

Subjects
Male, Time Factors, Physiology, MESH: Myocytes, Cardiac, Pharmacology, Mitochondrion, Ligands, medicine.disease_cause, Mitochondrial Membrane Transport Proteins, Mitochondria, Heart, Oxidative Phosphorylation, MESH: Benzodiazepinones, MESH: Lipid Peroxidation, MESH: Cholesterol, 0302 clinical medicine, MESH: Membrane Potential, Mitochondrial, MESH: Mitochondrial Membranes, Oximes, MESH: Ligands, MESH: Thiobarbituric Acid Reactive Substances, Myocytes, Cardiac, MESH: Animals, oxysterols, sterols, cholesterol, mass spectrometry, metabolomics, MESH: Receptors, GABA-A, Membrane Potential, Mitochondrial, Cardioprotection, Benzodiazepinones, 0303 health sciences, MESH: Oxidative Stress, biology, MESH: Mitochondrial Membrane Transport Proteins, MESH: Oximes, MESH: Myocardial Reperfusion Injury, Cholesterol, Biochemistry, Mitochondrial matrix, Mitochondrial Membranes, MESH: Mitochondria, Heart, Cardiology and Cardiovascular Medicine, MESH: Rats, Oxysterol, Membrane Fluidity, MESH: Biological Transport, MESH: Protective Agents, MESH: Secosteroids, Myocardial Reperfusion Injury, MESH: Carrier Proteins, Oxidative phosphorylation, Protective Agents, Thiobarbituric Acid Reactive Substances, 03 medical and health sciences, MESH: Oxidative Phosphorylation, Physiology (medical), Translocator protein, medicine, Animals, Secosteroids, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Rats, Wistar, 030304 developmental biology, Mitochondrial Permeability Transition Pore, MESH: Time Factors, Biological Transport, MESH: Rats, Wistar, Receptors, GABA-A, MESH: Male, Rats, Disease Models, Animal, Oxidative Stress, MESH: Cytoprotection, Mitochondrial permeability transition pore, Cytoprotection, biology.protein, Lipid Peroxidation, MESH: Disease Models, Animal, Carrier Proteins, MESH: Membrane Fluidity, 030217 neurology & neurosurgery, Oxidative stress
Abstract

International audience; AIMS: The translocator protein (TSPO) is located on the outer mitochondrial membrane where it is responsible for the uptake of cholesterol into mitochondria of steroidogenic organs. TSPO is also present in the heart where its role remains uncertain. We recently showed that TSPO ligands reduced infarct size and improved mitochondrial functions after ischaemia-reperfusion. This study, thus, sought to determine whether cholesterol could play a role in the cardioprotective effect of TSPO ligands. METHODS AND RESULTS: In a model of 30 min coronary occlusion/15 min reperfusion in Wistar rat, we showed that reperfusion induced lipid peroxidation as demonstrated by the increase in conjugated diene and thiobarbituric acid reactive substance formation and altered mitochondrial function (decrease in oxidative phosphorylation and increase in the sensitivity of mitochondrial permeability transition pore opening) in ex-vivo isolated mitochondria. This was associated with an increase in mitochondrial cholesterol uptake (89.5 ± 12.2 vs. 39.9 ± 3.51 nmol/mg protein in controls, P < 0.01) and a subsequent strong generation of auto-oxidized oxysterols, i.e. 7α- and 7β-hydroxycholesterol, 7-ketocholesterol, cholesterol-5α,6α-epoxide, and 5β,6β-epoxide (+173, +149, +165, +165, and +193% vs. controls, respectively; P < 0.01). Administration of the selective TSPO ligand 4'-chlorodiazepam inhibited oxidative stress, improved mitochondrial function, and abolished both mitochondrial cholesterol accumulation and oxysterol production. This was also observed with the new TSPO ligand TRO40303. CONCLUSION: These data suggest that 4'-chlorodiazepam inhibits oxidative stress and oxysterol formation by reducing the accumulation of cholesterol in the mitochondrial matrix at reperfusion and prevents mitochondrial injury. This new and original mechanism may contribute to the cardioprotective properties of TSPO ligands.

Published
2013

4. CCKA, but not CCKB, agonists suppress the hyperlocomotion induced by endogenous enkephalins, protected from enzymatic degradation by systemic RB 101

Author

Bernard P. Roques, Valérie Daugé, P. J. Corringer, Pharmacochimie moléculaire et structurale, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), We wish to thank Dr. A. Beaumont and Dr.J.Vierek for the stylistic revision of the paper, and C. Dupuis for her assistance in drafting it. We are grateful to S.Turcaud and P. Coric for the synthesis of RB 101., Cova Rodrigues, Ana, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-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
Male, Enkephalin, Narcotic Antagonists, [SDV]Life Sciences [q-bio], Clinical Biochemistry, RB-101, Devazepide, Inhibitor of enkephalin degradation, MESH: Amino Acid Sequence, Toxicology, Biochemistry, MESH: Benzodiazepinones, Behavioral Neuroscience, Mice, 0302 clinical medicine, Interactions between CCK and enkephalins, MESH: Enkephalins, MESH: Animals, Disulfides, Enzyme Inhibitors, MESH: Cholecystokinin, MESH: Peptide Fragments, MESH: Devazepide, 0303 health sciences, Benzodiazepinones, MESH: Receptors, Cholecystokinin, Chemistry, digestive, oral, and skin physiology, Enkephalins, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Naltrexone, CCKA and CCKB agonists, MESH: Motor Activity, [SDV] Life Sciences [q-bio], [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, MESH: Enzyme Inhibitors, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Naltrexone, MESH: Narcotic Antagonists, Cholecystokinin, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Agonist, Locomotor activity, medicine.medical_specialty, medicine.drug_class, Phenylalanine, Molecular Sequence Data, Motor Activity, 03 medical and health sciences, MESH: Phenylalanine, Naltrindole, Internal medicine, medicine, Animals, MESH: Disulfides, Amino Acid Sequence, Opioid peptide, MESH: Mice, Biological Psychiatry, 030304 developmental biology, Pharmacology, MESH: Molecular Sequence Data, Antagonist, Peptide Fragments, MESH: Male, Endocrinology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Receptors, Cholecystokinin, Physiological agonism and antagonism, 030217 neurology & neurosurgery
Abstract

International audience; Interactions between CCKergic and enkephalinergic systems were studied in mice using behavioral responses measured in Animex. The hyperlocomotion induced by 5 mg/kg of RB 101, a mixed inhibitor of enkephalin-degrading enzymes able to cross the blood-brain barrier, was previously shown to be mediated by delta-opioid receptor stimulation. The IP administration of a CCKA agonist, Boc-Tyr-Lys-(CONH-o-tolyl)-Asp-Phe-NH2 (0.1, 1, 10 micrograms/kg), suppressed the hyperlocomotion produced by IV injection of 5 mg/kg of RB 101. The effect of the CCKA agonist was suppressed by a selective CCKA antagonist, devazepide, injected IP at doses of 20 and 200 micrograms/kg and was potentiated by the selective delta-opioid antagonist naltrindole at the doses of 0.03 mg/kg. IP injection of the selective CCKB agonist BC 264 (0.1-1 mg/kg) did not modify the RB 101-induced hyperlocomotor effect. These results reinforce the observed physiological antagonism between the endogenous CCK and opioid systems but are at variance with the responses measured in stressful conditions. It is concluded that CCKA, but not CCKB, receptor activation counteracts the opioid-related hyperlocomotion.

Published
1995

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