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1. First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia

Author

Salamero, Olga, Montesinos, Pau, Willekens, Christophe, Pérez-Simón, José Antonio, Pigneux, Arnaud, Récher, Christian, Popat, Rakesh, Carpio Segura, Cecilia del Carmen, Molinero, César, Mascaró, Cristina, Vila, Joaquim, Arévalo, M. Isabel, Maes, Tamara, Buesa, Carlos, Bosch José, Francesc Xavier, The University of Manchester, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Salamero O, Carpio C, Bosch F] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Montesinos P] Hospital Universitari I Politécnic La Fe, València, Spain. Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, Madrid, Spain. [Willekens C] Institut Gustave Roussy, Villejuif Cedex, France. [Pérez-Simón JA] Hospital Universitario Virgen del Rocío, Sevilla, Spain. Instituto de Biomedicina de Sevilla (Insitituto de Biomedicina De Sevilla/Consejo Superior De Investigaciones Científicas/Centro de Investigación Biomédica en Red de Cáncer), Universidad de Sevilla, Sevilla, Spain. [Pigneux A] Centre Hospitalier Universitaire CHU Bordeaux, Hôpital du Haut Lévêque, Pessac, France. [Récher C] Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Université Toulouse III Paul Sabatier, Toulouse, France, Vall d'Hebron Barcelona Hospital Campus, Ministerio de Economía y Competitividad (España), European Commission, Cancer Research UK, Centro para el Desarrollo Tecnológico Industrial (España), National Institute for Health Research (UK), University College London, and NIHR Biomedical Research Centre (UK)

Subjects
Adult, Male, Cancer Research, Myeloid, Lysine-Specific Histone Demethylase 1A, acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos [COMPUESTOS QUÍMICOS Y DROGAS], neoplasias::neoplasias por tipo histológico::leucemia::leucemia mieloide::leucemia mieloide aguda [ENFERMEDADES], Refractory, In vivo, Recurrence, hemic and lymphatic diseases, medicine, Hematologic Malignancy, Humans, Other subheadings::/therapeutic use [Other subheadings], Enzyme Inhibitors, Aged, Aged, 80 and over, Histone Demethylases, business.industry, Leucèmia mieloide aguda, Otros calificadores::/uso terapéutico [Otros calificadores], Myeloid leukemia, Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Myeloid::Leukemia, Myeloid, Acute [DISEASES], KDM1A, ORIGINAL REPORTS, Middle Aged, medicine.disease, In vitro, Leukemia, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Oncology, Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors [CHEMICALS AND DRUGS], Cancer research, Female, business, Inhibidors enzimàtics - Ús terapèutic
Abstract

[Purpose] Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML)., [Methods] This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor., [Results] Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm., [Conclusion] Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36)., Supported by Oryzon Genomics and IPT-2012-0673-010000 of the INNPACTO program of the Spanish Ministry of Economy and Competitiveness, with contribution of Fondo Europeo de Desarrollo Regional (FEDER) from the European Union and CDTI_CIIP-20131005/EUROSTAR_E18159. T.C.P.S. is supported by Cancer Research UK Grant No. C5759/A20971. R.P. is supported by the National Institute for Health Research, University College London Hospitals, Biomedical Research Centre.

Published
2020

2. First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia

Author

Ministerio de Economía y Competitividad (España), European Commission, Cancer Research UK, Centro para el Desarrollo Tecnológico Industrial (España), National Institute for Health Research (UK), University College London, NIHR Biomedical Research Centre (UK), Salamero, Olga, Montesinos, Pau, Willekens, Christophe, Pérez-Simón, José A., Pigneux, Arnaud, Récher, Christian, Popat, Rakesh, Carpio, Cecilia, Molinero, César, Mascaró, Cristina, Vila Grajales, Joaquim, Arévalo, M. Isabel, Maes, Tamara, Buesa, Carlos, Bosch, Francesc, Somervaille, Tim C. P., Ministerio de Economía y Competitividad (España), European Commission, Cancer Research UK, Centro para el Desarrollo Tecnológico Industrial (España), National Institute for Health Research (UK), University College London, NIHR Biomedical Research Centre (UK), Salamero, Olga, Montesinos, Pau, Willekens, Christophe, Pérez-Simón, José A., Pigneux, Arnaud, Récher, Christian, Popat, Rakesh, Carpio, Cecilia, Molinero, César, Mascaró, Cristina, Vila Grajales, Joaquim, Arévalo, M. Isabel, Maes, Tamara, Buesa, Carlos, Bosch, Francesc, and Somervaille, Tim C. P.

Abstract

[Purpose] Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML)., [Methods] This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor., [Results] Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm., [Conclusion] Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).

Published
2020

4. Thermal Hyperalgesia and Light Touch Allodynia After Intradermal Mycobacterium butyricum Administration in Rat.

Author

Arévalo, M. Isabel, Escribano, Elvira, Calpena, Ana, Domenech, Josep, and Querlt, Josep

Subjects
HYPERALGESIA, ALLODYNIA, RATS as carriers of disease, ARTHRITIS, HYPERSENSITIVITY pneumonitis, ALLERGIES
Abstract

We examined the time course (7 weeks) of thermal hyperalgesia and light touch allodynia in rats after intradermal administration of Mycobacterium butyricum. Nociceptive thresholds to heat and light touch were assessed. Paw edema and temperature, motor function, body weight, and propioception were also tested. Some rats developed arthritis (named AA rats) but others did not (named non-AA rats). Both groups were compared with healthy animals. Persistent hyperalgesia was found in both groups; in AA rats it appeared before clinical evidence of arthritis. Transient allodynia ocurred only after edema development and fell when edema decreased. Motor function was impaired only in AA rats. The results of this study demonstrate that hyperalgesia, but not allodynia, appeared after Mycobacterium butyricum in both groups, suggesting that changes in sensitivity were not merely the result of local hypersensitivity of the inflamed tissue, but may also be due to alterations in nociception in the central nervous system. [ABSTRACT FROM AUTHOR]

Published
2003

5. The role of the c-Jun N-terminal kinase (JNK) pathway in insulin resistance

Author

Caelles Franch, Carme, Lanuza Masdeu, Jordi, Arévalo, M. Isabel, Díaz-Delfín, Julieta, Morcillo, Melisa, Bayod giron, Carles, and Universitat de Barcelona

Subjects
Obesitat, Non-insulin-dependent diabetes, Insulin resistance, Obesity, Resistència a la insulina, Diabetis no-insulinodependent
Abstract

Podeu consultar el llibre complet a: http://hdl.handle.net/2445/103042, Obesity is usually associated with a decreased response to insulin, a major metabolic defect known as insulin resistance and an early trait in the development of type 2 diabetes. The c-Jun N-terminal kinase (JNK) pathway has emerged as a central regulator of insulin sensitivity, locally and systemically, thereby, of body’s metabolic homeostasis. As the incidence of obesity and type 2 diabetes has alarmingly increased in the last few decades, there is a tremendous necessity to identify novel pharmacological targets to efficiently improve the therapeutic outcome. In this regard, the JNK pathway seems to meet most of the requirements for being an adequate candidate to direct pharmacological intervention.

6. First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia.

Author

Salamero O, Montesinos P, Willekens C, Pérez-Simón JA, Pigneux A, Récher C, Popat R, Carpio C, Molinero C, Mascaró C, Vila J, Arévalo MI, Maes T, Buesa C, Bosch F, and Somervaille TCP

Subjects
Adult, Aged, Aged, 80 and over, Enzyme Inhibitors pharmacology, Female, Humans, Male, Middle Aged, Recurrence, Enzyme Inhibitors therapeutic use, Histone Demethylases antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy
Abstract

Purpose: Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML)., Methods: This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor., Results: Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m 2 /d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m 2 /d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm., Conclusion: Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).

Published
2020
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