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1.
Nature ; 586(7828): 275-280, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33029001

RESUMEN

The development of intestinal organoids from single adult intestinal stem cells in vitro recapitulates the regenerative capacity of the intestinal epithelium1,2. Here we unravel the mechanisms that orchestrate both organoid formation and the regeneration of intestinal tissue, using an image-based screen to assay an annotated library of compounds. We generate multivariate feature profiles for hundreds of thousands of organoids to quantitatively describe their phenotypic landscape. We then use these phenotypic fingerprints to infer regulatory genetic interactions, establishing a new approach to the mapping of genetic interactions in an emergent system. This allows us to identify genes that regulate cell-fate transitions and maintain the balance between regeneration and homeostasis, unravelling previously unknown roles for several pathways, among them retinoic acid signalling. We then characterize a crucial role for retinoic acid nuclear receptors in controlling exit from the regenerative state and driving enterocyte differentiation. By combining quantitative imaging with RNA sequencing, we show the role of endogenous retinoic acid metabolism in initiating transcriptional programs that guide the cell-fate transitions of intestinal epithelium, and we identify an inhibitor of the retinoid X receptor that improves intestinal regeneration in vivo.


Asunto(s)
Organoides/citología , Organoides/fisiología , Fenotipo , Regeneración/fisiología , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Enterocitos/citología , Enterocitos/efectos de los fármacos , Homeostasis/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Intestinos/citología , Intestinos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Organoides/efectos de los fármacos , Organoides/metabolismo , Receptores de Ácido Retinoico/antagonistas & inhibidores , Receptores de Ácido Retinoico/metabolismo , Regeneración/efectos de los fármacos , Análisis de Secuencia de ARN , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Tretinoina/metabolismo , Vitamina A/farmacología
2.
Toxicol Pathol ; 52(2-3): 138-148, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38840532

RESUMEN

In December 2021, the United States Food and Drug Administration (FDA) issued the final guidance for industry titled Pathology Peer Review in Nonclinical Toxicology Studies: Questions and Answers. The stated purpose of the FDA guidance is to provide information to sponsors, applicants, and nonclinical laboratory personnel regarding the management and conduct of histopathology peer review as part of nonclinical toxicology studies conducted in compliance with good laboratory practice (GLP) regulations. On behalf of and in collaboration with global societies of toxicologic pathology and the Society of Quality Assurance, the Scientific and Regulatory Policy Committee (SRPC) of the Society of Toxicologic Pathology (STP) initiated a review of this FDA guidance. The STP has previously published multiple papers related to the scientific conduct of a pathology peer review of nonclinical toxicology studies and appropriate documentation practices. The objectives of this review are to provide an in-depth analysis and summary interpretation of the FDA recommendations and share considerations for the conduct of pathology peer review in nonclinical toxicology studies that claim compliance to GLP regulations. In general, this working group is in agreement with the recommendations from the FDA guidance that has added clear expectations for pathology peer review preparation, conduct, and documentation.


Asunto(s)
Patología , Revisión por Pares , Toxicología , United States Food and Drug Administration , Estados Unidos , Toxicología/normas , Toxicología/legislación & jurisprudencia , Toxicología/métodos , Revisión por Pares/normas , Patología/normas , Guías como Asunto , Animales , Pruebas de Toxicidad/normas , Pruebas de Toxicidad/métodos
3.
Toxicol Pathol ; 52(1): 13-20, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38445634

RESUMEN

The Tumor Combination Guide was created at the request of the U. S. Food and Drug Administration (FDA) by a Working Group of biopharmaceutical experts from international societies of toxicologic pathology, the Food and Drug Administration (FDA), and members of the Standard for Exchange of Nonclinical Data (SEND) initiative, to assist pharmacology/toxicology reviewers and biostatisticians in statistical analysis of nonclinical tumor data. The guide will also be useful to study and peer review pathologists in interpreting the tumor data. This guide provides a higher-level hierarchy of tumor types or categories correlating the tumor names from the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) publications with those available in the NEOPLASM controlled terminology (CT) code list in SEND. The version of CT used in a study should be referenced in the nonclinical study data reviewer's guide (SDRG) (section 3.1) of electronic submissions to the FDA. The tumor combination guide instructions and examples are in a tabular format to make informed decisions for combining tumor data for statistical analysis. The strategy for combining tumor types for statistical analysis is based on scientific criteria gleaned from the current scientific literature; as SEND and INHAND terminology and information evolve, this guide will be updated.


Asunto(s)
Pruebas de Carcinogenicidad , Animales , Pruebas de Carcinogenicidad/métodos , Pruebas de Carcinogenicidad/normas , Neoplasias/inducido químicamente , Neoplasias/patología , Estados Unidos , Ratas , United States Food and Drug Administration , Roedores , Ratones , Guías como Asunto , Interpretación Estadística de Datos
4.
Toxicol Pathol ; 50(8): 930-941, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36377245

RESUMEN

This article describes the Society of Toxicologic Pathology's (STP) five recommended ("best") practices for appropriate use of informed (non-blinded) versus masked (blinded) microscopic evaluation in animal toxicity studies intended for regulatory review. (1) Informed microscopic evaluation is the default approach for animal toxicity studies. (2) Masked microscopic evaluation has merit for confirming preliminary diagnoses for target organs and/or defining thresholds ("no observed adverse effect level" and similar values) identified during an initial informed evaluation, addressing focused hypotheses, or satisfying guidance or requests from regulatory agencies. (3) If used as the approach for an animal toxicity study to investigate a specific research question, masking of the initial microscopic evaluation should be limited to withholding only information about the group (control or test article-treated) and dose equivalents. (4) The decision regarding whether or not to perform a masked microscopic evaluation is best made by a toxicologic pathologist with relevant experience. (5) Pathology peer review, performed to verify the microscopic diagnoses and interpretations by the study pathologist, should use an informed evaluation approach. The STP maintains that implementing these five best practices has and will continue to consistently deliver robust microscopic data with high sensitivity for animal toxicity studies intended for regulatory review. Consequently, when conducting animal toxicity studies, the advantages of informed microscopic evaluation for maximizing sensitivity outweigh the perceived advantages of minimizing bias through masked microscopic examination.


Asunto(s)
Patólogos , Revisión por Pares , Animales , Humanos , Microscopía , Nivel sin Efectos Adversos Observados
5.
Toxicol Pathol ; 49(2): 232-234, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33397211

RESUMEN

The delivery of biotherapeutic molecules (antibodies, proteins, peptides) and nucleic acids via the respiratory route has presented challenges for regulatory approval, due in part to a lack of understanding of the expected pathology, mechanisms of toxicity, and immunogenicity induced by the inhalation route. Although the first inhaled biotherapeutic was approved some time ago (Dornase Alfa, Pulmozyme; Genetech, 1993), no other inhaled biotherapeutics have been marketed for the treatment of human disease other than the inhaled insulins (Exubera; Pfizer, 2006 and Afrezza; Mannkind Corporation, 2014). As a result, scientific knowledge within the toxicologic pathology community is fragmented with precious little publicly available data. Therefore, one of the aims of this special edition was to generate a collection of manuscripts that pathologists and toxicologists could refer in order to understand the pathology, mechanisms of toxicity, immunogenicity, and challenges associated with the development of inhaled biotherapeutics.


Asunto(s)
Productos Biológicos , Administración por Inhalación , Productos Biológicos/administración & dosificación , Humanos
6.
Toxicol Pathol ; 49(5): 1042-1047, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33576326

RESUMEN

Toxicologic Pathology is the official journal of the Society of Toxicologic Pathology (STP), the British Society of Toxicological Pathology, and the European STP (ESTP). Toxicologic Pathology publishes articles related to topics in various aspects of toxicologic pathology such as anatomic pathology, clinical pathology, experimental pathology, and biomarker research. Publications include society-endorsed Best Practice/Position and Points to Consider publications and ESTP Expert Workshop articles that are relevant to toxicologic pathology and scientific regulatory processes, Opinion articles under the banner of the STP Toxicologic Pathology Forum, Original Articles, Review Articles (unsolicited/contributed, mini, and invited), Brief Communications, Letters to the Editor, Meeting Reports, and Book Reviews. This article provides details on the various publication categories in Toxicologic Pathology and will serve as a reference for authors and readers.


Asunto(s)
Patología Clínica , Patología , Publicaciones/clasificación , Humanos
7.
Toxicol Pathol ; 49(5): 977-989, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33661059

RESUMEN

The sexual maturity status of animals in nonclinical safety studies can have a significant impact on the microscopic assessment of the reproductive system, the interpretation of potential test article-related findings, and ultimately the assessment of potential risk to humans. However, the assessment and documentation of sexual maturity for animals in nonclinical safety studies is not conducted in a consistent manner across the pharmaceutical and chemical industries. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology convened an international working group of pathologists and nonclinical safety scientists with expertise in the reproductive system, pathology nomenclature, and Standard for Exchange of Nonclinical Data requirements. This article describes the best practices for documentation of the light microscopic assessment of sexual maturity in males and females for both rodent and nonrodent nonclinical safety studies. In addition, a review of the microscopic features of the immature, peripubertal, and mature male and female reproductive system and general considerations for study types and reporting are provided to aid the study pathologist tasked with documentation of sexual maturity.


Asunto(s)
Patólogos , Pruebas de Toxicidad , Animales , Documentación , Femenino , Humanos , Masculino , Políticas , Proyectos de Investigación
8.
Toxicol Pathol ; 49(2): 235-260, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33455525

RESUMEN

The inhalation route is a relatively novel drug delivery route for biotherapeutics and, as a result, there is a paucity of published data and experience within the toxicology/pathology community. In recent years, findings arising in toxicology studies with inhaled biologics have provoked concern and regulatory challenges due, in part, to the lack of understanding of the expected pathology, mechanisms, and adversity induced by this mode of delivery. In this manuscript, the authors describe 12 case studies, comprising 18 toxicology studies, using a range of inhaled biotherapeutics (monoclonal antibodies, fragment antigen-binding antibodies, domain antibodies, therapeutic proteins/peptides, and an oligonucleotide) in rodents, nonhuman primates (NHPs), and the rabbit in subacute (1 week) to chronic (26 weeks) toxicology studies. Analysis of the data revealed that many of these molecules were associated with a characteristic pattern of toxicity with high levels of immunogenicity. Microscopic changes in the airways consisted of a predominantly lymphoid perivascular/peribronchiolar (PV/PB) mononuclear inflammatory cell (MIC) infiltrate, whereas changes in the terminal airways/alveoli were characterized by simple ("uncomplicated") increases in macrophages or inflammatory cell infiltrates ranging from mixed inflammatory cell infiltration to inflammation. The PV/PB MIC changes were considered most likely secondary to immunogenicity, whereas simple increases in alveolar macrophages were most likely secondary to clearance mechanisms. Alveolar inflammatory cell infiltrates and inflammation were likely induced by immune modulation or stimulation through pharmacologic effects on target biology or type III hypersensitivity (immune complex disease). Finally, a group of experts provide introductory thoughts regarding the adversity of inhaled biotherapeutics and the basis for reasonable differences of opinion that might arise between toxicologists, pathologists, and regulators.


Asunto(s)
Productos Biológicos , Hipersensibilidad , Administración por Inhalación , Animales , Productos Biológicos/efectos adversos , Líquido del Lavado Bronquioalveolar , Inflamación , Pulmón , Macrófagos Alveolares , Conejos
9.
Toxicol Pathol ; 49(1): 5-109, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33393871

RESUMEN

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/inhand.asp) is a joint initiative of the societies of toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in most tissues and organs from the dog used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions, lesions induced by exposure to test materials, and relevant infectious and parasitic lesions. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.


Asunto(s)
Animales de Laboratorio , Animales , Bases de Datos Factuales , Perros , Europa (Continente) , Japón
10.
J Toxicol Pathol ; 34(3 Suppl): 1S-182S, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34712008

RESUMEN

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in most tissues and organs from the nonhuman primate used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.

11.
Toxicol Pathol ; 48(4): 549-559, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32347786

RESUMEN

The Society of Toxicologic Pathology (STP) explored current institutional practices for selecting between non-blinded versus blinded histopathologic evaluation during Good Laboratory Practice (GLP)-compliant, regulatory-type animal toxicity studies using a multi-question survey and STP-wide discussion (held at the 2019 STP annual meeting). Survey responses were received from 107 individuals representing 83 institutions that collectively employ 589 toxicologic pathologists. Most responses came from industry (N = 46, mainly biopharmaceutical or contract research organizations) and consultants (N = 24). For GLP-compliant animal toxicity studies, histopathologic evaluation usually involves initial (primary) non-blinded analysis, with post hoc informal blinded re-examination at the study pathologist's discretion to confirm subtle findings or establish thresholds. Initial blinded histopathologic evaluation sometimes is chosen by study pathologists to test formal hypotheses and/or by sponsors to address non-pathologist expectations about histopathology data objectivity. Current practice is that a blinded histopathologic evaluation is documented only if formal blinding (ie, using slides with coded labels) is employed, using simple statements without detailed methodology in the study protocol (or an amendment) and/or pathology report. Blinding is not an appropriate strategy for the initial histopathologic evaluation performed during pathology peer reviews of GLP-compliant animal toxicity studies. [Box: see text].


Asunto(s)
Pruebas de Toxicidad/métodos , Animales , Animales de Laboratorio , Humanos , Patólogos , Patología/métodos , Revisión por Pares , Proyectos de Investigación , Encuestas y Cuestionarios , Toxicología/métodos
12.
Int J Toxicol ; 39(3): 198-206, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32372678

RESUMEN

The Tg.rasH2 mouse was developed as an alternative model to the traditional 2-year mouse bioassay for pharmaceutical carcinogenicity testing. This model has found extensive use in support of pharmaceutical drug development over the last few decades. It has the potential to improve quality and timeliness, reduce animal usage, and in some instances allow expedient decision-making regarding the human carcinogenicity potential of a drug candidate. Despite the increased use of the Tg.rasH2 model, there has been no systematic survey of current practices in the design, interpretation of results from the bioassay, and global health authority perspectives. Therefore, the aim of this work was to poll the pharmaceutical industry on study design practices used in the dose range finding and definitive 6-month studies and on results relative to the ongoing negotiations to revise The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S1 Guidance. Twenty-two member companies of International Consortium for Innovation and Quality in Pharmaceutical Development DruSafe Leadership Group participated in the survey, sharing experiences from studies conducted with 55 test compounds between 2010 and 2018. The survey results provide very useful insights into study design and interpretation. Importantly, the results identified several key opportunities for reducing animal use and increasing the value of testing for potential human carcinogenicity using this model. Recommended changes to study designs that would reduce animal usage include eliminating the requirement to include positive control groups in every study, use of nontransgenic wild-type littermates in the dose range finding study, and use of microsampling to reduce or eliminate satellite groups for toxicokinetics.


Asunto(s)
Pruebas de Carcinogenicidad/métodos , Carcinógenos/toxicidad , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Industria Farmacéutica/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Animales , Bioensayo , Genes ras , Ratones Transgénicos , Proyectos de Investigación , Encuestas y Cuestionarios
13.
Toxicol Pathol ; 45(1): 94-106, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27753639

RESUMEN

It has been long established that not only the species but also the strain and supplier of rodents used in preclinical safety studies can have a significant impact on the outcome of studies due to variability in their genetic background and thus spontaneous pathologic findings. In addition, local husbandry, housing, and other environmental conditions may have effects on the development and expression of comorbidities, particularly in longer-term or chronic studies. More recently, similar effects related to the source, including genetic and environmental variability, have been recognized in cynomolgus macaques ( Macaca fascicularis). The increased use of cynomolgus macaques from various sources of captive-bred animals (including nonnative, U.S./European Union-based breeding facilities or colonies) can affect study design and study results and outcome. It is important to acknowledge and understand the impact of this variability on the results and interpretation of research studies. This review includes recent examples where variability of preclinical animal models (rats and monkeys) affected the postmortem observations highlighting its relevance to study design or interpretation in safety studies.


Asunto(s)
Animales de Laboratorio/genética , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/normas , Proyectos de Investigación/normas , Animales , Evaluación Preclínica de Medicamentos/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Predisposición Genética a la Enfermedad , Macaca fascicularis , Ratas , Especificidad de la Especie
14.
Toxicol Pathol ; 43(6): 825-37, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26085543

RESUMEN

Glucokinase (GK) catalyzes the initial step in glycolysis and is a key regulator of glucose homeostasis. Therefore, glucokinase activators (GKa) have potential benefit in treating type 2 diabetes. Administration of a Bristol-Myers Squibb GKa (BMS-820132) to healthy euglycemic Sprague-Dawley (SD) rats and beagle dogs in 1 mo toxicology studies resulted in marked and extended hypoglycemia with associated clinical signs of toxicity and degenerative histopathological changes in the stomach, sciatic nerve, myocardium, and skeletal muscles at exposures comparable to those expected at therapeutic clinical exposures. To investigate whether these adverse effects were secondary to exaggerated pharmacology (prolonged hypoglycemia), BMS-820132 was administered daily to male Zucker diabetic fatty (ZDF) rats for 1 mo. ZDF rats are markedly hyperglycemic and insulin resistant. BMS-820132 did not induce hypoglycemia, clinical signs of hypoglycemia, or any of the histopathologic adverse effects observed in the 1 mo toxicology studies at exposures that exceeded those observed in SD rats and dogs. This indicates that the toxicity observed in euglycemic animals was secondary to the exaggerated pharmacology of potent GK activation. This study indicates that ZDF rats, with conventional toxicity studies, are a useful disease model for testing antidiabetic agents and determining toxicities that are independent of prolonged hypoglycemia.


Asunto(s)
Diabetes Mellitus/genética , Activadores de Enzimas/toxicidad , Hipoglucemia/inducido químicamente , Hipoglucemiantes/toxicidad , Ratas Zucker/metabolismo , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus/patología , Perros , Ingestión de Alimentos/efectos de los fármacos , Activadores de Enzimas/farmacocinética , Glucoquinasa/genética , Hipoglucemia/patología , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Insulina/sangre , Resistencia a la Insulina/genética , Masculino , Ratas , Especificidad de la Especie , Toxicocinética
15.
J Toxicol Pathol ; 27(3-4 Suppl): 1S-107S, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25516636

RESUMEN

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the female reproductive tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. There is also a section on normal cyclical changes observed in the ovary, uterus, cervix and vagina to compare normal physiological changes with pathological lesions. A widely accepted and utilized international harmonization of nomenclature for female reproductive tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

16.
Toxicol Pathol ; 39(4): 716-44, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21666103

RESUMEN

Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety.


Asunto(s)
Pruebas de Carcinogenicidad/métodos , Carcinógenos/toxicidad , Pruebas de Mutagenicidad/métodos , Animales , Pruebas de Carcinogenicidad/normas , Carcinógenos/normas , Bases de Datos Factuales , Árboles de Decisión , Modelos Animales de Enfermedad , Estudios de Evaluación como Asunto , Femenino , Guías como Asunto , Humanos , Inmunosupresores , Masculino , Ratones , Ratones Transgénicos , Pruebas de Mutagenicidad/normas , Neoplasias/inducido químicamente , Ratas , Ratas Endogámicas F344 , Factores de Riesgo , Estadística como Asunto , Pruebas de Toxicidad Crónica
17.
J Med Chem ; 63(6): 2958-2973, 2020 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-32077280

RESUMEN

Autoimmune deficiency and destruction in either ß-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting ß-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human ß-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).


Asunto(s)
Compuestos Aza/química , Compuestos Aza/farmacología , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Indoles/química , Indoles/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Compuestos Aza/farmacocinética , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Hipoglucemiantes/farmacocinética , Indoles/farmacocinética , Secreción de Insulina/efectos de los fármacos , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Ratones , Simulación del Acoplamiento Molecular , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Quinasas DyrK
18.
Toxicol Pathol ; 30(4): 483-91, 2002.
Artículo en Inglés | MEDLINE | ID: mdl-12187939

RESUMEN

A full assessment of all heart valves in rats and mice is often impractical and is usually not performed in routine toxicity studies, largely due to an inevitable inconsistency of histological sampling. The majority of reported heart valve changes involve the examination of a single, semirandom section through the heart and the valvulopathy occurring with age or induced by xenobiotics may have been generally underestimated in mice and rats. Here we describe the incidence and microscopic features of endocardial myxomatous change (EMC) in Hsd:S-D rats and CD-1 mice. EMC was common and widespread in both CD-1 mice and Hsd:S-D rats (188 of 220 rats and 96 of 215 mice were affected by EMC). Microscopically, EMC consisted of focal or segmental thickening of valves, primarily due to the presence of fibromyxoid tissue in the subendocardium. Occasionally, fibrin or thrombi deposits and collection of neutrophils or mononuclear cells were observed. These microscopic features were similar to those seen in valvular disease in humans induced by fenfluramine-phentermine (fen-phen), ergot alkaloids (ergotamine, methysergide), and carcinoid syndrome. The mitral valve in rats and pulmonary valve in mice were most frequently affected. An association between murine progressive cardiomyopathy (MPC) and EMC was noted only in rats, suggesting that there may be a possible relationship between MPC and EMC. However, additional research is needed to confirm a relationship between EMC and MPC in rats and/or mice.


Asunto(s)
Neoplasias Cardíacas/patología , Enfermedades de las Válvulas Cardíacas/patología , Mixoma/patología , Animales , Cardiomiopatías/patología , Femenino , Enfermedades de las Válvulas Cardíacas/inducido químicamente , Válvulas Cardíacas/patología , Masculino , Ratones , Ratones Endogámicos ICR , Ratas , Ratas Sprague-Dawley
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