125 research outputs found

    Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet

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    In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.Funding for open access charge: Universidad de Malaga/CBUA. The present study has been supported by grants from Instituto de Salud Carlos III (ISCIII) (contract numbers: PID2022–140169OB-C21; PI21/01248; PI19/00883) and from Consejería de Salud de Andalucía (contract number: PEMP-0127–2020, Spain), cofounded by the European Union. This research was funded by HORIZON-HLTH-2022-STAYHLTH-02, grant number 101095679. Funded by the European Union. Views and opinions expressed are however those of the authors only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. MK was partially supported by Grant UID/BIM/0009/2020 of the Portuguese Fundação para a Ciência e a Tecnologia (FCT). MVP and IAA hold Sara Borrell research contracts from ISCIII (CD21/00198 and CD20/00083, respectively). This research was supported by CIBERehd – Consorcio Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea – European Regional Development Fund. JIG and GPA are supported by NIHR Nottingham Biomedical Research Centre [NIHR203310]. The views expressed are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health. This publication is based upon work from COST Action “CA17112—Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology); www.cost.eu

    Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet

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    \ua9 2024 The AuthorsIn the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI

    Long-term effects of high-fat or high-carbohydrate diets on glucose tolerance in mice with heterozygous carnitine palmitoyltransferase-1a deficiency

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    Background: Abnormal fatty acid metabolism is an important feature in the mechanisms of insulin resistance and β-cell dysfunction. Carnitine palmitoyltransferase-1a (CPT-1a, liver isoform) has a pivotal role in the regulation of mitochondrial fatty acid oxidation. We investigated the role of CPT-1a in the development of impaired glucose tolerance using a mouse model for CPT-1a deficiency when challenged by either a high-carbohydrate (HCD) or a high-fat diet (HFD) for a total duration of up to 46 weeks

    High-dose clevudine impairs mitochondrial function and glucose-stimulated insulin secretion in INS-1E cells

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    <p>Abstract</p> <p>Background</p> <p>Clevudine is a nucleoside analog reverse transcriptase inhibitor that exhibits potent antiviral activity against hepatitis B virus (HBV) without serious side effects. However, mitochondrial myopathy has been observed in patients with chronic HBV infection taking clevudine. Moreover, the development of diabetes was recently reported in patients receiving long-term treatment with clevudine. In this study, we investigated the effects of clevudine on mitochondrial function and insulin release in a rat clonal β-cell line, INS-1E.</p> <p>Methods</p> <p>The mitochondrial DNA (mtDNA) copy number and the mRNA levels were measured by using quantitative PCR. MTT analysis, ATP/lactate measurements, and insulin assay were performed.</p> <p>Results</p> <p>Both INS-1E cells and HepG2 cells, which originated from human hepatoma, showed dose-dependent decreases in mtDNA copy number and cytochrome c oxidase-1 (Cox-1) mRNA level following culture with clevudine (10 μM-1 mM) for 4 weeks. INS-1E cells treated with clevudine had reduced total mitochondrial activities, lower cytosolic ATP contents, enhanced lactate production, and more lipid accumulation. Insulin release in response to glucose application was markedly decreased in clevudine-treated INS-1E cells, which might be a consequence of mitochondrial dysfunction.</p> <p>Conclusions</p> <p>Our data suggest that high-dose treatment with clevudine induces mitochondrial defects associated with mtDNA depletion and impairs glucose-stimulated insulin secretion in insulin-releasing cells. These findings partly explain the development of diabetes in patients receiving clevudine who might have a high susceptibility to mitochondrial toxicity.</p

    Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet

    Get PDF
    In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.The present study has been supported by grants from Instituto de Salud Carlos III (ISCIII) (contract numbers: PID2022–140169OB-C21; PI21/01248; PI19/00883) and from Consejería de Salud de Andalucía (contract number: PEMP-0127–2020, Spain), cofounded by the European Union. This research was funded by HORIZON-HLTH-2022-STAYHLTH-02, grant number 101095679. Funded by the European Union. Views and opinions expressed are however those of the authors only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. MK was partially supported by Grant UID/BIM/0009/2020 of the Portuguese Fundação para a Ciência e a Tecnologia (FCT). MVP and IAA hold Sara Borrell research contracts from ISCIII (CD21/00198 and CD20/00083, respectively). This research was supported by CIBERehd – Consorcio Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea – European Regional Development Fund. JIG and GPA are supported by NIHR Nottingham Biomedical Research Centre [NIHR203310]. The views expressed are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR or the Department of Health. This publication is based upon work from COST Action “CA17112—Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology); www.cost.eu.Peer reviewe

    Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet

    Get PDF
    Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.Peer reviewe
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