| アブストラクト | Adverse events resulting from drug therapy can be a cause of drug withdrawal, reduced and or restricted clinical use, as well as a major economic burden for society. To increase the safety of new drugs, there is a need to better understand the mechanisms causing the adverse events. One way to derive new mechanistic hypotheses is by linking data on drug adverse events with the drugs' biological targets. In this study, we have used data mining techniques and mutual information statistical approaches to find associations between reported adverse events collected from the FDA Adverse Event Reporting System and assay outcomes from ToxCast, with the aim to generate mechanistic hypotheses related to structural cardiotoxicity (morphological damage to cardiomyocytes and/or loss of viability). Our workflow identified 22 adverse event-assay outcome associations. From these associations, 10 implicated targets could be substantiated with evidence from previous studies reported in the literature. For two of the identified targets, we also describe a more detailed mechanism, forming putative adverse outcome pathways associated with structural cardiotoxicity. Our study also highlights the difficulties deriving these type of associations from the very limited amount of data available. |
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| ジャーナル名 | Chemical research in toxicology |
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| Pubmed追加日 | 2018/10/24 |
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| 投稿者 | Svensson, Fredrik; Zoufir, Azedine; Mahmoud, Samar; Afzal, Avid M; Smit, Ines; Giblin, Kathryn A; Clements, Peter J; Mettetal, Jerome T; Pointon, Amy; Harvey, James S; Greene, Nigel; Williams, Richard V; Bender, Andreas |
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| 組織名 | Centre for Molecular Informatics, Department of Chemistry , University of;Cambridge , Lensfield Road , Cambridge CB2 1EW , United Kingdom.;GlaxoSmithKline R&D Ltd , Park Road , Ware, Hertfordshire SG12 0DP , United;Kingdom.;Drug Safety and Metabolism , AstraZeneca , 35 Gatehouse Drive , Waltham ,;Massachusetts 02451 , United States.;Safety and ADME Translational Sciences , AstraZeneca , Cambridge Science Park,;Milton Road , Cambridge CB4 0WG , United Kingdom.;Predictive Compound Safety and ADME , AstraZeneca , 35 Gatehouse Drive , Waltham;, Massachusetts 02451 , United States.;Lhasa Limited , Granary Wharf House, 2 Canal Wharf , Leeds LS11 5PS , United |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/30350600/ |
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