| アブストラクト | Different computational approaches are employed to efficiently identify novel repositioning possibilities utilizing different sources of information and algorithms. It is critical to propose high-valued candidate-repositioning possibilities before conducting lengthy in vivo validation studies that consume significant resources. Here we report a novel multi-methodological approach to identify opportunities for drug repositioning. We performed analyses of real-world data (RWD) acquired from the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) and the claims database maintained by the Japan Medical Data Center (JMDC). These analyses were followed by cross-validation through bioinformatics analyses of gene expression data. Inverse associations revealed using disproportionality analysis (DPA) and sequence symmetry analysis (SSA) were used to detect potential drug-repositioning signals. To evaluate the validity of the approach, we conducted a feasibility study to identify marketed drugs with the potential for treating inflammatory bowel disease (IBD). Primary analyses of the FAERS and JMDC claims databases identified psycholeptics such as haloperidol, diazepam, and hydroxyzine as candidates that may improve the treatment of IBD. To further investigate the mechanistic relevance between hit compounds and disease pathology, we conducted bioinformatics analyses of the associations of the gene expression profiles of these compounds with disease. We identified common biological features among genes differentially expressed with or without compound treatment as well as disease-perturbation data available from open sources, which strengthened the mechanistic rationale of our initial findings. We further identified pathways such as cytokine signaling that are influenced by these drugs. These pathways are relevant to pathologies and can serve as alternative targets of therapy. Integrative analysis of RWD such as those available from adverse-event databases, claims databases, and transcriptome analyses represent an effective approach that adds value to efficiently identifying potential novel therapeutic opportunities. |
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| 投稿日 | 2018/10/10 |
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| 投稿者 | Hosomi, Kouichi; Fujimoto, Mai; Ushio, Kazutaka; Mao, Lili; Kato, Juran; Takada, Mitsutaka |
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| ジャーナル名 | PloS one |
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| 組織名 | Division of Clinical Drug Informatics, School of Pharmacy, Kindai University,;Kowakae, Higashi-osaka, Osaka, Japan.;Innovation and Entrepreneurship, Research, Takeda Pharmaceutical Company Limited,;Muraoka-Higashi, 2- Chome, Fujisawa, Kanagawa, Japan. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/30300381/ |
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