An integrative approach using real-world data to identify alternative therapeutic uses of existing drugs
| Autor: | Mitsutaka Takada, Lili Mao, Kazutaka Ushio, Kouichi Hosomi, Mai Fujimoto, Juran Kato |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Databases Factual Computer science lcsh:Medicine Gene Expression Disease Inflammatory bowel disease Adverse Event Reporting System Database and Informatics Methods Mathematical and Statistical Techniques Cell Signaling Japan Medicine and Health Sciences Membrane Receptor Signaling Claims database lcsh:Science Multidisciplinary Statistics Drugs Genomics Metaanalysis Middle Aged Colitis Immune Receptor Signaling Drug Marketing Drug repositioning Pharmaceutical Preparations Child Preschool Physical Sciences Cytokines Real world data Sequence Analysis Transcriptome Analysis Algorithms Research Article Signal Transduction Adult Drug marketing Drug Research and Development Drug-Related Side Effects and Adverse Reactions Bioinformatics MEDLINE Sequence Databases Computational biology Gastroenterology and Hepatology Research and Analysis Methods Food and drug administration 03 medical and health sciences Young Adult medicine Genetics Ulcerative Colitis Adverse Drug Reaction Reporting Systems Humans Relevance (information retrieval) Statistical Methods Pharmacology Diazepam United States Food and Drug Administration lcsh:R Inflammatory Bowel Disease Drug Repositioning Biology and Life Sciences Computational Biology Cell Biology medicine.disease Genome Analysis United States 030104 developmental biology Biological Databases lcsh:Q Mathematics |
| Zdroj: | PLoS ONE PLoS ONE, Vol 13, Iss 10, p e0204648 (2018) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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