| アブストラクト | In 2009 the U.S. Food and Drug Administration (FDA) placed a black box warning on metoclopramide (MCP) due to the increased risks and prevalence of tardive dyskinesia (TD). In this study, we developed a multi-step biomedical informatics screening (MSBIS) approach leveraging publicly available bioactivity and drug safety data to identify concomitant drugs that mitigate the risks of MCP-induced TD. MSBIS includes (1) TargetSearch (http://dxulab.org/software) bioinformatics scoring for drug anticholinergic activity using CHEMBL bioactivity data; (2) unadjusted odds ratio (UOR) scoring for indications of TD-mitigating effects using the FDA Adverse Event Reporting System (FAERS); (3) adjusted odds ratio (AOR) re-scoring by removing the effect of cofounding factors (age, gender, reporting year); (4) logistic regression (LR) coefficient scoring for confirming the best TD-mitigating drug candidates. Drugs with increasing TD protective potential and statistical significance were obtained at each screening step. Fentanyl is identified as the most promising drug against MCP-induced TD (coefficient: -2.68; p-value<0.01). The discovery is supported by clinical reports that patients fully recovered from MCP-induced TD after fentanyl-induced general anesthesia. Loperamide is identified as a potent mitigating drug against a broader range of drug-induced movement disorders through pharmacokinetic modifications. Using drug-induced TD as an example, we demonstrated that MSBIS is an efficient in silico tool for unknown drug-drug interaction detection, drug repurposing, and combination therapy design. |
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| 投稿日 | 2017/12/02 |
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| 投稿者 | Xu, Dong; Ham, Alexandrea G; Tivis, Rickey D; Caylor, Matthew L; Tao, Aoxiang; Flynn, Steve T; Economen, Peter J; Dang, Hung K; Johnson, Royal W; Culbertson, Vaughn L |
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| ジャーナル名 | EBioMedicine |
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| 組織名 | Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy,;Kasiska Division of Health Sciences, Idaho State University, Meridian, ID 83642,;USA. Electronic address: xudong@isu.edu.;College of Pharmacy, Kasiska Division of Health Sciences, Idaho State University,;Meridian, ID 83642, USA.;Idaho Center for Health Research, Kasiska Division of Health Sciences, Idaho;State University, Meridian, ID 83642, USA.;USA.;Department of Pharmacy Practice and Administrative Sciences, College of Pharmacy, |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/29191560/ |
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