Systems pharmacology of adverse event mitigation by drug combinations.
Systems pharmacology of adverse event mitigation by drug combinations.
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DOI：
10.1126/scitranslmed.3006548
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发表时间：
2013-10-09
影响因子：
17.1
通讯作者：
Iyengar R
中科院分区：
文献类型：
--
作者：
Zhao S;Nishimura T;Chen Y;Azeloglu EU;Gottesman O;Giannarelli C;Zafar MU;Benard L;Badimon JJ;Hajjar RJ;Goldfarb J;Iyengar R
药物是为治疗而设计的，但药物相关的不良事件很常见，风险/效益分析对于确定临床使用至关重要。罗格列酮是一种有效的抗糖尿病药物，但与心肌梗死（MI）增加有关，因此限制了其使用。由于糖尿病患者经常被处方多种药物，我们在美国食品和药物管理局的不良事件报告系统（FAERS）中搜索了第二种药物（“药物B”）的使用，该药物可以减轻罗格列酮（“药物A”）相关MI的风险。在FAERS中，罗格列酮的使用与MI的发生率增加相关，但其与艾塞那肽联合使用可显著降低罗格列酮相关的MI。来自西奈山数据仓库的临床数据支持FAERS的观察结果。使用逻辑回归分析混杂因素表明，他们不负责观察到的效果。使用细胞生物学网络，我们预测艾塞那肽对罗格列酮相关MI的缓解作用可能通过凝血调节发生。我们从db/db小鼠模型获得的数据与网络预测一致。为了确定多种药理学是否可以作为不良事件缓解的基础，我们分析了FAERS数据库中的其他药物组合，其中药物B减少了药物A使用时报告的严重不良事件，如过敏性休克和自杀。该分析揭示了19，133种可以进一步研究的组合。我们的结论是，这种使用FAERS等数据库的众包方法可以帮助识别可能被重新用于缓解严重不良事件的药物。
Drugs are designed for therapy, but medication-related adverse events are common, and risk/benefit analysis is critical for determining clinical use. Rosiglitazone, an efficacious antidiabetic drug, is associated with increased myocardial infarctions (MIs), thus limiting its usage. Because diabetic patients are often prescribed multiple drugs, we searched for usage of a second drug (“drug B”) in the Food and Drug Administration’s Adverse Event Reporting System (FAERS) that could mitigate the risk of rosiglitazone (“drug A”)–associated MI. In FAERS, rosiglitazone usage is associated with increased occurrence of MI, but its combination with exenatide significantly reduces rosiglitazone-associated MI. Clinical data from the Mount Sinai Data Warehouse support the observations from FAERS. Analysis for confounding factors using logistic regression showed that they were not responsible for the observed effect. Using cell biological networks, we predicted that the mitigating effect of exenatide on rosiglitazone-associated MI could occur through clotting regulation. Data we obtained from the db/db mouse model agreed with the network prediction. To determine whether polypharmacology could generally be a basis for adverse event mitigation, we analyzed the FAERS database for other drug combinations wherein drug B reduced serious adverse events reported with drug A usage such as anaphylactic shock and suicidality. This analysis revealed 19,133 combinations that could be further studied. We conclude that this type of crowdsourced approach of using databases like FAERS can help to identify drugs that could potentially be repurposed for mitigation of serious adverse events.
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影响因子：
158.5
作者：
Nissen, Steven E.;Wolski, Kathy
通讯作者：
Wolski, Kathy
DOI：
10.1073/pnas.1222878110
发表时间：
2013-02-26
影响因子：
11.1
作者：
Seok, Junhee;Warren, H. Shaw;Tompkins, Ronald G.
通讯作者：
Tompkins, Ronald G.
影响因子：
7.3
作者：
Scheiber, Josef;Jenkins, Jeremy L.;Davies, John W.
通讯作者：
Davies, John W.
影响因子：
37.8
作者：
NORDT, TK;SAWA, H;SOBEL, BE
通讯作者：
SOBEL, BE
影响因子：
13.7
作者：
Bertrand, M;Duflo, E;Mullainathan, S
通讯作者：
Mullainathan, S