降尿酸药物的心血管风险信号挖掘及机制研究

Cardiovascular risk signaling mining and mechanism of uric acid-lowering drugs

目的利用美国食品药品监督管理局不良反应报告系统(FAERS),挖掘降尿酸常用药物的心血管风险信号及风险因素,初步探讨其潜在机制,为临床合理用药提供参考。方法提取FAERS数据库中2004年第1季度至2021年第3季度以非布司他、别嘌醇、苯溴马隆、丙磺舒、拉布立酶、普瑞凯希为“首要怀疑药物”的心血管药品不良事件(ADE),采用报告比值比法及信息成分法进行风险信号挖掘,采用单因素logistic回归分析用药风险因素,并应用生物信息技术预测心血管风险的潜在机制。结果非布司他具有明显的心血管风险信号,主要表现为心力衰竭、缺血性心脏病及心律失常;患者年龄、体重、给药剂量、用药周期、联合用药情况,均与非布司他心血管风险有关;非布司他心血管风险可能与神经活性配体-受体的相互作用有关,且ITGAM表达量与非布司他呈剂量依赖性变化,可能为非布司他心血管风险的潜在作用靶点。结论降尿酸药物中非布司他具有明显心血管风险,在使用过程中应控制用药风险因素以确保用药安全,其心血管风险机制可能与扰乱单核细胞神经活性配体-受体的相互作用通路及ITGAM的表达有关。

Objective To provide reference for the rational clinical use of uric acid-lowering drugs given their potential cardiovascular risks using data from FAERS database.Methods The data on ADE with febuxostat,allopurinol,benzbromarone,probenecid,labrizine,and pregabalin as the main suspected drugs in FAERS database between First quarter 2004 and third quarter 2021 was extracted.The proportional reporting ratio method and Bayesian Confidence Propagation Neural Network were used for signal mining of cardiovascular risks.Univariate logistic regression was used to identify the risk factors in the process of drug administration while bioinformatics technology was used to predict potential mechanisms of cardiovascular risks.Results Febuxostat had a significant cardiovascular risk profile,mainly in the form of heart failure,ischemic heart disease and cardiac arrhythmias.Risk factor mining found that a patient’s age,weight,dose administered,dosing period,and combination of drugs were all associated with cardiovascular risks of febuxostat.The potential mechanism of febuxostat cardiovascular risks involved neuroactive ligand-receptor interactions.ITGAM expression in the core target showed dose-dependent changes with febuxostat,which might be a potential target for cardiovascular risks of febuxostat.Conclusion Among the uric acid-lowering drugs,febuxostat has obvious cardiovascular risks,and the risk factors should be controlled during medication.The mechanism for cardiovascular risks may be related to the disruption of the neuroactive ligand-receptor interaction pathway of monocytes and the expression of ITGAM.