Liang Shuang, Wang Xianying, Zhu Xiuqing
Department of Pharmacy, Hebei Medical University Third Hospital, Shijiazhuang, China.
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou Medical University, Guangzhou, China.
Front Pharmacol. 2024 Sep 4;15:1455212. doi: 10.3389/fphar.2024.1455212. eCollection 2024.
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat fever, pain, and inflammation. Concerns regarding their cardiovascular safety have been raised. However, the underlying mechanism behind these events remains unknown. We aim to investigate the cardiovascular safety signals and receptor mechanisms of NSAIDs, employing a comprehensive approach that integrates pharmacovigilance and pharmacodynamics.
This study utilized a pharmacovigilance-pharmacodynamic approach to evaluate the cardiovascular safety of NSAIDs and explore potential receptor mechanisms involved. Data were analyzed using the OpenVigil 2.1 web application, which grants access to the FDA Adverse Event Reporting System (FAERS) database, in conjunction with the BindingDB database, which provides target information on the pharmacodynamic properties of NSAIDs. Disproportionality analysis employing the Empirical Bayes Geometric Mean (EBGM) and Reporting Odds Ratio (ROR) methods was conducted to identify signals for reporting cardiovascular-related adverse drug events (ADEs) associated with 13 NSAIDs. This analysis encompassed three System Organ Classes (SOCs) associated with the cardiovascular system: blood and lymphatic system disorders, cardiac disorders, and vascular disorders. The primary targets were identified through the receptor-NSAID interaction network. Ordinary least squares (OLS) regression models explored the relationship between pharmacovigilance signals and receptor occupancy rate.
A total of 201,231 reports of cardiovascular-related ADEs were identified among the 13 NSAIDs. Dizziness, anemia, and hypertension were the most frequently reported Preferred Terms (PTs). Overall, nimesulide and parecoxib exhibited the strongest signal strengths of ADEs at SOC levels related to the cardiovascular system. On the other hand, our data presented naproxen and diclofenac as drugs of comparatively low signal strength. Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were identified as central targets. OLS regression analysis revealed that the normalized occupancy rate for either COX-1 or COX-2 was significantly inversely correlated with the log-transformed signal measures for blood and lymphatic system disorders and vascular disorders, and positively correlated with cardiac disorders and vascular disorders, respectively. This suggests that higher COX-2 receptor occupancy is associated with an increased cardiovascular risk from NSAIDs.
Cardiovascular safety of NSAIDs may depend on pharmacodynamic properties, specifically, the percentage of the occupied cyclooxygenase isoenzymes. More studies are needed to explore these relations and improve the prescription process.
非甾体抗炎药（NSAIDs）常用于治疗发热、疼痛和炎症。人们对其心血管安全性表示担忧。然而，这些事件背后的潜在机制仍不清楚。我们旨在采用综合方法，结合药物警戒和药效学，研究NSAIDs的心血管安全信号和受体机制。
本研究采用药物警戒-药效学方法评估NSAIDs的心血管安全性，并探索潜在的受体机制。使用OpenVigil 2.1网络应用程序分析数据，该程序可访问美国食品药品监督管理局不良事件报告系统（FAERS）数据库，同时结合BindingDB数据库，该数据库提供NSAIDs药效学特性的靶点信息。采用经验贝叶斯几何均值（EBGM）和报告比值比（ROR）方法进行不成比例分析，以识别与13种NSAIDs相关的心血管相关药物不良事件（ADEs）的报告信号。该分析涵盖与心血管系统相关的三个系统器官类别（SOCs）：血液和淋巴系统疾病、心脏疾病和血管疾病。通过受体-NSAID相互作用网络确定主要靶点。普通最小二乘法（OLS）回归模型探讨了药物警戒信号与受体占有率之间的关系。
在13种NSAIDs中，共识别出201,231例心血管相关ADEs报告。头晕、贫血和高血压是报告最频繁的首选术语（PTs）。总体而言，尼美舒利和帕罗西汀在与心血管系统相关的SOC水平上表现出最强的ADEs信号强度。另一方面，我们的数据显示萘普生和双氯芬酸的信号强度相对较低。环氧化酶-1（COX-1）和环氧化酶-2（COX-2）被确定为主要靶点。OLS回归分析显示，COX-1或COX-2的标准化占有率分别与血液和淋巴系统疾病以及血管疾病的对数转换信号测量值呈显著负相关，与心脏疾病和血管疾病呈正相关。这表明较高的COX-2受体占有率与NSAIDs导致的心血管风险增加有关。
NSAIDs的心血管安全性可能取决于药效学特性，特别是环氧化酶同工酶的占有率。需要更多研究来探索这些关系并改进处方过程。
