Wang Shuang, Song Liying, Sun Yuanjie, Zhou Haonan, Yao Jia
Department of Gastroenterology, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China.
Department of Thyroid Surgery, First Hospital of Shanxi Medical University, Taiyuan, China.
Front Pharmacol. 2025 May 2;16:1529416. doi: 10.3389/fphar.2025.1529416. eCollection 2025.
To combine pharmacovigilance and network toxicology methods to observe the acute pancreatitis (AP) following the use of antipsychotics, and potential toxic mechanisms, and to provide a reference for the safe use of drugs.
This study combined pharmacovigilance methods using real-world data and network toxicology methods to investigate AP associated with antipsychotics and the potential toxicological mechanism involved. First, the reports of antipsychotics were extracted from the US FDA Adverse Event Reporting System (FAERS), and the signals of AP were detected by four pharmacovigilance algorithms. The gene targets of drugs were predicted using multiple databases. The disease targets of AP were determined by bioinformatics methods. Protein-protein interaction (PPI) analysis was conducted using STRING database, gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analysis were also performed through R software. Molecular docking was applied to test the molecular affinity using AutoDock.
The signal intensity of AP was statistically significant in olanzapine, quetiapine, and fluphenazine. Due to the small number of reports associated with AP AEs on fluphenazine, our subsequent studies mainly focused on olanzapine and quetiapine. The results of stratification analysis suggested robustness of our results. Age ≤65, female, and weight >80 kg were identified as risk factors of the development of AP in patients receiving olanzapine, while weight >80 kg and age ≤65 were risk factors of that in patients receiving quetiapine. Network toxicology analysis and molecular docking suggested that olanzapine and quetiapine may exert their toxic effects through acting on hub genes.
The pharmacovigilance analysis investigated the signal intensity, clinical features, risk factors, and onset time of AP associated with olanzapine and quetiapine. Network toxicology analysis suggested that the toxic effects of olanzapine and quetiapine may be related to their hub genes.
结合药物警戒与网络毒理学方法，观察抗精神病药物使用后发生的急性胰腺炎（AP）及其潜在毒性机制，为药物安全使用提供参考。
本研究结合使用真实世界数据的药物警戒方法与网络毒理学方法，调查与抗精神病药物相关的AP及其潜在毒理学机制。首先，从美国食品药品监督管理局不良事件报告系统（FAERS）中提取抗精神病药物报告，并用四种药物警戒算法检测AP信号。使用多个数据库预测药物的基因靶点。通过生物信息学方法确定AP的疾病靶点。使用STRING数据库进行蛋白质-蛋白质相互作用（PPI）分析，还通过R软件进行基因本体（GO）和京都基因与基因组百科全书（KEGG）分析。应用分子对接通过AutoDock测试分子亲和力。
奥氮平、喹硫平和氟奋乃静中AP的信号强度具有统计学意义。由于与氟奋乃静相关的AP不良事件报告数量较少，我们后续的研究主要集中在奥氮平和喹硫平上。分层分析结果表明我们的结果具有稳健性。年龄≤65岁、女性和体重>80 kg被确定为接受奥氮平治疗患者发生AP的危险因素，而体重>80 kg和年龄≤65岁是接受喹硫平治疗患者发生AP的危险因素。网络毒理学分析和分子对接表明，奥氮平和喹硫平可能通过作用于枢纽基因发挥毒性作用。
药物警戒分析研究了与奥氮平和喹硫平相关的AP的信号强度、临床特征、危险因素和发病时间。网络毒理学分析表明，奥氮平和喹硫平的毒性作用可能与其枢纽基因有关。
