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Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis.
Archives of Toxicology ( IF 4.8 ) Pub Date : 2020-06-05 , DOI: 10.1007/s00204-020-02788-1
Christos Andronis 1 , João Pedro Silva 2 , Eftychia Lekka 1 , Vassilis Virvilis 1 , Helena Carmo 2 , Konstantina Bampali 3 , Margot Ernst 3 , Yang Hu 4 , Irena Loryan 4 , Jacques Richard 5 , Félix Carvalho 2 , Miroslav M Savić 6
Affiliation  

Drug-induced Mood- and Cognition-related adverse events (MCAEs) are often only detected during the clinical trial phases of drug development, or even after marketing, thus posing a major safety concern and a challenge for both pharmaceutical companies and clinicians. To fill some gaps in the understanding and elucidate potential biological mechanisms of action frequently associated with MCAEs, we present a unique workflow linking observational population data with the available knowledge at molecular, cellular, and psychopharmacology levels. It is based on statistical analysis of pharmacovigilance reports and subsequent signaling pathway analyses, followed by evidence-based expert manual curation of the outcomes. Our analysis: (a) ranked pharmaceuticals with high occurrence of such adverse events (AEs), based on disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database, and (b) identified 120 associated genes and common pathway nodes possibly underlying MCAEs. Nearly two-thirds of the identified genes were related to immune modulation, which supports the critical involvement of immune cells and their responses in the regulation of the central nervous system function. This finding also means that pharmaceuticals with a negligible central nervous system exposure may induce MCAEs through dysregulation of the peripheral immune system. Knowledge gained through this workflow unravels putative hallmark biological targets and mediators of drug-induced mood and cognitive disorders that need to be further assessed and validated in experimental models. Thereafter, they can be used to substantially improve in silico/in vitro/in vivo tools for predicting these adversities at a preclinical stage.



中文翻译:

通过药物警戒数据挖掘和功能丰富性分析的结合阐明了情绪和认知不良事件的分子基础。

药物诱发的情绪和认知相关不良事件(MCAE)通常仅在药物开发的临床试验阶段甚至在上市后才能检测到,因此对制药公司和临床医生都构成了重大的安全隐患和挑战。为了填补理解上的空白并阐明与MCAE经常相关的潜在生物学作用机制,我们提出了一个独特的工作流程,将观察人群数据与分子,细胞和心理药理学水平上的可用知识联系起来。它基于对药物警戒性报告的统计分析和随后的信号通路分析,然后是基于证据的专家对结果的人工管理。我们的分析:(a)对此类不良事件(AE)发生率很高的药物进行排名,基于FDA不良事件报告系统(FAERS)数据库的不成比例分析,并且(b)确定了120个相关基因和可能构成MCAE的共同途径节点。已鉴定的基因中有近三分之二与免疫调节有关,这支持了免疫细胞的关键参与及其在中枢神经系统功能调节中的反应。这一发现还意味着中枢神经系统暴露程度可忽略不计的药物可能会通过外周免疫系统失调而诱导MCAE。通过此工作流程获得的知识可揭示药物诱发的情绪和认知障碍的假定标志性生物学目标和介体,需要在实验模型中进行进一步评估和验证。之后,

更新日期:2020-06-05
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