Sultana Janet, Calabró Marco, Garcia-Serna Ricard, Ferrajolo Carmen, Crisafulli Concetta, Mestres Jordi, Trifirò' Gianluca
Department of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, Messina, Italy.
Department of Medical Informatics, Erasmus Medical Centre, Rotterdam, Netherlands.
PLoS One. 2017 Oct 27;12(10):e0187034. doi: 10.1371/journal.pone.0187034. eCollection 2017.
Antipsychotic (AP) safety has been widely investigated. However, mechanisms underlying AP-associated pneumonia are not well-defined.
The aim of this study was to investigate the known mechanisms of AP-associated pneumonia through a systematic literature review, confirm these mechanisms using an independent data source on drug targets and attempt to identify novel AP drug targets potentially linked to pneumonia.
A search was conducted in Medline and Web of Science to identify studies exploring the association between pneumonia and antipsychotic use, from which information on hypothesized mechanism of action was extracted. All studies had to be in English and had to concern AP use as an intervention in persons of any age and for any indication, provided that the outcome was pneumonia. Information on the study design, population, exposure, outcome, risk estimate and mechanism of action was tabulated. Public repositories of pharmacology and drug safety data were used to identify the receptor binding profile and AP safety events. Cytoscape was then used to map biological pathways that could link AP targets and off-targets to pneumonia.
The literature search yielded 200 articles; 41 were included in the review. Thirty studies reported a hypothesized mechanism of action, most commonly activation/inhibition of cholinergic, histaminergic and dopaminergic receptors. In vitro pharmacology data confirmed receptor affinities identified in the literature review. Two targets, thromboxane A2 receptor (TBXA2R) and platelet activating factor receptor (PTAFR) were found to be novel AP target receptors potentially associated with pneumonia. Biological pathways constructed using Cytoscape identified plausible biological links potentially leading to pneumonia downstream of TBXA2R and PTAFR.
Innovative approaches for biological substantiation of drug-adverse event associations may strengthen evidence on drug safety profiles and help to tailor pharmacological therapies to patient risk factors.
抗精神病药物（AP）的安全性已得到广泛研究。然而，AP相关性肺炎的潜在机制尚不明确。
本研究旨在通过系统的文献综述来探究AP相关性肺炎的已知机制，利用关于药物靶点的独立数据源确认这些机制，并尝试识别可能与肺炎相关的新型AP药物靶点。
在Medline和Web of Science中进行检索，以识别探索肺炎与抗精神病药物使用之间关联的研究，从中提取关于假设作用机制的信息。所有研究必须为英文，且必须涉及将AP用作任何年龄人群的干预措施以及用于任何适应症，前提是结局为肺炎。将关于研究设计、人群、暴露、结局、风险估计和作用机制的信息制成表格。利用药理学和药物安全数据的公共储存库来确定受体结合谱和AP安全事件。然后使用Cytoscape绘制可将AP靶点和脱靶与肺炎联系起来的生物途径。
文献检索共获得200篇文章；41篇被纳入综述。30项研究报告了假设的作用机制，最常见的是胆碱能、组胺能和多巴胺能受体的激活/抑制。体外药理学数据证实了文献综述中确定的受体亲和力。发现两个靶点，即血栓素A2受体（TBXA2R）和血小板活化因子受体（PTAFR）是可能与肺炎相关的新型AP靶点受体。使用Cytoscape构建的生物途径确定了可能导致TBXA2R和PTAFR下游肺炎的合理生物联系。
药物不良事件关联的生物学证实的创新方法可能会加强关于药物安全性概况的证据，并有助于根据患者风险因素调整药物治疗。
