Kheloufi Farid, Frankel Diane, Kaspi Elise, Lepelley Marion, Mallaret Michel, Boucherie Quentin, Roll Patrice, Micallef Joelle
Regional pharmacovigilance centre of Marseille Provence Corse, department of clinical pharmacology and pharmacovigilance, Assistance publique-Hôpitaux de Marseille, 270, boulevard Sainte-Marguerite, 13009 Marseille, France; CNRS 7289, neurosciences institute Timone, Aix-Marseille university, 13009 Marseille, France.
Inserm, GMGF UMRS 910, Aix-Marseille university, 13009 Marseille, France; Service of cell biology, hôpital la Timone, 13009 Marseille, France.
Therapie. 2018 May-Jun;73(3):273-281. doi: 10.1016/j.therap.2017.08.003. Epub 2017 Oct 14.
Proton pump inhibitors (PPIs) are among the most frequently prescribed drugs. Even if PPI are usually considered as safe, there is a growing concern for a range of adverse effects of chronic PPI therapy often in the absence of appropriate indications. We propose, after a summary of renal, cardiovascular and neurological complications (dementia, chronic kidney disease, myocardial infarction and stroke), an integrative overview of the potential biological mechanisms involved. Eleven positive pharmacoepidemiological studies, mainly based on health insurance database linkage to hospital database, reported an increased risk of complications associated to PPI use and often a graded association suggesting also a possible dose-response relationship. Several mechanisms have been suggested through in vitro studies (endothelial dysfunction, endothelial senescence, hypomagnesemia, increase of chromogranin A levels, decrease of nitric oxide in endothelial cells) leading to the impairment of vascular homesostasis, paving the way to these complications. Evidence that PPIs may have off-targets and pleiotropic effects are mounting and may impose a cautious attitude in the prescription of PPI's, especially in elderly and/or in the context of chronic use.
质子泵抑制剂（PPIs）是最常被处方的药物之一。即使PPIs通常被认为是安全的，但人们越来越担心长期使用PPIs治疗会产生一系列不良反应，而这些不良反应往往缺乏适当的指征。在总结了肾脏、心血管和神经方面的并发症（痴呆、慢性肾病、心肌梗死和中风）之后，我们提出了对潜在生物学机制的综合概述。十一项阳性药物流行病学研究主要基于医疗保险数据库与医院数据库的关联，报告了使用PPIs相关并发症的风险增加，而且通常存在分级关联，这也表明可能存在剂量反应关系。通过体外研究提出了几种机制（内皮功能障碍、内皮衰老、低镁血症、嗜铬粒蛋白A水平升高、内皮细胞中一氧化氮减少），这些机制导致血管稳态受损，从而引发这些并发症。越来越多的证据表明PPIs可能具有脱靶效应和多效性，这可能会使医生在开具PPIs处方时持谨慎态度，尤其是在老年人中或长期使用的情况下。
