The efficacy of nonsteroidal anti‐inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long‐term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX‐2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine‐associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti‐inflammatory therapy.

中文翻译：

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非甾体类抗炎治疗：走向安全的旅程

直到今天，非甾体类抗炎药（NSAID）对抗炎症，疼痛和发烧的功效一直支持其在疼痛性疾病和慢性炎症性疾病中的全球使用。但是，NSAIDs的长期治疗很快与胃肠道不良事件的高发生率相关。因此，随着COX-2选择性抑制剂（coxibs）的开发和商业化，人们开始寻找具有更高安全性的新型药物。然而，当由于心血管毒性而将多种考昔布撤出市场时，兴奋很快变成了失望。此类事件再次触发了克服NSAIDs毒性的不同策略。这里，提供了一个综合综述来解决两种主要方法的突破：（i）NSAID与保护性介质的缔合；（ii）设计针对花生四烯酸级联反应的下游和/或多种酶的新型化合物。迄今为止，只有一种磷脂酰胆碱相关的NSAID已获准商业化。然而，迄今为止获得的临床前和临床数据表明，两种策略均可以提高非甾体类抗炎治疗的安全性。