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Pharmacogenomics of off‐target adverse drug reactions

机译:脱靶药物不良反应的药物基因组学

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Off‐target adverse drug reactions (ADRs) are associated with significant morbidity and costs to the healthcare system, and their occurrence is not predictable based on the known pharmacological action of the drug's therapeutic effect. Off‐target ADRs may or may not be associated with immunological memory, although they can manifest with a variety of shared clinical features, including maculopapular exanthema, severe cutaneous adverse reactions (SCARs), angioedema, pruritus and bronchospasm. Discovery of specific genes associated with a particular ADR phenotype is a foundational component of clinical translation into screening programmes for their prevention. In this review, genetic associations of off‐target drug‐induced ADRs that have a clinical phenotype suggestive of an immunologically mediated process and their mechanisms are highlighted. A significant proportion of these reactions lack immunological memory and current data are informative for these ADRs with regard to disease pathophysiology, therapeutic targets and biomarkers which may identify patients at greatest risk. Although many serious delayed immune‐mediated (IM)‐ADRs show strong human leukocyte antigen associations, only a small subset have successfully been implemented in screening programmes. More recently, other factors, such as drug metabolism, have been shown to contribute to the risk of the IM‐ADR. In the future, pharmacogenomic targets and an understanding of how they interact with drugs to cause ADRs will be applied to drug design and preclinical testing, and this will allow selection of optimal therapy to improve patient safety.
机译:脱靶药物不良反应(ADR)与高发病率和医疗保健系统成本相关联,并且基于药物治疗作用的已知药理作用,无法预测它们的发生。脱靶ADR可能与免疫记忆有关,也可能不与免疫记忆有关,尽管它们可以表现出多种共有的临床特征,包括斑丘疹性皮疹,严重的皮肤不良反应(SCAR),血管性水肿,瘙痒和支气管痉挛。发现与特定ADR表型相关的特定基因是临床翻译成筛查程序以预防其的基本组成部分。在这篇综述中,突出了具有临床表型的脱靶药物诱导的ADR的遗传关联,提示其是免疫介导的过程及其机制。这些反应中有很大一部分缺乏免疫记忆,并且当前的数据对于这些ADR在疾病病理生理学,治疗靶标和生物标志物方面的信息是有用的,这些疾病可能会识别出风险最高的患者。尽管许多严重的延迟免疫介导(IM)-ADR显示出强大的人类白细胞抗原关联,但只有一小部分在筛选程序中成功实施。最近,其他因素(例如药物代谢)已显示出导致IM-ADR风险的因素。将来,药物基因组学目标及其与药物如何相互作用以引起ADR的理解将被用于药物设计和临床前测试,这将有助于选择最佳疗法以提高患者安全性。

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