Abstract

Polypharmacy (use of ≥5 medications) and increasing Drug Burden Index (DBI) score (measure of person’s total exposure to anticholinergic/sedative medications) are associated with impaired physical function in observational studies of older adults. Deprescribing, the supervised withdrawal of medications for which harms outweigh benefits for an individual, may be a useful intervention. Current knowledge is limited to clinical observational studies that are unable to determine causality. Here, we establish a preclinical model that investigates the effects of chronic polypharmacy, increasing DBI, and deprescribing on global health outcomes in aging. In a longitudinal study, middle-aged (12 months) male C57BL/6J (B6) mice were administered control feed or feed and/or water containing polypharmacy or monotherapy with different DBI scores. At 21 months, each treatment group was subdivided (stratified by frailty at 21 months) to either continue on treatment for life or to have treatment withdrawn (deprescribed). Frailty and physical function were evaluated at 12, 15, 18, and 24 months, and were analyzed using a mixed modeling approach. Polypharmacy with increasing DBI and monotherapy with citalopram caused mice to become frailer, less mobile, and impaired their strength and functional activities. Critically, deprescribing in old age reversed a number of these outcomes. This is the first preclinical study to demonstrate that chronic polypharmacy with increasing DBI augments frailty and impairs function in old age, and that drug withdrawal in old age reversed these outcomes. It was not the number of drugs (polypharmacy) but the type and dose of drugs (DBI) that caused adverse geriatric outcomes.

中文翻译：

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增加药物负担指数的慢性多药使用会加剧老年小鼠的虚弱和损害身体功能，其影响会因停药而减弱

摘要

在老年人的观察性研究中，多重用药（使用 ≥ 5 种药物）和增加的药物负担指数 (DBI) 评分（衡量人对抗胆碱能/镇静药物的总暴露量）与身体机能受损有关。取消处方，即在监督下停用对个人危害大于益处的药物，可能是一种有用的干预措施。目前的知识仅限于无法确定因果关系的临床观察研究。在这里，我们建立了一个临床前模型，该模型研究慢性多重用药、增加 DBI 和减少对全球老龄化健康结果的影响。在一项纵向研究中，对中年（12 个月）雄性 C57BL/6J (B6) 小鼠给予对照饲料或饲料和/或含有不同 DBI 评分的多药或单一疗法的水。在 21 个月时，每个治疗组都被细分（按 21 个月时的虚弱程度进行分层），要么继续接受终生治疗，要么停止治疗（取消）。在 12、15、18 和 24 个月时评估虚弱和身体功能，并使用混合建模方法进行分析。增加 DBI 的多药治疗和西酞普兰单药治疗导致小鼠变得更虚弱、行动不便，并削弱了它们的力量和功能活动。至关重要的是，在老年时取消处方逆转了许多这些结果。这是第一项临床前研究，证明随着 DBI 增加的慢性多重用药会增加老年时的虚弱和损害功能，而老年时停药则逆转了这些结果。导致老年不良后果的不是药物的数量（多药），而是药物的类型和剂量（DBI）。