Departments of Clinical Pharmacology and Aged Care, Royal North Shore Hospital, St Leonards, New South Wales, Australia.
Laboratory of Ageing and Pharmacology, Kolling Institute of Medical Research, Faculty of Medicine and Health, University of Sydney and Royal North Shore Hospital, St Leonards, New South Wales, Australia.
J Gerontol A Biol Sci Med Sci. 2021 Sep 13;76(10):1748-1756. doi: 10.1093/gerona/glab088.
Males and females may respond differently to medications, yet knowledge about sexual dimorphisms in the effects of polypharmacy remains limited, particularly in aging. This study aimed to assess the effect of high Drug Burden Index (DBI) polypharmacy treatment compared to control on physical function and behavior in young and old, male and female mice. We studied whether age and sex play a role in physical function and behavior following polypharmacy treatment and whether they are paralleled by differences in serum drug levels. Young (2.5 months) and old (21.5 months), C57BL/6 mice were randomized to control or high DBI polypharmacy treatment (simvastatin, metoprolol, oxybutynin, oxycodone, and citalopram; n = 6-8/group) for 4-6 weeks. Compared to control, polypharmacy reduced physical function (grip strength, rotarod latency, gait speed, and total distance), middle zone distance (increased anxiety), and nesting score (reduced activities of daily living) in mice of both ages and sexes (p < .001). Old animals had a greater decline in nesting score (p < .05) and midzone distance (p < .001) than young animals. Grip strength declined more in males than females (p < .05). Drug levels at steady state were not significantly different between polypharmacy-treated animals of both ages and sexes. We observed polypharmacy-induced functional impairment in both age and sex groups, with age and sex interactions in the degree of impairment, which were not explained by serum drug levels. Studies of the pathogenesis of functional impairment from polypharmacy may improve management strategies in both sexes.
男性和女性可能对药物的反应不同，但对于多药治疗的性别差异的了解仍然有限，尤其是在老龄化方面。本研究旨在评估高药物负担指数（DBI）多药治疗与对照相比对年轻和年老、雄性和雌性小鼠身体功能和行为的影响。我们研究了年龄和性别在多药治疗后身体功能和行为中的作用，以及它们是否与血清药物水平的差异平行。年轻（2.5 个月）和年老（21.5 个月）的 C57BL/6 小鼠被随机分为对照组或高 DBI 多药治疗组（辛伐他汀、美托洛尔、奥昔布宁、羟考酮和西酞普兰；每组 n = 6-8），治疗 4-6 周。与对照组相比，多药治疗降低了所有年龄和性别的小鼠的身体功能（握力、转棒潜伏期、步态速度和总距离）、中区域距离（增加焦虑）和筑巢评分（减少日常生活活动）（p <.001）。老年动物的筑巢评分（p <.05）和中区域距离（p <.001）下降幅度大于年轻动物。与雌性相比，雄性的握力下降更多（p <.05）。在稳态时，两组年龄的多药治疗动物的药物水平没有显著差异。我们观察到多药治疗在所有年龄和性别组中都引起了功能障碍，并且在损伤程度上存在年龄和性别相互作用，这不能用血清药物水平来解释。对多药治疗引起的功能障碍发病机制的研究可能会改善两性的管理策略。
