Diurnal effects of polypharmacy with high drug burden index on physical activities over 23\xa0h differ with age and sex

Trang Tran,Harry Wu,John Mach,Christopher B Little,Sarah N Hilmer,Gizem Gemikonakli,Heather Allore,Susan E Howlett

doi:10.1038/s41598-022-06039-4

Abstract

Aging, polypharmacy (concurrent use of ≥ 5 medications), and functional impairment are global healthcare challenges. However, knowledge of the age/sex-specific effects of polypharmacy is limited, particularly on daily physical activities. Using continuous monitoring, we demonstrated how polypharmacy with high Drug Burden Index (DBI—cumulative anticholinergic/sedative exposure) affected behaviors over 23 h in male/female, young/old mice. For comparison, we also evaluated how different drug regimens (polypharmacy/monotherapy) influenced activities in young mice. We found that after 4 weeks of treatment, high DBI (HDBI) polypharmacy decreased exploration (reduced mean gait speed and climbing) during the habituation period, but increased it during other periods, particularly in old mice during the transition to inactivity. After HDBI polypharmacy, mean gait speed consistently decreased throughout the experiment. Some behavioral declines after HDBI were more marked in females than males, indicating treatment × sex interactions. Metoprolol and simvastatin monotherapies increased activities in young mice, compared to control/polypharmacy. These findings highlight that in mice, some polypharmacy-associated behavioral changes are greater in old age and females. The observed diurnal behavioral changes are analogous to drug-induced delirium and sundowning seen in older adults. Future mechanistic investigations are needed to further inform considerations of age, sex, and polypharmacy to optimize quality use of medicines.

Highlights

Aging, polypharmacy, and functional impairment are global healthcare challenges
Recognizing the clinical gap in literature, in this study, we evaluated changes in physical performance over 23 h, using the LABORAS, following 4 weeks of high DBI (HDBI, DBI score 1.612) polypharmacy compared to controls in male and female, young and old mice
Further analyzing in young mice, we found that low DBI (LDBI) polypharmacy, and monotherapy of metoprolol or simvastatin significantly increased distance travelled (Fig. 2a,b), durations of locomotion (Supplementary Fig. 3a,b) and rearing (Fig. 2e,f), compared to control

Summary

Introduction

Polypharmacy (concurrent use of ≥ 5 medications), and functional impairment are global healthcare challenges. In particular, could benefit from this[15], because there are multiple agerelated changes in circadian rhythm, leading to several altered body rhythmic characteristics including activity levels[16], which could be identified with prolonged/continuous observations[17]. These circadian disruptions could alter drug responses in aging[18]. To date, no clinical study has employed continuous monitoring of physical performance to observe changes associated with polypharmacy, age, and sex

Methods

Results

Conclusion