Polypharmacy Results in Functional Impairment in Mice: Novel Insights Into Age and Sex Interactions

Abstract

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 parallelled 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, citalopram) (n=6-8/group) for 4-6 weeks. Compared to control, polypharmacy reduced physical function (grip strength, rotarod latency, gait speed, total distance), middle zone distance (increased anxiety) and nesting score (reduced activities of daily living) in mice of both ages and sexes (p<0.001). Old animals had a greater decline in nesting score (p<0.05) and midzone distance (p<0.001) than young animals. Grip strength declined more in males than females (p<0.05). 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 pathogenesis of the functional impairment from polypharmacy may improve management strategies in both sexes.

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

“…No significant weight loss (Supplementary Fig. 1 ), or reduction in food/water intake was observed over 23 h during the LABORAS recording, or during the whole 4 weeks of intervention 24 , which are indicators of tolerance issues.…”

“…Recently, mice administered polypharmacy with high Drug Burden Index (DBI—measuring an individual’s cumulative exposure to anticholinergic and sedative medications 23 ) showed functional impairment in short physical tests, with varying effects in different ages/sexes 24 . Increasing DBI also increased frailty and functional impairments in aged male mice in conventional out-of-cage behavioral experiments 12 .…”

“…We also determined the effects of different drug regimens (4 weeks of HDBI polypharmacy; low DBI (LDBI) polypharmacy, DBI score 0.5 12 ; metoprolol monotherapy, and simvastatin monotherapy) on physical performance over 23 h in young male and female mice. Medications studied belong to drug classes commonly prescribed in older adults 24 , and do not require routine dose-adjustment in old age 25 . They have similar pharmacokinetic/pharmacodynamic properties in mice and humans, and are unlikely to cause toxicity when administered alone to healthy animals 25 .…”

Deprescribing in the Older Patient: A Narrative Review of Challenges and Solutions

“…Recently, preclinical studies have sought to fill this knowledge gap by determining the impact of polypharmacy and deprescribing on geriatric outcomes. [15][16][17] The first polypharmacy mouse model found that administration of therapeutic doses of five drugs (metoprolol, simvastatin, omeprazole, paracetamol and citalopram) for 4 weeks impaired physical function in old but not young male mice. 16 A subsequent study found that 4-6 weeks of polypharmacy with a higher anticholinergic and sedative load (metoprolol, simvastatin, oxycodone, oxybutynin and citalopram) impaired physical function in young and old male and female mice, with greater effects in old age, and greater reduction in grip strength in males.…”

“…16 A subsequent study found that 4-6 weeks of polypharmacy with a higher anticholinergic and sedative load (metoprolol, simvastatin, oxycodone, oxybutynin and citalopram) impaired physical function in young and old male and female mice, with greater effects in old age, and greater reduction in grip strength in males. 15 Polypharmacy for 8 weeks (metoprolol, simvastatin, paracetamol, aspirin and citalopram) in young male mice reduced exploration and spatial working memory. 18 A longitudinal study of treatment from middle to old age, found that polypharmacy regimens with increasing Drug Burden Index 19 (a measure of cumulative exposure to drugs with anticholinergic and sedative effects) impaired physical function in old male mice, which was attenuated by deprescribing.…”