COVID-19 pandemic led many countries to implement lockdown measures. Italy declared lockdown from 9th March to 3rd May 2020, and universities shifted to online classes. Home confinement could prevent students from achieving the physical activity and sleep levels recommended for their psychophysical health, and medicine students are already known to be at risk of inactivity and reduced sleep due to their time-consuming curricula. This study aimed at describing medicine students' behaviours during lockdown and comparing them with pre-lockdown data and current recommendations. A crosssectional questionnaire survey was conducted among 6th-year Italian medicine students (n = 714; age=25 ± 2 y; female: 62%; male: 38%) in October-November 2019. The same survey was repeated in 6th-year students during lockdown (n = 394; age=25 ± 2 y; female: 73%; male: 27%), and extended to 1st-5th year (total 1st-6th-year sample during lockdown: n = 1471; age=23 ± 2 y; female: 70%; male: 30%). International Physical Activity Questionnaire Short Form (IPAQ) and selected questions from Pittsburgh Sleep Quality Index were administered to evaluate physical activity, sitting and sleep time. Decreased physical activity, and increased sitting and sleep time were observed from pre-to during lockdown in 6thyear students (p<0.01). 1st-6th-year students featured 10 [8-12] hours sitting (median [Q1-Q3]) and an IPAQ score of 1170 MET-min/week. Even participants with higher physical activity featured high sitting time. Sleeping less than recommended (<7 h/night) was associated with more sitting time and less energies to perform daily activities. Strategies fostering compliance with current guidelines for physical activity, sedentary behaviour and sleep should be implemented, especially in case of a repeated or intermittent lockdown.

Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit beta-amyloid(1)(-)(42) (Abeta42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Abeta42 inhibitory potency while removing anti-COX activity. In vitro ADME developability parameters were taken into account in order to identify optimized compounds at an early stage of the project. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency on Abeta42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma Abeta42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.

Background and purpose:We evaluated the effects of 1-(3′,4′-dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a new g-secretase modulator, on brain b-amyloid pathology and spatial memory in transgenic mice expressing the Swedish and London mutations of human amyloid precursor protein (hAPP). Experimental approach: Sixty 6-month-old hAPP mice were treated for 6 months with CHF5074 or ibuprofen (375 ppm in the diet) or standard diet. Twenty-one wild-type mice received standard diet. Key results: Compared with transgenic controls, CHF5074 treatment significantly reduced the area occupied by plaques in cortex (P = 0.003) and hippocampus (P = 0.004). The number of plaques were also reduced by CHF5074 in both cortex (P = 0.022) and hippocampus (P = 0.005). Plaque-associated microglia in CHF5074-treated animals was lower than in transgenic controls in cortex (P = 0.008) and hippocampus (P = 0.002). Ibuprofen treatment significantly reduced microglia area in cortex and hippocampus but not b-amyloid burden. On the last day of the Morris water maze, transgenic controls performed significantly worse than the non-transgenic animals and the CHF5074-treated transgenic mice, on the swimming path to reach the hidden platform. Ibuprofen-treated animals did not perform significantly better than transgenic controls. Conclusions and implications: Chronic CHF5074 treatment reduced brain b-amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel g-secretase modulator is a promising therapeutic agent for Alzheimer's disease.

The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.