Aqueous solubility was identified as a barrier to its oral bioavailability while solubilizing PTS with HP-β-CD substantially increased its bioavailability; dose manipulation was a practical strategy to enhance its bioavailability and systemic exposure; and its delivery through oral mucosa was feasible. As PTS possessed superior pharmacokinetics, it is a favorable candidate for further development.

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Context There is convincing evidence that physician empathy leads to better patient care. As a result, there has been considerable research interest in investigating how empathy changes during undergraduate medical studies. Early (generally North American) studies raised concerns that medical training causes a decline in empathy. More recent studies (conducted around the world) have begun to suggest that either a slight increase or decrease in empathy occurs during undergraduate medical training, which has led some to argue that empathy changes indiscriminately (with no discernible pattern). This paper explores whether there is evidence to suggest that empathy changes indiscriminately or with a discernible geo‐sociocultural pattern during undergraduate medical training. Methods Literature that investigated change in empathy during undergraduate medical training was reviewed. Cross‐sectional and longitudinal studies were tabulated separately according to their respective geographical locations. The tabulated results were analysed to investigate whether empathy changed similarly or differently within different geographical locations. Results The studies reviewed indicate similar patterns of empathy change within approximate geo‐sociocultural clusters. Whereas US studies predominantly show small but significant decreases in empathy, Far Eastern studies mostly show small but significant increases in empathy as undergraduates progress through the medical course. Conclusions These results suggest that change in empathy during undergraduate medical education is not as indiscriminate (patternless) as once thought. Additionally, these results support the notion that empathy is a locally construed global construct.

*Equal contribution. BACKGROUND AND PURPOSEChronic obstructive pulmonary disease (COPD) is a corticosteroid-resistant airway inflammatory condition. Resveratrol exhibits anti-inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aimed to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti-inflammatory agent for COPD by examining its effects in vitro and pharmacokinetics in vivo. EXPERIMENTAL APPROACHPrimary human airway epithelial cells derived from healthy and COPD subjects, and A549 epithelial cells were incubated with isorhapontigenin or resveratrol and stimulated with IL-1β in the presence or absence of cigarette smoke extract. Effects of isorhapontigenin and resveratrol on the release of IL-6 and chemokine (C-X-C motif) ligand 8 (CXCL8), and the activation of NF-κB, activator protein-1 (AP-1), MAPKs and PI3K/Akt/FoxO3A pathways were determined and compared with those of dexamethasone. The pharmacokinetic profiles of isorhapontigenin, after i.v. or oral administration, were assessed in Sprague-Dawley rats. KEY RESULTSIsorhapontigenin concentration-dependently inhibited IL-6 and CXCL8 release, with IC 50 values at least twofold lower than those of resveratrol. These were associated with reduced activation of NF-κB and AP-1 and, notably, the PI3K/Akt/FoxO3A pathway, that was relatively insensitive to dexamethasone. In vivo, isorhapontigenin was rapidly absorbed with abundant plasma levels after oral dosing. Its oral bioavailability was approximately 50% higher than resveratrol. CONCLUSIONS AND IMPLICATIONSIsorhapontigenin, an orally bioavailable dietary polyphenol, displayed superior anti-inflammatory effects compared with resveratrol. Furthermore, it suppressed the PI3K/Akt pathway that is insensitive to corticosteroids. These favourable efficacy and pharmacokinetic properties support its further development as a novel anti-inflammatory agent for COPD. AbbreviationsA549, human alveolar epithelial cells; AP-1, activator protein-1; AUC 0!last , plasma exposure; Cl, clearance; C max , maximal plasma concentration; COPD, chronic obstructive pulmonary disease; CXCL8, chemokine (C-X-C motif) ligand 8; ECL, Enhanced chemiluminescence; F, absolute oral bioavailability; FoxO3A, forkhead box O3A; H 2 DCF-DA, 2′,7′-dichlorodihydrofluorescein diacetate; MTT 0!last , mean transition time; TBS, Tris balanced salt solution