Topical ophthalmologic treatments have been facing great challenges with main limitations of low drug bioavailability, due to highly integrative defense mechanisms of the eye. This study rationally devised strategies to increase drug bioavailability by increasing ocular surface residence time of drug-loaded nanoliposomes dispersed within thermo-sensitive hydrogels (Pluronic F-127). Alternatively, we utilized sub-conjunctival injections as a depot technique to localize nanoliposomes. Senicapoc was encapsulated and sustainably released from free nanoliposomes and hydrogels formulations in vitro. Residence time increased up to 12-fold (60 min) with 24% hydrogel formulations, as compared to 5 min for free liposomes, which was observed in the eyes of Sprague-Dawley rats using fluorescence measurements. Pharmacokinetic results obtained from flushed tears, also showed that the hydrogels had greater drug retention capabilities to that of topical viscous solutions for up to 60 min. Senicapoc also remained quantifiable within sub-conjunctival tissues for up to 24 h post-injection.

Objective/background

Evidence on sex differences in the association between obstructive sleep apnea (OSA) and cardiovascular outcomes is limited and controversial. We conducted a historical cohort study to investigate this relationship.

Patients/methods

Clinical data on adults who underwent sleep study at a large urban academic hospital (Toronto, Canada) between 1994 and 2010 were linked to provincial health administrative data from 1991 to 2015. We fit Cox regressions to investigate the association between OSA severity and a cardiovascular composite outcome (all-cause mortality or hospitalization due to myocardial infarction, stroke, heart failure or atrial fibrillation), controlling for risk factors and stratifying by sex.

Results

A total of 10,149 subjects were included: median age of 49 years, 38% women. Over a median of 9.3 years, 1782 (18%) participants developed an outcome. The association between percentage of sleep time spent with oxygen saturation <90% and outcome was stronger for women (HR for IQR, 3 vs 0% = 1.30, 1.19-1.42) than for men (HR for IQR = 1.13, 1.06-1.21) (p for interaction = 0.01) in the adjusted model. Stratifying by sex, oxygen desaturations and heart rate in sleep were significant predictors in both men and women, while presence of daytime sleepiness, sleep efficiency and periodic leg movements in sleep were predictive in women but not in men.

Conclusions

In a large clinical cohort with suspected OSA, the impact of OSA as measured by the degree of nocturnal oxygen desaturation on the composite outcome was found to be greater in women than in men. We also found a different predictive ability of OSA-related factors by sex.