Lack of in vitro-in vivo correlation for a UC781-releasing vaginal ring in macaques

This study describes the preclinical development of a matrix-type silicone elastomer vaginal ring device designed to provide controlled release of UC781, a non-nucleoside re- verse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities consid- ered sufficient to maintain vaginal fluid concentrations at levels 82–860-fold higher than the in vitro IC50 (2.0 to 10.4 nM) and therefore potentially protect against mucosal trans- mission of HIV. The 100-mg UC781 rings were well tolerated in pig-tailed macaques, did not induce local inflammation as determined by cytokine analysis and maintained median con- centrations in vaginal fluids of UC781 in the range of 0.27 to 5.18 mM during the course of the 28-day study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque pharmacokinetic studies revealed that 57 and 5 mg of UC781 was released, respectively. The pharmacokinetic analysis of a 100-mg UC781 vaginal ring in pig-tailed macaques showed poor in vivo–in vitro correlation, attributed to the very poor solubility of UC781 in vaginal fluid and resulting in a dissolution-controlled drug release mecha- nism rather than the expected diffusion-controlled mechanism.

Swift and Conversational Culture

Swift often noted his aversion to coffee-house conversation and to tavern talk, to gossip and company, and to being buried in Dublin in the years of his Deanship. Yet the popular myth of a morose, unsociable Swift belies both his engagement with various literary and political clubs in his early career and his participation in collaborative and experimental poetic games in his Dublin circles. This essay considers Swift’s involvement with three clubs in London (the Saturday Club, the Brothers’ Club, and the Scriblerians) and his writings on a number of fictional clubs (the Athenian Society, the Calves-Head Club, and a putative Society for the correction of the English language). While Swift wrote very little of his experience of actual clubs, the latter three, in addition to the Scriblerian Club as an imagined, rather than actual clubs, resulted in a number of defining poems and works in his career. When Swift settled in Dublin, poetry written and exchanged in a number of sociable circles characterised much of his published verse and gave glimpses of the circles and informal clubs which he formed among friends there. Although these poems are often dismissed as ‘trifles’, the essay argues that the poems are crucial for our understandings of ‘conversational culture’ or sociability in Swift’s Dublin.