Evaluation of local tolerance of the antiretroviral spermicide (WHI‐07)‐loaded gel‐microemulsion in the porcine female reproductive tract

Abstract

The local tolerance of the antiretroviral spermicide, WHI-07 (5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)-methoxyalaninyl phosphate)-loaded gel-microemulsion was evaluated in a physiologically relevant and sensitive porcine model. Gilts (Duroc) in nonestrus stages of the reproductive cycle received either a single or a daily intravaginal application of 2.0% WHI-07 via a gel-microemulsion for 6 days. Cervicovaginal lavage (CVL) fluid was obtained for up to 72 h after a single exposure and the cellular profile and levels of inflammatory cytokines (IL-1beta, IL-8, IFN-gamma and TNF-alpha) were quantitated by flow cytometry and chemiluminescence-based multiplex immunoassay, respectively. The reproductive tract (vagina, cervix, uteri and Fallopian tubes) harvested on day 7 was scored histologically for evidence of mucosal irritation using a new scoring criterion for ten histological endpoints that reflect pathological changes in the epithelial/ subepithelial and vascular/perivascular compartments. When compared with irritant reactions caused by the detergent-type spermicide, benzalkonium chloride (BZK), the scatter profile of CVL immune cells and basal levels of proinflammatory cytokines (IL-1beta, IL-8, IFN-gamma and TNF-alpha) in CVL fluid were unaffected by intravaginal exposure to 2% WHI-07. Unlike BZK, endpoint histology of the proximal and distal regions of the reproductive tract from gilts treated with 2.0% WHI-07 via gel-microemulsion for 6 days did not result in mucosal irritation or alteration in the epithelium, subepithelium/lamina propria, vessels/perivascular tissues and underlying/surrounding muscles. Based on surrogate markers for inflammation, leukocyte profile and histologic data for local tolerance, repeated intravaginal administration of WHI-07 via gel-microemulsion as a prophylactic contraceptive is unlikely to cause vaginal irritation.

In Vitro and Ex Vivo Evaluation of Polymeric Nanoparticles for Vaginal and Rectal Delivery of the Anti-HIV Drug Dapivirine

“…Evaluation of the toxicity of dapivirine-loaded PCL-based NPs to pig vaginal and rectal mucosa was performed in order to expand data for cell-based studies. Alongside the standard rabbit vaginal irritation test, the pig is considered as a potentially interesting preclinical vaginal irritation model, again due to the notable anatomical and physiological similarities with humans, and has been previously used for assessing the toxicity of microbicides. , Results for tissue viability (MTS assay) and toxicity (LDH release assay) are presented in Figure (A and B). Free dapivirine and drug-loaded PEO-PCL NPs did not show differences when compared to results obtained from tissues incubated with plain medium.…”

Recent Advances in Anogenital Antiretroviral Microbicides and Multimodal Delivery Systems

“…In animal toxicity studies performed in mice, rabbits, cats, and/ or pigs, intravaginal administration of gel microemulsion with or without 2.0% WHI-05 or WHI-07 was not associated with any mucosal, systemic, developmental, and/or reproductive toxicity [74,221,[377][378][379][380][381][382][383]. Topical application of WHI-07 as a single agent and in combination via a nontoxic gel microemulsion was shown to block vaginal as well as rectal transmission of feline AIDS (FAIDS) by chronically FIVinfected feline T cells in the natural host model [375].…”