title: 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.
authors.affiliation: Paradigm Pharmaceuticals, LLC, St Paul, Minnesota 55113, USA. dcruz915@comcast.net
authors.forename: Osmond J
authors.initials: OJ
authors.lastname: D'Cruz
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000282:Administration, Intravaginal; D000818:Animals; D044966:Anti-Retroviral Agents / Q000008:administration & dosage / Q000633:toxicity*; D001548:Benzalkonium Compounds / Q000008:administration & dosage / Q000633:toxicity; D001826:Body Fluids / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D054306:Dideoxynucleotides / Q000633:toxicity*; D004655:Emulsions / Q000008:administration & dosage; D005260:Female; D005434:Flow Cytometry; D005836:Genitalia, Female / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007509:Irritants / Q000008:administration & dosage / Q000633:toxicity; D007962:Leukocytes / Q000187:drug effects; D009092:Mucous Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013089:Spermatocidal Agents / Q000008:administration & dosage / Q000633:toxicity*; D013552:Swine; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives* / Q000633:toxicity; D018675:Toxicity Tests; D014622:Vaginal Creams, Foams, and Jellies / Q000008:administration & dosage / Q000633:toxicity; D044364:Vaginal Douching; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: C114570:5-bromo-6-methoxy-5, 6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate; D044966:Anti-Retroviral Agents; D001548:Benzalkonium Compounds; D016207:Cytokines; D054306:Dideoxynucleotides; D004655:Emulsions; D007509:Irritants; D013089:Spermatocidal Agents; D014622:Vaginal Creams, Foams, and Jellies; D013938:Thymidine Monophosphate; D015215:Zidovudine