1. Evaluation of local tolerance of the antiretroviral spermicide (WHI-07)-loaded gel-microemulsion in the porcine female reproductive tract.
- Author
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D'Cruz OJ and Uckun FM
- Subjects
- Administration, Intravaginal, Animals, Anti-Retroviral Agents administration & dosage, Benzalkonium Compounds administration & dosage, Benzalkonium Compounds toxicity, Body Fluids cytology, Body Fluids drug effects, Body Fluids metabolism, Cytokines metabolism, Emulsions administration & dosage, Female, Flow Cytometry, Genitalia, Female metabolism, Genitalia, Female pathology, Irritants administration & dosage, Irritants toxicity, Leukocytes drug effects, Mucous Membrane metabolism, Mucous Membrane pathology, Spermatocidal Agents administration & dosage, Swine, Thymidine Monophosphate toxicity, Toxicity Tests, Vaginal Creams, Foams, and Jellies administration & dosage, Vaginal Creams, Foams, and Jellies toxicity, Vaginal Douching, Zidovudine toxicity, Anti-Retroviral Agents toxicity, Dideoxynucleotides toxicity, Genitalia, Female drug effects, Mucous Membrane drug effects, Spermatocidal Agents toxicity, Thymidine Monophosphate analogs & derivatives, Zidovudine analogs & derivatives
- 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.
- Published
- 2008
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