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A Study of the Potential of the Pig as a Model for the Vaginal Irritancy of Benzalkonium Chloride in Comparison to the Nonirritant Microbicide PHI-443 and the Spermicide Vanadocene Dithiocarbamate

¹ Drug Discovery Program, Department of Reproductive Biology
² Experimental Pathology
³ Virology, Parker Hughes Institute, St. Paul, Minnesota 55113
⁴ Paradigm Pharmaceuticals, LLC, St. Paul, Minnesota 55113

Correspondence: Address correspondence to: Dr. Osmond J. D’Cruz, Parker Hughes Institute, 2657 Patton Road, St. Paul, Minnesota 55113, USA; e-mail:odcruz{at}ih.org

A porcine model was established to test the mucosal toxicity potential of a thiophene thiourea (PHI-443)-based anti-HIV microbicide and a vanadocene-based spermicide, vanadocene dithiocarbamate (VDDTC) in comparison to benzalkonium chloride (BZK). Nine domestic pigs (Duroc) in nonestrus stage received a single intravaginal application of 2% BZK, 2% PHI-443, or 0.1% VDDTC-containing gel. At various times after gel application, cell differentials and levels of inflammatory cytokines (IL-1β, IL-4, IL-6, IL-8, IL-10, IL-18, IFN-, and TNF-) in cervicovaginal lavage (CVL) fluid were monitored by flow cytometry and ELISA, respectively. Eight pigs were exposed intravaginally to a gel with and without BZK or VDDTC for 4 consecutive days and vaginal tissues were scored histologically for inflammation using a new scoring system. Only CVL fluid from pigs exposed to BZK showed a significant increase of IL-1β, IL-8, and also IL-18 production when compared to the controls, PHI-443 or VDDTC-treated groups. Maximum levels of BZK-induced IL-1β (100-fold), IL-8 (2,500-fold), IL-18 (80-fold), and IFN-(10-fold) were found at 24 hours. In the in vivo porcine vaginal irritation model, increased levels of vaginal IL-1β, IL-8, and IL-18 were associated with histological changes consistent with vaginal inflammation. These results demonstrate that key cervicovaginal inflammatory cytokines are useful in vivo biomarkers for predicting the mucosal toxicity potential of vaginal products in the physiologically relevant and sensitive porcine model.

Key Words: cytokines • HIV/AIDS • inflammation • microbicide • porcine • spermicide • vagina

Abbreviations: BZK, benzalkonium chloride • Cp₂, bis(cyclopentadienyl) • CVL, cervicovaginal lavage • ELISA, enzyme-linked immunosorbent assay • FDA, food and drug administration • FACS, fluorescence-activated cell sorter • H&E, hematoxylin and eosin • HPLC, high performance liquid chromatography • HIV-1, human immunodeficiency virus type-1 • IL, interleukin • IFN, interferon • GM-CSF, granulocyte-macrophage colony-stimulating factor • MIP, macrophage inflammatory protein • NNRTI, nonnucleoside reverse transcriptase inhibitor • N-9, nonoxynol-9 • PHI-443, N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]thiourea • OTC, over-the-counter • PBS, phosphate buffered saline • RANTES, regulated on activation, normally T cell expressed and secreted • TGF, transforming growth factor • TMB, tetramethylbenzidine • TNF, tumor necrosis factor • VDDTC, vanadocene dithiocarbamate

Toxicologic Pathology, Vol. 33, No. 4, 465-476 (2005)
DOI: 10.1080/01926230590959866


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