期刊
FERTILITY AND STERILITY
卷 88, 期 -, 页码 1197-1206出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.fertnstert.2007.01.131
关键词
HIV/AIDS; cytokines; chemokines; inflammation; microbicide; vagina
资金
- NIAID NIH HHS [AI056909] Funding Source: Medline
- NICHD NIH HHS [HD042884, HD043683, HD042889] Funding Source: Medline
Objective: To investigate the in vitro and in vivo mucosal safety of a nonnucleoside reverse transcriptase (RT) inhibitor (PHI-443) and a nucleoside analogue RT inhibitor (stampidine)-based anti-HIV microbicide either alone or in combination. Design: In vitro and in vivo studies using three-dimensional vaginal epithelia integrating Langerhans cells and 16 1 New Zealand White rabbits, respectively. Setting: Research laboratory. Intervention(s): Rabbits in groups of four were exposed intravaginally to a gel with and without 1% PHI-443, 1% stampidine, or 1% PHI-443 plus 1% stampidine for 14 days. Cytokine/chemokine release by three-dimensional co-cultures in the presence and absence of PHI-443 or stampidine. Main Outcome Measures(s): Histologic scoring of vaginal tissue for mucosal toxicity at 24 hours after dosing. Simultaneous evaluation of levels of 10 cytokines (granulocyte-macrophage colony-stimulating factor, interleukin-la, interleukin-13, macrophage inflammatory protein-1 beta, granulocyte colony-stimulating factor, interleukin-18, tumor necrosis factor-a, interleukin-6, interleukin-1 beta, and interferon-y) and 6 chemokines (epithelia] neutrophil-activating peptide-78, interleukin-8, monocyte/macrophage chemoattractant protein- 1, macrophage inflammatory protein-3 alpha, interferon-inducible protein-10,and regulated upon activation of normal T-cell expressed and secreted) in culture media by a multiplexed chemiluminescence-based immunoassay. Result(s): In the rabbit model, repeated intravaginal administration of PHI-443 plus stampidine via a gel formulation at concentrations nearly 2,000 and 10,000 times higher than their respective in vitro anti-RIV IC50 values did not result in vaginal irritation. The levels of proinflammatory cytokines/chemokines secreted by multilayered human genital epithelia integrating Langerhans cells were unaffected by prolonged exposure to PHI-443 or stampidine. Conclusion(S): The combination of PHI-443 and stampidine was noncytotoxic to vaginal epithelial cells nonirritating to vaginal mucosa, and did not induce the secretion of proinflammatory cytokines and chemokines by cocultures of human genital epithelia and Langerhans cells. These attributes are particularly useful for the clinical development of PHI-443 and stampidine as a combination microbicide and as a prophylactic anti-HIV agent to curb genital transmission of HIV-1 by semen. (Fertil Steril (R) 2007;88(Suppl 2):1197-206. (C)2007 by American Society for Reproductive Medicine.)
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