In vitro evaluation of viability, integrity, and inflammation in genital epithelia upon exposure to pharmaceutical excipients and candidate microbicides.

Abstract

The use of microbicides is a promising approach for the prevention of HIV-1 transmission. Unfortunately, various candidates failed in clinical trials. In some cases, the candidate microbicide even resulted in enhanced virus transmission. Therefore, there is an urgent need to develop more predictive preclinical strategies to anticipate the in vivo efficiency/toxicity rate, including in vitro assays that evaluate effects on epithelial integrity and inflammation. The present study aims to identify potential safety issues concerning the use of microbicides and excipients commonly used in vaginal microbicide preparations. The toxicities of various active pharmaceutical ingredients (APIs; TMC-120, UC-781, tenofovir [PMPA], PRO-2000, and glycerol monolaurate [GML]) and excipients (preservatives, cosolvents, surfactants, and cyclodextrins) were evaluated using an in vitro dual-chamber model and uterine cervical explants. Epithelial viability and permeation of fluorescent virus-sized beads, as well as induction of interleukin-8 (IL-8; as a sensitive marker of an inflammatory response), were assessed. Surprisingly, cell viability and epithelial layer integrity were compromised by most excipients at concentrations near the typical concentration used in vaginal gels, and a significant increase in the production of IL-8 was observed at subtoxic concentrations. Within the APIs, TMC-120, UC-781, and PMPA showed higher selectivity indices than PRO-2000 and GML. In conclusion, identification of safety issues concerning the use of pharmaceutical excipients could help to formulate less toxic vaginal microbicide preparations.

• Authors: Youssef Gali, Olivier Delezay, Joachim Brouwers, Noura Addad, Patrick Augustijns, Thomas Bourlet, Hind Hamzeh-Cognasse, Kevin K Ariën, Bruno Pozzetto, Guido Vanham
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 54 Issue 12 Pg. 5105-14 (Dec 2010) ISSN: 1098-6596 [Electronic] United States
• PMID: 20921308 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anilides
• Anti-Infective Agents
• Benzofurans
• Furans
• Interleukin-8
• Laurates
• Monoglycerides
• Naphthalenesulfonates
• Organophosphonates
• PRO 2000
• Polymers
• Reverse Transcriptase Inhibitors
• Thioamides
• monolaurin
• Tenofovir
• Adenine
• UC-781

Topics

• Adenine (analogs & derivatives, pharmacology)
• Anilides (pharmacology)
• Anti-Infective Agents (pharmacology)
• Benzofurans (pharmacology)
• Cell Line
• Cell Survival (drug effects)
• Cervix Uteri (cytology, drug effects, virology)
• Epithelium (drug effects, virology)
• Female
• Furans (pharmacology)
• HIV Infections (drug therapy, pathology)
• Humans
• In Vitro Techniques
• Interleukin-8 (metabolism)
• Laurates (pharmacology)
• Monoglycerides (pharmacology)
• Naphthalenesulfonates (pharmacology)
• Organophosphonates (pharmacology)
• Polymers (pharmacology)
• Reverse Transcriptase Inhibitors (pharmacology)
• Tenofovir
• Thioamides