In Vitro evaluation of viability, integrity and inflammation in genital epithelia upon exposure to pharmaceutical excipients and candidate microbicides
Autor: | Joachim Brouwers, Guido Vanham, Olivier Delézay, Kevin K. Ariën, Bruno Pozzetto, Noura Addad, Hind Hamzeh-Cognasse, Thomas Bourlet, Patrick Augustijns, Youssef Gali |
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Jazyk: | angličtina |
Rok vydání: | 2010 |
Předmět: |
Polymers
HIV Infections Cervix Uteri Epithelial cells Pharmacology Epithelium Anti-Infective Agents Naphthalenesulfonates Anilides Pharmacology (medical) Evaluation Active ingredient Analytical Procedures Antiinfective agent Pharmacology. Therapy In vitro toxicology AIDS Infectious Diseases Viability Monoglycerides Reverse Transcriptase Inhibitors Female Safety medicine.drug Cell Survival Organophosphonates Excipient Viral diseases In Vitro Techniques Biology PRO 2000 Cell Line Exposure Vaginal inflammation In vitro Microbicide medicine Humans Genital Viability assay Furans Tenofovir Benzofurans Inflammation Disease transmission sexual Vaginal microbicide Adverse effects Adenine Prevention Interleukin-8 Vaginal gel Microbicides Thioamides Microbicides for sexually transmitted diseases HIV-1 Pharmaceutical products Laurates |
Zdroj: | Antimicrobial agents and chemotherapy |
ISSN: | 0066-4804 |
Popis: | 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. |
Databáze: | OpenAIRE |
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