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
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