PRECLINICAL STUDIES ON THIOCARBOXANILIDE UC-781 AS A VIRUCIDAL AGENT

Background: Thiocarboxanilide UC-781 is a highly potent and selective nonnucleoside reverse transcriptase inhibitor (NNRTI) of HIV-I, which also has virucidal properties. Recent studies have shown that UC-781 w ould seem an ideal candidate for application as a vaginal virucide. Ob jective: To investigate the antiviral potency and stability of UC-781 in a lipophilic gel formulation. Methods: UC-781 was formulated in rep lens gel at different concentrations and administered intravaginally t o rabbits at 5% in replens gel for 10 days. UC-781 was also exposed to temperatures of 4, 37 and 50 degrees C, and to low pH (6.0, 4.3, 2.0 and 1.2). A number of microorganisms were exposed in culture to serial dilutions of UC-781. Results: The drug was stable under low pH condit ions and did not lose its antiviral potency upon 4 h exposure to pH 3. 5 (the estimated vaginal pH). UC-781 can be easily formulated into a l ipophilic gel (replens; up to 5%) and proved fully stable at 50 degree s C for 30 days. There was no effect on the growth of microorganisms ( i.e., Candida and Lactobacillus strains) that are present in the vagin al flora. Neither systemic side-effects, nor local inflammation or dam age of the vaginal mucosa or epithelium were observed in rabbits to wh ich 5% UC-781 in replens gel had been administered. UC-781, formulated as 0.5, 0.2 and 0.05% replens gel, and UC-38, alpha-APA and zidovudin e, formulated as 0.5 or 0.2% replens gel, were effective in protecting CEM cells in the very beginning against productive HIV-I replication. This points to an efficient diffusion of the drugs from the lipophili c gel to the hydrophilic culture medium. However, subsequent subcultiv ations at a dilution rate of 1 :10 every 3-4 days resulted in a rapid breakthrough of virus with all drugs except UC-781 in its 0.5 and 0.2% gel formulation. These cultures were fully protected against HIV-1 an d remained completely cleared from virus for at least 10 subcultivatio ns. Conclusions: The virus that emerged under 0.05% UC-781 remained hi ghly sensitive to the NNRTI, including UC-781, in cell culture, sugges ting a lack of resistance development under our experimental condition s. (C) 1998 Lippincott-Raven Publishers.