Preclinical studies on thiocarboxanilide UC-781 as a virucidal agent.
BACKGROUND
Thiocarboxanilide UC-781 is a highly potent and selective non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1, which also has virucidal properties. Recent studies have shown that UC-781 would seem an ideal candidate for application as a vaginal virucide.


OBJECTIVE
To investigate the antiviral potency and stability of UC-781 in a lipophilic gel formulation.


METHODS
UC-781 was formulated in replens gel at different concentrations and administered intravaginally to 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 conditions 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 lipophilic gel (replens; up to 5%) and proved fully stable at 50 degrees C for 30 days. There was no effect on the growth of microorganisms (i.e., Candida and Lactobacillus strains) that are present in the vaginal flora. Neither systemic side-effects, nor local inflammation or damage of the vaginal mucosa or epithelium were observed in rabbits to which 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 zidovudine, formulated as 0.5 or 0.2% replens gel, were effective in protecting CEM cells in the very beginning against productive HIV-1 replication. This points to an efficient diffusion of the drugs from the lipophilic gel to the hydrophilic culture medium. However, subsequent subcultivations 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 and remained completely cleared from virus for at least 10 subcultivations.


CONCLUSIONS
The virus that emerged under 0.05% UC-781 remained highly sensitive to the NNRTI, including UC-781, in cell culture, suggesting a lack of resistance development under our experimental conditions.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Naesens
L
L
Verbeken
E
E
Laga
M
M
Van Damme
L
L
Parniak
M
M
Van Mellaert
L
L
Anné
J
J
De Clercq
E
E
D000163:Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D000282:Administration, Intravaginal; D000813:Anilides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D002175:Candida / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004267:DNA Viruses / Q000187:drug effects; D004355:Drug Stability; D005260:Female; D005663:Furans / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005782:Gels; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008055:Lipids; D008826:Microbial Sensitivity Tests; D012328:RNA Viruses / Q000187:drug effects; D011817:Rabbits; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013696:Temperature; D013854:Thioamides; D014621:Vagina / Q000187:drug effects*; D014622:Vaginal Creams, Foams, and Jellies
D000813:Anilides; D019380:Anti-HIV Agents; D005663:Furans; D005782:Gels; D008055:Lipids; C085472:Replens; D018894:Reverse Transcriptase Inhibitors; D013854:Thioamides; D014622:Vaginal Creams, Foams, and Jellies; C100668:UC-781