Preclinical studies on thiocarboxanilide UC-781 as a virucidal agent.

Abstract

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.

• Authors: J Balzarini, L Naesens, E Verbeken, M Laga, L Van Damme, M Parniak, L Van Mellaert, J Anné, E De Clercq
• Journal: AIDS (London, England) (AIDS) Vol. 12 Issue 10 Pg. 1129-38 (Jul 09 1998) ISSN: 0269-9370 [Print] England
• PMID: 9677161 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anilides
• Anti-HIV Agents
• Furans
• Gels
• Lipids
• Replens
• Reverse Transcriptase Inhibitors
• Thioamides
• Vaginal Creams, Foams, and Jellies
• UC-781

Topics

• Acquired Immunodeficiency Syndrome (prevention & control)
• Administration, Intravaginal
• Anilides (administration & dosage, chemistry, pharmacology)
• Animals
• Anti-HIV Agents (administration & dosage, chemistry, pharmacology)
• Bacteria (drug effects)
• Candida (drug effects)
• Cells, Cultured
• Chromatography, High Pressure Liquid
• DNA Viruses (drug effects)
• Drug Stability
• Female
• Furans (administration & dosage, chemistry, pharmacology)
• Gels
• HIV-1 (drug effects)
• Humans
• Hydrogen-Ion Concentration
• Lipids
• Microbial Sensitivity Tests
• RNA Viruses (drug effects)
• Rabbits
• Reverse Transcriptase Inhibitors (pharmacology)
• Temperature
• Thioamides
• Vagina (drug effects)
• Vaginal Creams, Foams, and Jellies