In vitro and in vivo influenza virus-inhibitory effects of viramidine

• Published in: Antiviral research 2005-10, Vol.68 (1), p.10-17
• Main Authors: Sidwell, Robert W., Bailey, K.W., Wong, M.-H., Barnard, D.L., Smee, D.F.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - administration & dosage; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Biological and medical sciences; Cell Line; Drug Evaluation, Preclinical; Female; Human viral diseases; Infectious diseases; Influenza; Influenza A virus - drug effects; Influenza B virus - drug effects; Influenza virus; Lethal Dose 50; Lung - virology; Medical sciences; Mice; Orthomyxoviridae Infections - blood; Orthomyxoviridae Infections - drug therapy; Orthomyxoviridae Infections - virology; Oximetry; Oxygen - blood; Pharmacology. Drug treatments; Purine-Nucleoside Phosphorylase - antagonists & inhibitors; Ribavirin; Ribavirin - administration & dosage; Ribavirin - analogs & derivatives; Ribavirin - pharmacology; Ribavirin - therapeutic use; Viral diseases; Viral diseases of the respiratory system and ent viral diseases; Viramidine
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2005.06.003

Viramidine, the 3-carboxamidine derivative of ribavirin, was effective against a spectrum of influenza A (H1N1, H3N2 and H5N1) and B viruses in vitro, with the 50% effective concentration (EC 50) ranging from 2 to 32 μg/ml. The mean 50% cytotoxic concentration (CC 50) in the MDCK cells used in these experiments was 760 μg/ml. Ribavirin, run in parallel, had a similar antiviral spectrum, with EC 50 values ranging from 0.6 to 5.5 μg/ml; the mean CC 50 for ribavirin was 560 μg/ml. Oral gavage administrations of viramidine or ribavirin to mice infected with influenza A/NWS/33 (H1N1), A/Victoria/3/75 (H3N2), B/Hong Kong/5/72 or B/Sichuan/379/99 viruses were highly effective in preventing death, lessening decline in arterial oxygen saturation, inhibition of lung consolidation and reducing lung virus titers. The minimum effective dose of viramidine in these studies ranged from 15 to 31 mg/kg/day, depending upon the virus infection, when administered twice daily for 5 days beginning 4 h pre-virus exposure. The LD 50 of the compound was 610 mg/kg/day. Ribavirin's minimum effective dose varied between 18 and 37.5 mg/kg/day with the LD 50 determined to be 220 mg/kg/day. Viramidine's efficacy was also seen against an influenza A/NWS/33 (H1N1) virus infection in mice, when the compound was administered in the drinking water, the minimum effective dose being 100 mg/kg/day. Delay of the initiation of either viramidine or ribavirin therapy, using the approximate 1/3 LD 50 dose of each, was protective as late as 48 h after exposure to the A/NWS/33 virus. While both compounds appear to have similar efficacy against influenza virus infections, when one considers the lesser toxicity, viramidine may warrant further evaluation as a possible therapy for influenza.