tamiphosphor and Orthomyxoviridae-Infections

The efficacy of intravenous peramivir against influenza A (H1N1) 2009 virus infection was evaluated in mice in which the immune system was suppressed by cyclophosphamide (CP) treatment. The mortality rate of the vehicle control group was 100%, and the mice lost 20% of their body weight on average by day 13 postinfection (p.i.). Repeated administration of peramivir (40 mg/kg of body weight once a day, given intravenously for 20 days), starting at 1 h p.i., significantly reduced mortality, body weight loss, viral titers, and cytokine production in infected mice compared with results for administration of vehicle (P < 0.01). In addition, repeated administration of peramivir, starting at 24 h, 48 h, or 72 h p.i., also resulted in increases in survival rates and reduction of viral titers in the lungs (P < 0.01). The mean days to death (MDD) of the vehicle group was 14.5 days, while in the groups treated with peramivir starting at 24 h, 48 h, and 72 h p.i., the MDDs were >23.0, 20.9, and 21.8 days, respectively. In comparison, repeated administration of oseltamivir phosphate (5 mg/kg twice a day, given orally for 20 days), starting at 24 h, 48 h, and 72 h p.i., also significantly prevented body weight loss, whereas no significant differences in mortality rates and viral titers in the lungs were observed compared with results for the vehicle group. These data indicated that repeated administration of peramivir was effective in promoting the survival and reducing virus replication in immunosuppressed mice infected with influenza A (H1N1) 2009 virus.

Topics: Acids, Carbocyclic; Animals; Antiviral Agents; Body Weight; Cyclopentanes; Cyclophosphamide; Drug Administration Schedule; Female; Guanidines; Immunosuppressive Agents; Influenza A Virus, H1N1 Subtype; Injections, Intravenous; Lung; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Oseltamivir; Phosphorous Acids; Survival Analysis; Treatment Outcome

Oseltamivir phosphonic acid (tamiphosphor, 3a), its monoethyl ester (3c), guanidino-tamiphosphor (4a), and its monoethyl ester (4c) are potent inhibitors of influenza neuraminidases. They inhibit the replication of influenza viruses, including the oseltamivir-resistant H275Y strain, at low nanomolar to picomolar levels, and significantly protect mice from infection with lethal doses of influenza viruses when orally administered with 1 mg/kg or higher doses. These compounds are stable in simulated gastric fluid, liver microsomes, and human blood and are largely free from binding to plasma proteins. Pharmacokinetic properties of these inhibitors are thoroughly studied in dogs, rats, and mice. The absolute oral bioavailability of these compounds was lower than 12%. No conversion of monoester 4c to phosphonic acid 4a was observed in rats after intravenous administration, but partial conversion of 4c was observed with oral administration. Advanced formulation may be investigated to develop these new anti-influenza agents for better therapeutic use.

Topics: Acetamides; Administration, Oral; Alphainfluenzavirus; Animals; Antiviral Agents; Betainfluenzavirus; Biological Availability; Blood Proteins; Cyclohexenes; Cytopathogenic Effect, Viral; Dogs; Drug Resistance, Viral; Drug Stability; Female; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Madin Darby Canine Kidney Cells; Male; Mice; Mice, Inbred BALB C; Microsomes, Liver; Mutation; Neuraminidase; Orthomyxoviridae Infections; Oseltamivir; Phosphorous Acids; Protein Binding; Rats; Structure-Activity Relationship