Exacerbation of Influenza Virus Infections in Mice by Intranasal Treatments and Implications for Evaluation of Antiviral Drugs
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Compounds lacking oral activity may be delivered intranasally to treat influenza virus infections in mice. However, intranasal treatments greatly enhance the virulence of such virus infections. This can be partially compensated for by giving reduced virus challenge doses. These can be 100-1,000 fold lower than infections without such treatment and still cause equivalent mortality. We found intranasal liquid treatments to facilitate virus production (probably through enhanced virus spread) and lung pneumonia that was delayed by only two days relative to a 1000-fold higher virus challenge dose not accompanied by intranasal treatments. In one study, zanamivir was 90-100% effective at 10 mg/kg/day by oral, intraperitoneal, and intramuscular routes against influenza A/California/04/2009 (H1N1) in mice. However, the same compound administered intranasally at 20 mg/kg/day for 5 days gave no protection from death, although the time to death was significantly delayed. A related compound, Neu5Ac2en, was ineffective at 100 mg/kg/day. Intranasal zanamivir and Neu5Ac2en were 70-100% protective against influenza A/NWS/33 (H1N1) virus infections at 0.1-10 and 30-100 mg/kg/day, respectively. Somewhat more difficult to treat was A/Victoria/3/75 that required 10 mg/kg/day of zanamivir to achieve full protection. These results illustrate that treatment of influenza virus infections by intranasal route require consideration of both virus challenge dose and virus strain in order to not overwhelm the effectiveness of a potentially useful antiviral agent. In addition, the intranasal treatments were shown to facilitate virus replication and promote lung pathology.
Antimicrobial Agents and Chemotherapy