Increased survival after gemfibrozil treatment of severe mouse influenza

Abstract

Gemfibrozil, an agent that inhibits production of proinflammatory cytokines in addition to its clinically useful lipid-lowering activity, increased survival in BALB/c mice that were already ill from infection by influenza virus A/Japan/305/57 (H2N2). Gemfibrozil was administered intraperitoneally once daily from days 4 to 10 after intranasal exposure to the virus. Survival increased from 26% in vehicle-treated mice (n = 50) to 52% in mice given gemfibrozil at 60 mg/kg/day (n = 46) (P = 0.0026). If this principle translates to patients, a drug already approved for human use, albeit by a different route for another purpose, might be adapted relatively fast for use against influenza, conceivably including human infection with a derivative of the avian H5N1 strain.

FIG. 1.

Effect of gemfibrozil on survival of BALB/c mice with severe influenza. Mice were infected with influenza virus A/Japan/305/57 and treated with vehicle or 20 mg/kg, 40 mg/kg, or 60 mg/kg gemfibrozil once daily from days 4 to 10 after virus exposure. These results are from a single experiment (vehicle, n = 9; 20 mg/kg, n = 10; 40 mg/kg, n = 9; 60 mg/kg, n = 10).

FIG. 2.

Effect of 60 mg/kg gemfibrozil on survival of BALB/c mice with severe influenza. Mice were infected with influenza virus A/Japan/305/57 and treated with vehicle or 60 mg/kg gemfibrozil once daily from days 4 to 10 after virus exposure. These results are pooled from four separate experiments (vehicle, n = 50; gemfibrozil, n = 46). Statistical analysis using the log rank test determined the increase in survival time with gemfibrozil treatment to be significant (P = 0.0026).

FIG. 3.

Effect of 60 mg/kg gemfibrozil on survival of BALB/c mice with severe systemic inflammation. Mice were given 30 mg/kg LPS (E. coli serotype O111:B4) and treated with a single dose of vehicle or 60 mg/kg gemfibrozil either 1 h before or 2 h after LPS injection. These results are from a single experiment; n = 20 for each group. Statistical analysis using the log rank test determined that a single dose of 60 mg/kg gemfibrozil 1 h before LPS significantly increased survival (P < 0.001).