N-Acetylcysteine Synergizes with Oseltamivir in Protecting Mice from Lethal Influenza Infection

Abstract

Many studies have shown that oxidative stress is important in the pathogenesis of pulmonary damage during influenza virus infections. Antioxidant molecules are therefore potentially useful against viral infection. Our previous studies show that N-acetylcysteine (NAC) has a protective effect in a model of lethal influenza infection in mice. NAC administration significantly decreased the mortality in infected mice. Further studies have demonstrated that NAC enhanced survival in combination with the antiviral agent ribavirin. In the present study, we report the effect of combined treatment with NAC and Oseltamivir, clinically used in the treatment and prevention of influenza virus infection, in a murine model of lethal influenza infection. NAC was given as a single daily dose of 1000 mg/Kg starting from 4 h before infection and until day 4 after infection; Oseltamivir was given twice daily at dose of 1 mg/Kg/die for 5 days, starting from 4 h before infection. End-point evaluation was 21-days' survival. NAC alone was slightly effective (20%), since a suboptimal treatment was used. Survival increased to 60% with Oseltamivir and to 100% with Oseltamivir and NAC used in combination. Since NAC alone does not show any antiviral action, the present findings suggest that antioxidant therapy increase survival by an improvement in host defense mechanisms, and/or by a direct antioxidant effect against oxidative stress associated with viral infection. Our studies demonstrate the effectiveness of combining agents acting through different mechanisms, such as antiviral drugs oseltamivir and the antioxidant NAC, indicating a possible advantage of combining the two treatments.

Antioxidant Therapy as a Potential Approach to Severe Influenza-Associated Complications

“…Furthermore, a combination of NAC and oseltamivir also synergistically reduced the lethal effect of influenza virus infection in mice [51]. These results support the notion that combinations of antioxidant therapy with current drugs can improve the treatment of influenza virus infections.…”

N-acetyl-l-cysteine (NAC) inhibits virus replication and expression of pro-inflammatory molecules in A549 cells infected with highly pathogenic H5N1 influenza A virus

“…Antioxidant molecules including reduced glutathione and its precursor N-acetyl-Lcysteine (NAC) are potentially useful against infection with influenza A viruses [20][21][22][23].…”

Nitrostative stress status during seasonal and pdmH1N1 infection in Iraq

“…Further evidence of involvement of nitrosative stress in influenza A is the demonstration of strong 8-nitroguanosine immunostaining in the cytosol of bronchial and bronchiolar epithelial cells of influenza virus-infected wild-type mice but not iNOS-deficient mice [15]. Moreover, a number of studies have demonstrated that reactive oxygen species contribute to the exacerbation of lung inflammation and lethality in influenza-infected mice, while the use of glutathione precursor promotes survival in influenza-infected mice [16,17]. The results reported in this work are in agreement with those of a study by Li et al, who demonstrated a 2.4-fold increase in nitric oxide production in patients infected with influenza A [8], and also showed that the production of nitric oxide in pdmH1N1 was significantly less than that of seasonal influenza A.…”