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Nitazoxanide inhibits the replication of Japanese encephalitis virus in cultured cells and in a mouse model.

Shi Z, Wei J, Deng X, Li S, Qiu Y, Shao D, Li B, Zhang K, Xue F, Wang X, Ma Z - Virol. J. (2014)

Bottom Line: NTZ significantly inhibited the replication of JEV in cultured cells in a dose dependent manner with 50% effective concentration value of 0.12 ± 0.04 μg/ml, a non-toxic concentration in cultured cells (50% cytotoxic concentration = 18.59 ± 0.31 μg/ml).The viral yields of the NTZ-treated cells were significantly reduced at 12, 24, 36 and 48 h post-infection compared with the mock-treated cells.NTZ was found to exert its anti-JEV effect at the early-mid stage of viral infection.

View Article: PubMed Central - HTML - PubMed

Affiliation: Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, No, 518, Ziyue Road, Shanghai 200241, PR China. zhiyongma@shvri.ac.cn.

ABSTRACT

Background: Japanese encephalitis virus (JEV) has a significant impact on public health. An estimated three billion people in 'at-risk' regions remain unvaccinated and the number of unvaccinated individuals in certain Asian countries is increasing. Consequently, there is an urgent need for the development of novel therapeutic agents against Japanese encephalitis. Nitazoxanide (NTZ) is a thiazolide anti-infective licensed for the treatment of parasitic gastroenteritis. Recently, NTZ has been demonstrated to have antiviral properties. In this study, the anti-JEV activity of NTZ was evaluated in cultured cells and in a mouse model.

Methods: JEV-infected cells were treated with NTZ at different concentrations. The replication of JEV in the mock- and NTZ-treated cells was examined by virus titration. NTZ was administered at different time points of JEV infection to determine the stage at which NTZ affected JEV replication. Mice were infected with a lethal dose of JEV and intragastrically administered with NTZ from 1 day post-infection. The protective effect of NTZ on the JEV-infected mice was evaluated.

Findings: NTZ significantly inhibited the replication of JEV in cultured cells in a dose dependent manner with 50% effective concentration value of 0.12 ± 0.04 μg/ml, a non-toxic concentration in cultured cells (50% cytotoxic concentration = 18.59 ± 0.31 μg/ml). The chemotherapeutic index calculated was 154.92. The viral yields of the NTZ-treated cells were significantly reduced at 12, 24, 36 and 48 h post-infection compared with the mock-treated cells. NTZ was found to exert its anti-JEV effect at the early-mid stage of viral infection. The anti-JEV effect of NTZ was also demonstrated in vivo, where 90% of mice that were treated by daily intragastric administration of 100 mg/kg/day of NTZ were protected from a lethal challenge dose of JEV.

Conclusions: Both in vitro and in vivo data indicated that NTZ has anti-JEV activity, suggesting the potential application of NTZ in the treatment of Japanese encephalitis.

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Structure of nitazoxanide (NTZ).
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Figure 1: Structure of nitazoxanide (NTZ).

Mentions: Nitazoxanide (2-acetyloxy-N-(5-nitro-2-thiazolyl) benzamide) (NTZ) (Figure 1) is a thiazolide anti-infective, originally licensed in the United States (Alinia; Romark Laboratories, Tampa, FL, USA), for the treatment of parasitic enteritis caused by Cryptosporidium parvum and Giardia lamblia in children and adults [1-3]. The antiviral properties of NTZ were discovered during the treatment of cryptosporidiosis in patients with acquired immune deficiency syndrome [4]. Recently, clinical trials have proven the antiviral effectiveness of NTZ in treating rotavirus gastroenteritis in young children, and rotavirus ancd norovirus gastroenteritis in adults [5,6]. In addition, NTZ has been demonstrated to have antiviral properties against hepatitis B virus (HBV), hepatitis C virus (HCV) and human-, avian- and canine-lineage influenza virus [7-10], suggesting that NTZ is a new class of broad-spectrum antiviral drug [11]. In the United States, NTZ is undergoing phase II clinical trials as a combinatorial drug in the treatment of chronic hepatitis C [12].


Nitazoxanide inhibits the replication of Japanese encephalitis virus in cultured cells and in a mouse model.

Shi Z, Wei J, Deng X, Li S, Qiu Y, Shao D, Li B, Zhang K, Xue F, Wang X, Ma Z - Virol. J. (2014)

Structure of nitazoxanide (NTZ).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927656&req=5

Figure 1: Structure of nitazoxanide (NTZ).
Mentions: Nitazoxanide (2-acetyloxy-N-(5-nitro-2-thiazolyl) benzamide) (NTZ) (Figure 1) is a thiazolide anti-infective, originally licensed in the United States (Alinia; Romark Laboratories, Tampa, FL, USA), for the treatment of parasitic enteritis caused by Cryptosporidium parvum and Giardia lamblia in children and adults [1-3]. The antiviral properties of NTZ were discovered during the treatment of cryptosporidiosis in patients with acquired immune deficiency syndrome [4]. Recently, clinical trials have proven the antiviral effectiveness of NTZ in treating rotavirus gastroenteritis in young children, and rotavirus ancd norovirus gastroenteritis in adults [5,6]. In addition, NTZ has been demonstrated to have antiviral properties against hepatitis B virus (HBV), hepatitis C virus (HCV) and human-, avian- and canine-lineage influenza virus [7-10], suggesting that NTZ is a new class of broad-spectrum antiviral drug [11]. In the United States, NTZ is undergoing phase II clinical trials as a combinatorial drug in the treatment of chronic hepatitis C [12].

Bottom Line: NTZ significantly inhibited the replication of JEV in cultured cells in a dose dependent manner with 50% effective concentration value of 0.12 ± 0.04 μg/ml, a non-toxic concentration in cultured cells (50% cytotoxic concentration = 18.59 ± 0.31 μg/ml).The viral yields of the NTZ-treated cells were significantly reduced at 12, 24, 36 and 48 h post-infection compared with the mock-treated cells.NTZ was found to exert its anti-JEV effect at the early-mid stage of viral infection.

View Article: PubMed Central - HTML - PubMed

Affiliation: Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science, No, 518, Ziyue Road, Shanghai 200241, PR China. zhiyongma@shvri.ac.cn.

ABSTRACT

Background: Japanese encephalitis virus (JEV) has a significant impact on public health. An estimated three billion people in 'at-risk' regions remain unvaccinated and the number of unvaccinated individuals in certain Asian countries is increasing. Consequently, there is an urgent need for the development of novel therapeutic agents against Japanese encephalitis. Nitazoxanide (NTZ) is a thiazolide anti-infective licensed for the treatment of parasitic gastroenteritis. Recently, NTZ has been demonstrated to have antiviral properties. In this study, the anti-JEV activity of NTZ was evaluated in cultured cells and in a mouse model.

Methods: JEV-infected cells were treated with NTZ at different concentrations. The replication of JEV in the mock- and NTZ-treated cells was examined by virus titration. NTZ was administered at different time points of JEV infection to determine the stage at which NTZ affected JEV replication. Mice were infected with a lethal dose of JEV and intragastrically administered with NTZ from 1 day post-infection. The protective effect of NTZ on the JEV-infected mice was evaluated.

Findings: NTZ significantly inhibited the replication of JEV in cultured cells in a dose dependent manner with 50% effective concentration value of 0.12 ± 0.04 μg/ml, a non-toxic concentration in cultured cells (50% cytotoxic concentration = 18.59 ± 0.31 μg/ml). The chemotherapeutic index calculated was 154.92. The viral yields of the NTZ-treated cells were significantly reduced at 12, 24, 36 and 48 h post-infection compared with the mock-treated cells. NTZ was found to exert its anti-JEV effect at the early-mid stage of viral infection. The anti-JEV effect of NTZ was also demonstrated in vivo, where 90% of mice that were treated by daily intragastric administration of 100 mg/kg/day of NTZ were protected from a lethal challenge dose of JEV.

Conclusions: Both in vitro and in vivo data indicated that NTZ has anti-JEV activity, suggesting the potential application of NTZ in the treatment of Japanese encephalitis.

Show MeSH
Related in: MedlinePlus