Thiazolides: A new class of antiviral drugs

The Romark Institute for Medical Research, Tampa, Florida 33607, USA.
Expert Opinion on Drug Metabolism & Toxicology (Impact Factor: 2.83). 06/2009; 5(6):667-74. DOI: 10.1517/17425250902988487
Source: PubMed


Thiazolides have emerged as a new class of broad-spectrum antiviral drugs, and the first thiazolide, nitazoxanide, is in late-stage clinical trials for treating chronic hepatitis C.
To review the chemistry, pharmacology, toxicology and efficacy of thiazolides as antiviral agents with emphasis on clinical development of nitazoxanide in treating chronic hepatitis C.
Literature search, information from Romark Laboratories and my personal experience with the discovery and development of thiazolides serve as the sources for this review.
Thiazolides are metabolically stable, highly bound to plasma proteins and are associated with a favorable toxicology profile. Phase II clinical trials have demonstrated efficacy and safety of nitazoxanide added to peginterferon with or without ribavirin in treating patients with chronic hepatitis C. More limited clinical data indicated potential in treating chronic hepatitis B, and three randomized controlled trials have demonstrated efficacy in reducing the duration of viral gastroenteritis. New generation thiazolides with the nitro group of nitazoxanide replaced by a non-reducible group are not active against anaerobes but retain broad-spectrum activity against viruses. Further studies are needed. Research indicates that these drugs may play an important and complementary role in combination with other classes of antiviral drugs.

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    • "The data in the current series of investigations confirm previous speculations that HCV resistance to NTZ in replicon cell culture is not due to mutations in the virus. Together with the observation that TIZ does not directly affect HCV enzymatic activities and the broad spectrum of antiviral activity exhibited by NTZ (Korba et al., 2008b; Rossignol, 2009), these data are consistent with earlier hypotheses that the antiviral activity of this drug is due to its interactions with a cellular target(s) that are yet to be identified. "
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    ABSTRACT: Nitazoxanide (NTZ) exhibits potent antiviral activity against hepatitis C virus (HCV) in cell culture. Previously, HCV replicon-containing cell lines resistant to NTZ were selected, but transfer the HCV NTZ-resistance phenotype was not observed following transfection of whole cell RNA. To further explore the nature of the resistance of HCV to NTZ, full length HCV replicon sequences were obtained from two NTZ-resistant (NTZ-11, TIZ-9), and the parental (RP7) cell lines. Numerous nucleotide changes were observed in individual HCV genomes relative to the RP7 HCV consensus sequence, but no common mutations in the HCV non-structural genes or 3'-UTR were detected. A cluster of single nucleotide mutations was found within a 5-base portion of the 5'-UTR in 20/21 HCV replicon sequences from both resistant cell lines. Three mutations (5'-UTR G17A, G18A, C20U) were individually inserted into CON1 ('wild-type') HCV replicons, showed reduced replication (5 to 50-fold), but none conferred resistance to NTZ. RP7, NTZ-11, and TIZ-9 were cured of HCV genomes by serial passage under interferon. Transfection of cured NTZ-11 and TIZ-9 with either whole cell RNAs from RP7, NTZ-11, or TIZ-9, 'wild-type' or the 5'-UTR mutation-containing replicon RNAs exhibited an NTZ-resistance phenotype. TIZ (the active metabolite of NTZ) was found to be inactive against the activity of HCV polymerase, protease, and helicase in enzymatic assays. These data confirm previous speculations that HCV resistance to NTZ is not due to mutations in the virus, and demonstrate that HCV resistance and most likely the antiviral activity of TIZ are due to interactions with cellular target(s).
    Preview · Article · Jun 2011 · Antiviral research
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    • "Indiscriminate use of oseltamivir could potentially reduce Veterinary Medicine International the effectiveness of treatment during an influenza pandemic [5] [6] [7] [8]. Nitazoxanide (NTZ), a thiazolide compound, has been shown to have antimicrobial activity against a variety of parasites, anaerobic bacteria, and viruses [9] [10] [11] [12] [13]. The drug is labeled for treatment of infectious enteritis caused by Giardia lamblia and Cryptosporidium parvum in humans and for the treatment of equine protozoal myeloencephalitis (EPM) in horses. "
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    ABSTRACT: Infection of dogs with canine influenza virus (CIV) is considered widespread throughout the United States following the first isolation of CIV in 2004. While vaccination against influenza A infection is a common and important practice for disease control, antiviral therapy can serve as a valuable adjunct in controlling the impact of the disease. In this study, we examined the antiviral activity of nitazoxanide (NTZ) and tizoxanide (TIZ) against three CIV isolates in vitro. NTZ and TIZ inhibited virus replication of all CIVs with 50% and 90% inhibitory concentrations ranging from 0.17 to 0.21 μM and from 0.60 to 0.76 μM, respectively. These results suggest that NTZ and TIZ are effective against CIV and may be useful for treatment of canine influenza in dogs but further investigation of the in vivo efficacy against CIV as well as the drug's potential for toxicity in dogs is needed.
    Full-text · Article · Aug 2010 · Veterinary Medicine International
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    ABSTRACT: Hepatitis C virus (HCV) causes significant morbidity and mortality worldwide with nearly 3% of the world population infected by this virus. Fortunately, this virus does not establish latency, and hence it may be possible to eradicate it. HCV is strongly associated with liver cirrhosis and hepatocellular carcinoma and is currently treated with pegylated interferon-alpha (peg-IFN-alpha) and ribavirin. Unfortunately, these limited treatment options often produce significant side effects, and currently, complete eradication of virus with combined drug modalities has not yet been achieved for the majority of chronically HCV-infected individuals. Restricted treatment options, lack of a universal cure for HCV and the link between chronic infection, liver cirrhosis and hepatocellular carcinoma necessitate design of novel drugs and treatment options. Understanding the relationship between the immune response, viral clearance and inhibition of viral replication with pharmacology-based design can ultimately allow for complete eradication of HCV. This review focuses upon significant novel preclinical and clinical specifically targeted antiviral therapy (STAT-C) drugs under development, highlights their mechanism of action, and discusses their impact on systemic viral loads and permanent clearance of infection.
    No preview · Article · Feb 2010 · Journal of Viral Hepatitis
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