1181. Nitazoxanide, a Novel Potential Anti-Influenza Drug, Acting in Synergism with Neuraminidase Inhibitors
Session: Poster Abstract Session: New Approaches to Anti-Viral Therapy
Saturday, October 22, 2011
Room: Poster Hall B1
Handouts
  • IDSA 2011 NTZ poster Belardo et al Final 100611.pdf (117.5 kB)
  • Background: Influenza viruses present a serious threat to global health. Resistance to current antiviral drugs underscore the need for additional therapies. Nitazoxanide (NTZ) and its active metabolite tizoxanide (TIZ) were found to inhibit the replication of H1N1 PR8 influenza A virus by a novel mechanism, impairing hemagglutinin maturation and virus morphogenesis. Herein we investigated the activity of NTZ and TIZ against a broad spectrum of human and avian influenza strains. Furthermore, the synergistic potential of NTZ in combination with neuraminidase inhibitors (NI) oseltamivir (OST) and zanamivir (ZAN) was explored.

    Methods: The effect of NTZ/TIZ activity was investigated in MDCK cells after infection (5 HAU/105 cells) with the following influenza A strains: H1N1 A/Puerto Rico/8/34 (PR8), H1N1 A/Wisconsin/33, H3N2 A/Firenze/7/03, H3N2 amantadine-resistant A/Parma/06/07 (AMD-R), H1N1 OST-resistant A/Parma/24/09 (OST-R), and avian H5N9-LP A/Ck/Italy/9097/97, H1N1 A/Goose/Italy/296246/03 and H7N1 A/Turkey/Italy/RA5563/99, as well as B/Parma/3/04 influenza B strain, kindly supplied by I. Donatelli, ISS, Italy. Virus titers were determined by hemagglutinin titration and infectivity assay, and cell viability by MTT assay, as described (Rossignol et al, JBC 284:29798,2009). Combination studies utilizing NI with NTZ were undertaken using isobologram analysis. Statistical analysis and combination index (CI) were determined using CalcuSyn V2 software.

    Results: NTZ and TIZ were tested against 8 strains of influenza A and one strain of influenza B. IC50, ranging from 0.3 - 1.5 µg/ml were recorded in all strains, including  OST and AMD-resistant strains. In all cases LD50 were above 50 μg/ml. In PR8 infected cells (single-step conditions) IC50 for OST and ZAN alone were 11.2 μM and 2.1 μM respectively; when combined with NTZ 1 μg/ml there was a 3- and 7-fold increase in potency versus OST and ZAN alone respectively.

    Conclusion: NTZ and its active metabolite TIZ possess potent antiviral activity in vitro against human and avian influenza viruses, including oseltamivir-resistant and amantadine-resistant strains. In addition, NTZ is synergistic in combination with neuraminidase inhibitors OST and ZAN with CI values ranging from 0.32 - 0.58.


    Subject Category: V. Virology including clinical and basic studies of viral infections, including hepatitis

    Giuseppe Belardo, PhD1, Simone La Frazia, PhD1, Orlando Cenciarelli, MS1, Stefania Carta, PhD1, Jean-Francois Rossignol, MD, FRCPath, PhD, FRSC2,3 and M. Gabriella Santoro, PhD1, (1)Department of Biology, University of Rome Tor Vergata, Rome, Italy, (2)Romark Institute for Medical Research, Tampa, FL, (3)Department of Biochemistry, Oxford University, Glycobiology Institute, Oxford, United Kingdom

    Disclosures:

    G. Belardo, Romark Laboratories: Consultant, Research support

    S. La Frazia, None

    O. Cenciarelli, Romark Laboratories: Consultant, Research support

    S. Carta, Romark Laboratories: Consultant, Research support

    J. F. Rossignol, Romark Laboratories: Board Member, Employee and Shareholder, Licensing agreement or royalty and Salary

    M. G. Santoro, Romark Laboratories: Consultant, Research support

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