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VIRAL BIOTERRORISM AND ANTIVIRAL COUNTERMEASURES
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31. Bray, M.; Kefauver, D.; Martinez, M.; West, M.; Roy, C. Treatment of aerosolized cowpox virus infection in mice with aerosolized cidofovir. Antiviral Res. 2002, 54, 129 142. 32. Roy, C.; Baker, R.; Washburn, K.; Bray, M. Aerosolized cidofovir is retained in the respiratory tract and protects mice against intranasal cowpox virus challenge. Antimicrob. Agents Chemother. 2003, 47, 2933 2937. 33. Kern, E. R.; Hartline, C.; Harden, E.; Keith, K.; Rodriguez, N.; Beadle, J. R.; Hostetler, K. Y. Enhanced inhibition of orthopoxvirus replication in vitro by alkoxyalkyl esters of cidofovir and cyclic cidofovir. Antimicrob. Agents Chemother. 2002, 46, 991 995. 34. Ciesla, S.; Trahan, J.; Wan, W. B.; Beadle, J. R.; Aldern, K. A.; Painter, G. R.; Hostetler, K. Y. Esteri cation of cidofovir with alkoxyalkanols increases oral bioavailability and diminishes drug accumulation in kidney. Antiviral Res. 2003, 59,163 171. 35. Bray. M; Martinez, M.; Smee, D.; Kefauver, D.; Thompson, E.; Huggins, J. W. Cidofovir protects mice against lethal aerosol or intranasal cowpox virus infection. J. Infect. Dis. 2000, 181, 10 19. 36. Andrei, G.; De Clercq, E. Molecular approaches for the treatment of hemorrhagic fever virus infections. Antiviral Res. 1993, 22, 45 75. 37. Bray, M.; Paragas, J. Experimental therapy of lovirus infections. Antiviral Res. 2002, 54, 1 17. 38. Geisbert, T. W.; Hensley, L. E.; Jahrling, P. B.; Larsen, T.; Geisbert, J. B.; Paragas, J.; Young, H. A.; Fredeking, T. M.; Rote, W. E.; Vlasuk, G. P. Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet 2003, 362, 1953 1958.
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Overview of Antiviral Drug Discovery and Development
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National Institute of Allergy and Infectious Diseases, National Institutes of Health
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INTRODUCTION
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The continuous global emergence of new and reemerging/resurging infectious diseases during the last few decades is the cause of serious public health problems. Besides these natural infections, the intentional spread of deliberately emerging microbes, such as the 2001 anthrax attack, further complicates the dif cult challenge of protecting the public health.1 4 Although there is no approved antiviral therapy for any of the emerging/reemerging viral diseases, recent advances in biology and chemistry in addition to past drug discovery efforts have provided a promising blueprint for the therapeutic management of these diseases.5 7 In the past 30 years, the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) have reported more than 50 new or newly identi ed pathogens that cause human diseases.8 10 Table 3.1 shows a list of emerging viral pathogens causing disease in humans and Table 3.2 provides a list of biodefense Category A C viral pathogens according to the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH). In response to the challenge of biodefense, NIAID has developed a strategic plan to guide the implementation of basic and translational biodefense research and to encourage partners in academia, industry, and other private and public-sector entities to develop biodefense-related diagnostics, therapeutics, and vaccines (see http://www.niaid.nih.gov/ and http://www2.niaid.nih.gov/ biodefense/).
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Antiviral Drug Discovery for Emerging Diseases and Bioterrorism Threats. Edited by Paul F. Torrence Copyright # 2005 John Wiley & Sons, Inc.
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OVERVIEW OF ANTIVIRAL DRUG DISCOVERY AND DEVELOPMENT
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TABLE 3.1 1973: 1975: 1977: 1980: 1982: 1983: 1988: 1989: 1991: 1993: 1994: 1995: 1997: 1999: 2001: 2003:
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Emerging Viruses in Humans
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Rotavirus Parvovirus B19 Ebola virus, Hantaan virus Human T-lymphotrophic virus (HTLV-I) HTLV-II Human immunode ciency virus (HIV) Human herpesvirus-6 (HHV-6), hepatitis E virus Hepatitis C virus (HCV) Guanarito virus Sin Nombre virus Sabia virus, Hendra virus HHV-8 Avian in uenza virus (H5N1) Nipah virus, West Nile virus (in U.S.A.) Human metapneumovirus Severe acute respiratory syndrome coronavirus
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BROAD-SPECTRUM ANTIVIRAL AGENTS
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In a series of reviews by De Clercq, compounds with broad-spectrum antiviral activity were classi ed as follows: inosine monophosphate dehydrogenase (IMPDH) inhibitors, orotidylic acid (OMP) decarboxylase inhibitors, CTP synthetase inhibitors, S-adenosylhomocysteine (SAH) hydrolase inhibitors, immunomodulators, and interferons (IFNs).11 13 3.2.1 Ribavirin
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In an event of an outbreak of a new emerging viral infection, ribavirin 1 has almost always been the rst drug tried. This might be because ribavirin has demonstrated ef cacy against a variety of DNA and RNA viruses in cell cultures, in animal models, and in certain clinical cases (see Tables 3.3 and 3.4) since it was rst reported in 1972.14 18 In 1986, it was approved by the U.S. FDA for clinical use only as an aerosol for the treatment of hospitalized infants and young children with
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