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Chemical Compound Review

AC1NRS7R     (4S,5R,6R)-5-(carboxyamino)- 4...

Synonyms:
 
 
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Disease relevance of zanamivir

  • CONCLUSIONS: In adults with influenza A or B virus infections, direct administration of a selective neuraminidase inhibitor, zanamivir, to the respiratory tract is safe and reduces symptoms if begun early [1].
  • CONTEXT: Influenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered [2].
  • Safety and efficacy of once daily intranasal zanamivir in preventing experimental human influenza A infection [3].
  • Furthermore, flu NA-mediated positive effect on HIV-1 biology was abrogated with zanamivir, a specific flu NA inhibitor [4].
  • OBJECTIVE: To examine which clinical signs and symptoms are most predictive of influenza infection in patients with influenza-like illness using a large data set derived from clinical trials of zanamivir [5].
 

High impact information on zanamivir

  • A neuraminidase-inhibition assay and sequencing of the neuraminidase and hemagglutinin genes revealed no zanamivir-resistant variants [6].
  • A total of 417 adults with influenza-like illness of < or =48 hours' duration were randomly assigned to one of three treatments: 6.4 mg of zanamivir by intranasal spray plus 10 mg by inhalation, 10 mg of zanamivir by inhalation plus placebo spray, or placebo by both routes [1].
  • Viral titers of nasal washings in the group given inhaled and intranasal zanamivir were significantly lower than those in the placebo group [1].
  • Recombinant viruses possessing the 1918 NA or both the 1918 HA and 1918 NA were inhibited effectively in both tissue culture and mice by the NA inhibitors, zanamivir and oseltamivir [7].
  • We conducted two studies to assess the pharmacokinetics and protective efficacy of a reduced frequency dosing regimen of topical zanamivir [3].
 

Chemical compound and disease context of zanamivir

 

Biological context of zanamivir

  • Among the 43 subjects evaluated, decreases in viral shedding occurred in the group receiving one dose of zanamivir 4 h prior to inoculation, whereas no significant benefit was observed in those receiving a single dose 48 h prior to challenge [3].
  • In addition, phagocytosis of cells infected with the wild-type virus was severely inhibited when the cells had been maintained in the presence of the NA inhibitor zanamivir [12].
  • METHODS: Clinical diagnosis, viral isolation, hemagglutinin inhibition serology, and multiplex, reverse transcription polymerase chain reaction were used to diagnose influenza in patients enrolled in international phase 3 studies designed to investigate the efficacy and safety of an anti-influenza drug (inhaled zanamivir) [13].
  • The anti-influenza virus agent 4-GU-DANA (zanamivir) inhibits cell fusion mediated by human parainfluenza virus and influenza virus HA [14].
  • The absolute oral bioavailability of zanamivir was low, averaging 2% [15].
 

Anatomical context of zanamivir

 

Associations of zanamivir with other chemical compounds

 

Gene context of zanamivir

  • Treatment with zanamivir prevented the infection and abrogated the local cytokine and chemokine responses [26].
  • Both compounds also considerably decreased NO generation in the IFN-gamma-stimulated macrophages, and zanamivir in the influenza-infected cells as well [27].
  • Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group [1].
  • We report here that for Newcastle disease virus, the HN receptor avidity is increased by zanamivir, due to activation of a second site that has higher receptor avidity [28].
  • In contrast, the enzymatic activities of WSN/Unstable-NAs, the replication of which had no effect on pretreatment with zanamivir, were undetectable in cells under the same conditions [29].
 

Analytical, diagnostic and therapeutic context of zanamivir

  • Zanamivir for the treatment of influenza A and B infection in high-risk patients: a pooled analysis of randomized controlled trials [30].
  • METHODS: Meta-analysis of 7 randomized, double-blind, placebo-controlled trials; 3815 mainly healthy adolescents and adults (mean age, 34 years) with an influenzalike illness of less than 2 days' duration were randomly assigned to receive combined inhaled and intranasal zanamivir, inhaled zanamivir, or corresponding placebos [31].
  • Zanamivir should have the potential to provide protection during the 2- to 4-week period before full immunity is induced, following vaccination at a time when influenza is circulating in the community [32].
  • Chemoprophylaxis of influenza A virus infections, with single doses of zanamivir, demonstrates that zanamivir is cleared slowly from the respiratory tract [33].
  • Zanamivir shows potential for prophylaxis in persons for whom vaccination is contraindicated or ineffective, in elderly or high-risk patients in long-term care facilities and in households [34].

References

  1. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenzavirus infections. GG167 Influenza Study Group. Hayden, F.G., Osterhaus, A.D., Treanor, J.J., Fleming, D.M., Aoki, F.Y., Nicholson, K.G., Bohnen, A.M., Hirst, H.M., Keene, O., Wightman, K. N. Engl. J. Med. (1997) [Pubmed]
  2. Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment. Hayden, F.G., Treanor, J.J., Fritz, R.S., Lobo, M., Betts, R.F., Miller, M., Kinnersley, N., Mills, R.G., Ward, P., Straus, S.E. JAMA (1999) [Pubmed]
  3. Safety and efficacy of once daily intranasal zanamivir in preventing experimental human influenza A infection. Calfee, D.P., Peng, A.W., Hussey, E.K., Lobo, M., Hayden, F.G. Antivir. Ther. (Lond.) (1999) [Pubmed]
  4. Syncytium formation and HIV-1 replication are both accentuated by purified influenza and virus-associated neuraminidase. Sun, J., Barbeau, B., Sato, S., Boivin, G., Goyette, N., Tremblay, M.J. J. Biol. Chem. (2002) [Pubmed]
  5. Clinical signs and symptoms predicting influenza infection. Monto, A.S., Gravenstein, S., Elliott, M., Colopy, M., Schweinle, J. Arch. Intern. Med. (2000) [Pubmed]
  6. Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group. Hayden, F.G., Gubareva, L.V., Monto, A.S., Klein, T.C., Elliot, M.J., Hammond, J.M., Sharp, S.J., Ossi, M.J. N. Engl. J. Med. (2000) [Pubmed]
  7. Existing antivirals are effective against influenza viruses with genes from the 1918 pandemic virus. Tumpey, T.M., García-Sastre, A., Mikulasova, A., Taubenberger, J.K., Swayne, D.E., Palese, P., Basler, C.F. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  8. Mutations in a conserved residue in the influenza virus neuraminidase active site decreases sensitivity to Neu5Ac2en-derived inhibitors. McKimm-Breschkin, J.L., Sahasrabudhe, A., Blick, T.J., McDonald, M., Colman, P.M., Hart, G.J., Bethell, R.C., Varghese, J.N. J. Virol. (1998) [Pubmed]
  9. A single amino acid alteration in the human parainfluenza virus type 3 hemagglutinin-neuraminidase glycoprotein confers resistance to the inhibitory effects of zanamivir on receptor binding and neuraminidase activity. Murrell, M.T., Porotto, M., Greengard, O., Poltoratskaia, N., Moscona, A. J. Virol. (2001) [Pubmed]
  10. Comparison of efficacies of RWJ-270201, zanamivir, and oseltamivir against H5N1, H9N2, and other avian influenza viruses. Govorkova, E.A., Leneva, I.A., Goloubeva, O.G., Bush, K., Webster, R.G. Antimicrob. Agents Chemother. (2001) [Pubmed]
  11. Mechanism by which mutations at his274 alter sensitivity of influenza a virus n1 neuraminidase to oseltamivir carboxylate and zanamivir. Wang, M.Z., Tai, C.Y., Mendel, D.B. Antimicrob. Agents Chemother. (2002) [Pubmed]
  12. Role of phosphatidylserine exposure and sugar chain desialylation at the surface of influenza virus-infected cells in efficient phagocytosis by macrophages. Watanabe, Y., Shiratsuchi, A., Shimizu, K., Takizawa, T., Nakanishi, Y. J. Biol. Chem. (2002) [Pubmed]
  13. Diagnosis of influenza in the community: relationship of clinical diagnosis to confirmed virological, serologic, or molecular detection of influenza. Zambon, M., Hays, J., Webster, A., Newman, R., Keene, O. Arch. Intern. Med. (2001) [Pubmed]
  14. The anti-influenza virus agent 4-GU-DANA (zanamivir) inhibits cell fusion mediated by human parainfluenza virus and influenza virus HA. Greengard, O., Poltoratskaia, N., Leikina, E., Zimmerberg, J., Moscona, A. J. Virol. (2000) [Pubmed]
  15. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Cass, L.M., Efthymiopoulos, C., Bye, A. Clinical pharmacokinetics. (1999) [Pubmed]
  16. Influence of the human parainfluenza virus 3 attachment protein's neuraminidase activity on its capacity to activate the fusion protein. Porotto, M., Murrell, M., Greengard, O., Doctor, L., Moscona, A. J. Virol. (2005) [Pubmed]
  17. Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection. Calfee, D.P., Peng, A.W., Cass, L.M., Lobo, M., Hayden, F.G. Antimicrob. Agents Chemother. (1999) [Pubmed]
  18. Direct measurement of the anti-influenza agent zanamivir in the respiratory tract following inhalation. Peng, A.W., Milleri, S., Stein, D.S. Antimicrob. Agents Chemother. (2000) [Pubmed]
  19. The low potential for drug interactions with zanamivir. Daniel, M.J., Barnett, J.M., Pearson, B.A. Clinical pharmacokinetics. (1999) [Pubmed]
  20. Analysis of the desialidation process of the haemagglutinin protein of influenza B virus: the host-dependent desialidation step. Luo, C., Nobusawa, E., Nakajima, K. J. Gen. Virol. (2002) [Pubmed]
  21. Cost-effectiveness of newer treatment strategies for influenza. Smith, K.J., Roberts, M.S. Am. J. Med. (2002) [Pubmed]
  22. Characterization of human influenza virus variants selected in vitro in the presence of the neuraminidase inhibitor GS 4071. Tai, C.Y., Escarpe, P.A., Sidwell, R.W., Williams, M.A., Lew, W., Wu, H., Kim, C.U., Mendel, D.B. Antimicrob. Agents Chemother. (1998) [Pubmed]
  23. Comparison of the activities of zanamivir, oseltamivir, and RWJ-270201 against clinical isolates of influenza virus and neuraminidase inhibitor-resistant variants. Gubareva, L.V., Webster, R.G., Hayden, F.G. Antimicrob. Agents Chemother. (2001) [Pubmed]
  24. Influenza vaccination and antiviral therapy: is there a role for concurrent administration in the institutionalised elderly? Drinka, P.J. Drugs & aging. (2003) [Pubmed]
  25. Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor. Sidwell, R.W., Huffman, J.H., Barnard, D.L., Bailey, K.W., Wong, M.H., Morrison, A., Syndergaard, T., Kim, C.U. Antiviral Res. (1998) [Pubmed]
  26. Nasal cytokine and chemokine responses in experimental influenza A virus infection: results of a placebo-controlled trial of intravenous zanamivir treatment. Fritz, R.S., Hayden, F.G., Calfee, D.P., Cass, L.M., Peng, A.W., Alvord, W.G., Strober, W., Straus, S.E. J. Infect. Dis. (1999) [Pubmed]
  27. Neuraminidase inhibitors reduce nitric oxide production in influenza virus-infected and gamma interferon-activated RAW 264.7 macrophages. Kacergius, T., Ambrozaitis, A., Deng, Y., Gravenstein, S. Pharmacological reports : PR (2006) [Pubmed]
  28. Paramyxovirus receptor-binding molecules: engagement of one site on the hemagglutinin-neuraminidase protein modulates activity at the second site. Porotto, M., Fornabaio, M., Greengard, O., Murrell, M.T., Kellogg, G.E., Moscona, A. J. Virol. (2006) [Pubmed]
  29. Sialidase activity of influenza A virus in an endocytic pathway enhances viral replication. Suzuki, T., Takahashi, T., Guo, C.T., Hidari, K.I., Miyamoto, D., Goto, H., Kawaoka, Y., Suzuki, Y. J. Virol. (2005) [Pubmed]
  30. Zanamivir for the treatment of influenza A and B infection in high-risk patients: a pooled analysis of randomized controlled trials. Lalezari, J., Campion, K., Keene, O., Silagy, C. Arch. Intern. Med. (2001) [Pubmed]
  31. Impact of zanamivir on antibiotic use for respiratory events following acute influenza in adolescents and adults. Kaiser, L., Keene, O.N., Hammond, J.M., Elliott, M., Hayden, F.G. Arch. Intern. Med. (2000) [Pubmed]
  32. Coadministration of orally inhaled zanamivir with inactivated trivalent influenza vaccine does not adversely affect the production of antihaemagglutinin antibodies in the serum of healthy volunteers. Webster, A., Boyce, M., Edmundson, S., Miller, I. Clinical pharmacokinetics. (1999) [Pubmed]
  33. Chemoprophylaxis of influenza A virus infections, with single doses of zanamivir, demonstrates that zanamivir is cleared slowly from the respiratory tract. Fenton, R.J., Morley, P.J., Owens, I.J., Gower, D., Parry, S., Crossman, L., Wong, T. Antimicrob. Agents Chemother. (1999) [Pubmed]
  34. Zanamivir: an update of its use in influenza. Cheer, S.M., Wagstaff, A.J. Drugs (2002) [Pubmed]
 
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