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Die Therapie der Influenza mit Neuraminidase-Inhibitoren

  • Sabine Leitzke
Chapter

Zusammenfassung

Influenza-Epidemien verursachen auch heute noch — trotz breit angelegter Impfkampagnen-jährlich weltweit Zehntausende von Todesfällen, insbesondere in den Risikogruppen der älteren oder immungeschwächten Menschen. Die zur Zeit als zugelassen verfügbaren Arzneimittel zur Prophylaxe bzw. Therapie sind Amantadin oder Rimantadin, bei deren Anwendung aber gravierende Probleme auftreten: keine Wirkung gegen Influenza B, schnelle Resistenzentwicklung und deutliche Nebenwirkungen. Dagegen zeigen gezielt entwickelte, gegen influenza-spezifische Neuraminidasen gerichtete Hemmstoffe wie das nur inhalativ anzuwendende Zanamivir und das auch oral verfügbare GS4071/GS4104 sowohl in vitro als auch in Tiermodellen und in experimentellen Humanstudien eine prophylaktische und therapeutische Wirksamkeit gegen Influenza A und B, gekoppelt mit einer geringen Nebenwirkungsrate. In Zellkulturmodellen sind gegen beide Substanzen resistente Influenza-Stämme aufgetreten, das Ausmaß der Resistenzentwicklung bei klinischer Anwendung der Neuraminidase-Inhibitoren ist aber noch ungeklärt. Der bisher erkennbar größte Nachteil der Neuraminidase-Inhibitoren besteht darin, daß die Therapie wie bei der Anwendung von Amantadin/Rimantadin innerhalb von 30 bis 48 Stunden nach Einsetzen der Symptome beginnen muß, was für den klinischen Alltag eher unrealistisch erscheint. Noch bleibt es gezielt angelegten klinischen Studien vorbehalten zu zeigen, ob Neuraminidase-Hemmstoffe, die bisher überwiegend nach experimentellen Daten beurteilt werden können, tatsächlich imstande sind, in den für die Influenza besonders empfänglichen Risikogruppen die Morbidität, den Krankheitsverlauf und die Mortalität bei prophylaktischer und therapeutischer Anwendung positiv zu beeinflussen.

Schlüsselwörter

Influenza-Chemoprophylaxe Influenza-Chemotherapie Neuraminidase-Hemm-stoffe 

The therapy of influenza with neuraminidase inhibitors

Summary

Despite wide-spread immunisation programs epidemic influenza continues to cause ten thousands of deaths worldwide, every year, especially in the high risk groups of elderly or immunocompromised persons. At present, amantadine and rimantadine are the only approved agents available for prophylactic and therapeutic use, yet, the deployment of these substances is problematic: neither of the two drugs is effective against influenza B, their use is accompanied by rapid development of viral resistance, and they show many adverse effects. In contrast, zanamivir and GS4071/GS4104 are rationally developed influenza-specific neuraminidase inhibitors, proving prophylactic and therapeutic efficacy against influenza A and B, as well in vitro as in animal models, and in experimental human studies. Zanamivir and GS4071/GS4104 are well tolerated without adverse reactions after topic and oral administration, respectively. Resistant viral strains have been found in cell culture in the presence of both drugs, but the frequency of resistance emergence during clinical use is unclear. To date, the biggest recognizable disadvantage of neuraminidase inhibitors and Amantadin/Rimantadin alike is that they need to be given within 30-48 h after onset of symptoms, but seeking medical attention at this stage of infection does not seem to be realistic in medical practice. As neuraminidase inhibitors up to now could mainly be assessed by experimental data, specifically performed clinical trials will have to prove the positive influence of these drugs on the morbidity, course of infection, and mortality of high risk persons when administered for prophylaxis as well as for therapy.

Key words

Influenza drug prevention Influenza drug therapy Neuraminidase inhibitors 

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Literatur

  1. 1.
    Cate TR (1987) Clinical manifestations and consequences of influenza. Am J Med 82:15–19.PubMedCrossRefGoogle Scholar
  2. 2.
    Wintermeyer SM, Nahata MC (1995) Rimantadine: a clinical perspective. Annals of Pharmacotherapy 29(3):299–310.PubMedGoogle Scholar
  3. 3.
    Hayden FG (1994) Amantidine and rimantadine resistance in influenza A viruses. Curr Opin Infect Dis 7:674–677.CrossRefGoogle Scholar
  4. 4.
    Belshe RB, Burk B, Newman F, Cerruti RL, Sim IS (1989) Resistance of influenza A virus to amantadine and rimantadine: results of one decade of surveillance. J Infect Dis 159:430–435.PubMedCrossRefGoogle Scholar
  5. 5.
    Colman PM (1994) Influenza virus neuraminidase: structure, antibodies, and inhibitors. Protein Sci 3 (10): 1687–1696.PubMedCrossRefGoogle Scholar
  6. 6.
    Schultz-Cherry S, Hinshaw VS (1996) Influenza virus neuraminidase activates latent transforming growth factor beta. J Virol 70 (12): 8624–8629.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Houde M, Arora DJ (1990) Stimulation of tumor necrosis factor secretion by purified influenza virus neuraminidase. Cell Immunol 129 (I): 104–111.PubMedCrossRefGoogle Scholar
  8. 8.
    Murphy BR, Kasel JA, Channock RM (1972) Association of serum anti-neuraminidase antibody with resistance to influenza in man. N Engl J Med 286 (25): 1329–1332.PubMedCrossRefGoogle Scholar
  9. 9.
    Webster RG, Reay PA, Laver WG (1988) Protection against lethal influenza with neuraminidase. Virology 164(I): 230–237.PubMedCrossRefGoogle Scholar
  10. 10.
    Colman PM, Varghese JN, Laver WG (1983) Structure of the catalytic and antigenic sites in influenza virus neuraminidase. Nature 303 (5912): 41–44.PubMedCrossRefGoogle Scholar
  11. 11.
    Meindl R Tuppy H (1969) 2-deoxy.2,3-dehy-droxialic acids I. Syntheses and properties of2-deoxy,3dehydro-N-acylneuraminic acids and their methyl esters. Monatsc Chem 100:1295–1306.CrossRefGoogle Scholar
  12. 12.
    Hart GJ, Bethell RC (1995) 2,3-didehydro-2,4-dideoxy-4-guanidino-N-acetyl-D-neurami-nic acid (4-guanidino-Neu5Ac2en) is a slow binding inhibitor of sialidase from both influenza A virus and influenza B virus. Biochem Mol Biol Int 36(4): 695–703.PubMedGoogle Scholar
  13. 13.
    Kim CU, Lew W, Williams MA, et al. (1997) Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc 119:681–690.PubMedCrossRefGoogle Scholar
  14. 14.
    Ryan DM Jicehurst J, Dempsey MH, etal. (1994) Inhibition of influenza virus replication in mice by GG167 (4-guanidino-2,4-dideoxy-2.3-dehydro-N-acetylneuraminic acid) is consistent with extracellular activity of viral neuraminidase (sialidase). Anti-microb Agents Chemother 38(10): 2270–2275.CrossRefGoogle Scholar
  15. 15.
    Efthymiopoulos C Barrington R Patel JA. (1994) Pharmacokinetics of the neuraminidase inhibitor 4-guanidino Neu5Ac2en (GG167) following intravenous, intranasal, and inhaled administration in man (abstract no. H70). 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society of Microbiology, Orlando: 265.Google Scholar
  16. 16.
    Li W, Escarpe PA, Eisenberg EJ, et al. (1998) Identification of GS4104 as an orally bio-available prodrug of the influenza virus neuraminidase inhibitor GS4071. Antimic-rob Agents Chemother 42(3): 647–653.Google Scholar
  17. 17.
    Wood ND, Aitken M, Sharp S, et al. (1997) Tole-rability and pharmacokinetics of the influenza neuraminidase inhibitor Ro-64-0802 (GS4071) following oral administration of the prodrug Ro-64-0796 (GS 4104) to healthy male volunteers (abstract no. A-123). 37th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, p25.Google Scholar
  18. 18.
    Hayden FG, Rollins BS (1997) In vitro activity of the neuraminidase inhibitor GS4071 against influenza viruses (abstract no. 159). Antiviral Res 34: A86.Google Scholar
  19. 19.
    Sidwell RW, Huffman JH, Barnard DL, etal. (1998) Inhibition of influenza virus infection in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor. Antiviral Res 37:107–120.PubMedCrossRefGoogle Scholar
  20. 20.
    Mendel DB Jai CY, Escarpe PA, et al. (1998) Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS4071 protects mice and ferrets against influenza infection. Antimicrob Agents Chemother 42(3): 640–646.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Hayden FG Jreanor JJ, Betts RF, et al. (1996) Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza. JAMA 275(4): 295–299.PubMedCrossRefGoogle Scholar
  22. 22.
    Hayden FG, Lobo M, Hussey EK, et al. (1996) Efficacy of intranasal GG167 in experimental human influenza A and B virus infection. In: Brown LE, Hampson AW, Webster RG (eds) Options for the control of influenza III. Elsevier Science, Amsterdam, pp 718–725.Google Scholar
  23. 23.
    Monto AS, Robinson DP, Herlocher ML et al. (1999) Zanamivir in the prevention of influenza among healthy adults: a randomized cotrolled trial. JAMA 282(1): 31–35.PubMedCrossRefGoogle Scholar
  24. 24.
    von Itzstein M, Wu WY, Kok GB, etal.(1993) Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 363 (6428): 418–423.CrossRefGoogle Scholar
  25. 25.
    Ryan DM Jicehurst J, Dempsey MH (1995) GG167(4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is a potent inhibitor of influenza virus in ferrets. Antimicrob Agents Chemother 39 (11): 2583–2584.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Hayden FG, Osterhaus ADVM Jreanor JJ, et al. (1997) Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza virus infection. N Engl J Med 337 (13): 874–879.PubMedCrossRefGoogle Scholar
  27. 27.
    The MIST Study Group (1998) Randomised trial of efficacy and safety of inhaled zanamivir in treatment of influenza A and B infections. Lancet 352:1877–1881.CrossRefGoogle Scholar
  28. 28.
    Read RC (1998) Treating influenza with zanamivir (comment). Lancet 352:1872–1873.PubMedCrossRefGoogle Scholar
  29. 29.
    Fleming DM (1999) Treating influenza with zanamivir (correspondence). Lancet 353: 669.Google Scholar
  30. 30.
    McKimm-Breschkin JL, Blick TJ, Sahasrabudhe A (1996) Influenza virus variants with decreased sensitivity to 4-amino-and 4-gua-nidino-Neu5Ac2en. In: Brown LE, Hampson AW, Webster RG (eds) Options for the control of influenza III. Elsevier Science, Amsterdam, pp 726–734.Google Scholar
  31. 31.
    Gubareva LV, Matrosovich MN, Brenner MK, et al. (im Druck) Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis.Google Scholar
  32. 32.
    Calfee DP, Hayden FG (1998) New approaches to Influenza chemotherapy. Drugs 56(4): 537–553.PubMedCrossRefGoogle Scholar
  33. 33.
    Couch RB (1997) A new antiviral agent for Influenza — is there a clinical niche? N Engl JMed337(13):927–928.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • Sabine Leitzke
    • 1
  1. 1.Bundesinstitut für Arzneimittel und MedizinprodukteBerlinDeutschland

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