Category:Anti-influenza agents: Difference between revisions
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The first effective anti-influenza medicine was [[wikipedia:Amantadine|amantadine]], synthesised in 1963 at DuPont as a candidate antiviral on the basis of its symmetric tricyclic structure and shown shortly afterwards to inhibit influenza A virus replication. The clinical mechanism was elucidated in the 1980s: amantadine blocks the M2 proton channel of the influenza A virion envelope, preventing the acidification of the viral interior that is required for uncoating after endocytosis. The medicine was active against influenza A only (influenza B has a structurally distinct M2-equivalent that amantadine does not bind), and its clinical use was limited by central-nervous-system adverse effects (insomnia, dizziness, in older adults occasional psychosis) and by the development of resistance through a single S31N substitution in the M2 channel. By the 2005-2006 season, essentially 100 percent of circulating H3N2 influenza A isolates carried the S31N mutation; the medicine has been retired from anti-influenza use since approximately 2008 and is now used principally for Parkinson's disease. | The first effective anti-influenza medicine was [[wikipedia:Amantadine|amantadine]], synthesised in 1963 at DuPont as a candidate antiviral on the basis of its symmetric tricyclic structure and shown shortly afterwards to inhibit influenza A virus replication. The clinical mechanism was elucidated in the 1980s: amantadine blocks the M2 proton channel of the influenza A virion envelope, preventing the acidification of the viral interior that is required for uncoating after endocytosis. The medicine was active against influenza A only (influenza B has a structurally distinct M2-equivalent that amantadine does not bind), and its clinical use was limited by central-nervous-system adverse effects (insomnia, dizziness, in older adults occasional psychosis) and by the development of resistance through a single S31N substitution in the M2 channel. By the 2005-2006 season, essentially 100 percent of circulating H3N2 influenza A isolates carried the S31N mutation; the medicine has been retired from anti-influenza use since approximately 2008 and is now used principally for Parkinson's disease. | ||
The transformative event of contemporary anti-influenza pharmacology was the development of the neuraminidase inhibitors. The viral neuraminidase, an enzyme on the influenza envelope that cleaves sialic acid residues from cell-surface glycoproteins and so allows release of newly synthesised virions from infected cells, was identified in the 1950s and crystallised in 1983 by [[wikipedia:Peter Colman|Peter Colman]] at the CSIRO in Melbourne, Australia. Colman's group, working with the GlaxoWellcome team led by Mark von Itzstein, used the crystal-structure-derived knowledge of the active site to design [[wikipedia:Zanamivir|zanamivir]] (Relenza, GlaxoWellcome 1999), the first structure-based | The transformative event of contemporary anti-influenza pharmacology was the development of the neuraminidase inhibitors. The viral neuraminidase, an enzyme on the influenza envelope that cleaves sialic acid residues from cell-surface glycoproteins and so allows release of newly synthesised virions from infected cells, was identified in the 1950s and crystallised in 1983 by [[wikipedia:Peter Colman|Peter Colman]] at the CSIRO in Melbourne, Australia. Colman's group, working with the GlaxoWellcome team led by Mark von Itzstein, used the crystal-structure-derived knowledge of the active site to design [[wikipedia:Zanamivir|zanamivir]] (Relenza, GlaxoWellcome 1999), the first structure-based-design success in antiviral pharmacology.<ref name="vonitzstein1993">von Itzstein M, Wu WY, Kok GB, Pegg MS, Dyason JC, Jin B, Phan TV, Smythe ML, White HF, Oliver SW, et al. Rational design of potent sialidase-based inhibitors of influenza virus replication. ''Nature''. 1993 Jun 3;363(6428):418-423. PMID 8502295.</ref> Zanamivir's poor oral bioavailability restricted it to inhalation; [[Oseltamivir|oseltamivir]] (Tamiflu, Gilead/Roche 1999), an oral prodrug whose active metabolite oseltamivir carboxylate binds the same active site, became the standard oral anti-influenza medicine. The intravenous [[wikipedia:Peramivir|peramivir]] (Rapivab, BioCryst 2014) and the inhaled long-acting [[wikipedia:Laninamivir|laninamivir]] (Inavir, Japan 2010) extended the class. The neuraminidase inhibitors are active against both influenza A and B, with substantially lower clinically meaningful resistance than the M2 inhibitors (resistance is reported but has not become epidemic to the extent of M2 resistance). | ||
The clinical effect of neuraminidase inhibitors in influenza is meaningful but modest. In immunocompetent adults treated within 48 hours of symptom onset, oseltamivir reduces symptom duration by approximately one day and reduces the rate of secondary lower-respiratory complications and antibacterial prescription; the absolute benefit is larger in high-risk populations (the elderly, the immunocompromised, pregnant women, those with chronic cardiopulmonary disease) and in severe disease requiring hospitalisation, where intravenous oseltamivir or peramivir may reduce mortality. The 2014 publication of the Cochrane review of the oseltamivir trial data (after a multi-year effort to obtain the full clinical-study reports from Roche) re-evaluated the medicine's benefit downward; the response from the influenza-clinical community has been that the Cochrane analysis underweighted the high-risk-population benefit and that the medicine retains an important role in selected patients. | The clinical effect of neuraminidase inhibitors in influenza is meaningful but modest. In immunocompetent adults treated within 48 hours of symptom onset, oseltamivir reduces symptom duration by approximately one day and reduces the rate of secondary lower-respiratory complications and antibacterial prescription; the absolute benefit is larger in high-risk populations (the elderly, the immunocompromised, pregnant women, those with chronic cardiopulmonary disease) and in severe disease requiring hospitalisation, where intravenous oseltamivir or peramivir may reduce mortality. The 2014 publication of the Cochrane review of the oseltamivir trial data (after a multi-year effort to obtain the full clinical-study reports from Roche) re-evaluated the medicine's benefit downward; the response from the influenza-clinical community has been that the Cochrane analysis underweighted the high-risk-population benefit and that the medicine retains an important role in selected patients. | ||