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• W4249757706 abstract "Relenza is a new anti-flu ‘designer’ drug, which is being trumpeted by its manufacturers — the pharmaceutical giant Glaxo Wellcome — as the first breakthrough in flu treatment for 30 years. Zanamivir, GG167 or 4-guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid. In other words, it's an unsaturated analogue of sialic acid with a guanidino group substituting for the hydroxyl group at position 4. It blocks the action of the enzyme neuraminidase (also called sialidase) on the surface of types A and B influenza viruses, preventing them from spreading to other cells. Influenza viruses bind to sialic acids on the surface of host cells through the viral haemagglutinin glycoprotein. The haemagglutinin causes the virus envelope to fuse with the membrane of the endosome, allowing the virus ribonucleprotein (RNP) into the cytoplasm. The RNP complex then moves to the nucleus for transcription and amplification. Newly formed virus RNPs leave the nucleus and then virus particles bud from the cell at the plasma membrane. Normally, neuraminidase ‘untethers’ newly assembled virus particles bound to sialic acid on the surface of the cell and on the glycoproteins of other virus particles, but neuraminidase inhibitors can block virus spread at this stage. In cultured cells, virus aggregates can be seen at the cell surface when Relenza is present (see Figure). Work on neuraminidase inhibitors began in the mid-1970s but it was only after work on the structure of the neuraminidase — carried out in the early 1980s in Australia — that the inhibitors began to be refined by researchers at the CSIRO and Monash University. Relenza was found to be the most effective of several candidates; its guanidino group was selected to fit into a pocket in the neuraminidase that has two glutamate groups at the bottom. The initial work had been partly funded by the Australian company Biota, and in 1989 Glaxo Wellcome did a deal with Biota to fund research and bring any product to market. Biota receives royalties on sales of the drug. Relenza is marketed in Australia and New Zealand and has been approved in the EU, the US and in Switzerland. The drug has been recently submitted for approval in Japan. But flu sufferers in the UK will have to wait for Relenza, unless they're private patients; it has recently been at the centre of a stand-off between Glaxo Wellcome and the UK government, which has refused permission for it to be prescribed within the National Health Service (NHS). Strong sales of Relenza might help restore the fortunes of Glaxo Wellcome, which has seen falling profits since the patent expired on its money-spinning ulcer drug, Zantac, two years ago. The drug is highly effective in animal models, decreasing fever and virus-shedding in mice and ferrets infected with influenza. In human trials, the drug (an aerosol spray) cut the severity of flu symptons by 44% and reduced recovery time by about one third. The elderly are at most risk from flu-related death but the efficacy of Relenza within this group has yet to be demonstrated convincingly. There were only 70 elderly patients among the 6,000 in the Relenza clinical trials, which is why the UK government is not yet prepared to allow prescription on the NHS. Glaxo Wellcome will be running more trials on older patients this winter. Yes, several. Gilead and Hoffmann-La Roche have a compound GS4104, marketed as Tamiflu, which can be taken by mouth. It is not active in itself but in the body is converted to GS4071, a neuraminidase inhibitor. Tamiflu is approved in Switzerland and is likely to be licensed later this year in the US and Canada. J McCauley, Institute for Animal Health, Compton, Newbury, Berkshire RG20 7NN, UK." @default.
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• W4249757706 title "Relenza" @default.
• W4249757706 doi "https://doi.org/10.1016/s0960-9822(99)80491-6" @default.
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