Molecular structure of zanamivir
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Zanamivir is a neuraminidase inhibitor used in the treatment of and prophylaxis of both influenza A and influenza B. Zanamivir was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline under the trade name Relenza®. more...

Zoledronic acid


Zanamivir was discovered in 1989 by scientists at the Australian biotechnology company Biota Holdings, working in conjunction with the CSIRO and the Victorian College of Pharmacy. The development was part of Biota's ongoing program to develop antiviral agents through rational drug design. An outline of the successful rational design strategy used was published in a paper in Nature (von Itzstein et al., 1993).

The strategy relied on the availability of the crystal structure of influenza neuraminidase which was achieved by x-ray crystallography. It was known as far back as 1974 that 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA), a sialic acid analogue, was an inhibitor of neuraminidase (Meindl et al., 1974). Using the crystal structure of neuraminidase and DANA as a starting point, the researchers employed a computer-aided process to attempt to design a molecule which better fitted (and therefore inhibited) the active site of neuraminidase. Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.

In 1990, zanamivir was licensed to Glaxo (now GlaxoSmithKline) for exclusive worldwide development and marketing. In 1999, the product was approved for marketing in the US and subsequently has been registered by GSK in a total of 70 countries.


Whilst zanamivir proved to be a potent and effective inhibitor of influenza neuraminidase and inhibitor of influenza virus replication in vitro and in vivo, this didn't necessarily translate into a successful clinical treatment for influenza. In clinical trials it was found that zanamivir was able to reduce the time to symptom resolution by 1.5 days provided therapy was started within 48 hours of the onset of symptoms.

A further limitation concerns the poor oral bioavailability of zanamivir. This meant that oral dosing was impossible limiting dosing to the parenteral routes. Zanamivir, therefore, is administered by inhalation - a route that was chosen for patient compliance with therapy. But even this route of administration is not acceptable to many in the community.

A troubled commercial venture

Biota, being only a small company, was not able to bring the drug to market by itself. Consequently, it was licensed to Glaxo (now GlaxoSmithKline) to complete development and to market internationally as Relenza, delivered via Glaxo's proprietary, and some would say cumbersome, Diskhaler inhalation device. The license agreement entitled Biota to receive a 7% royalty on Glaxo's sales of Relenza.

A combination of factors has resulted in the limited commercial success of zanamivir (Relenza). The relatively small effect on the timecourse of influenza symptoms, the inhalation dosage form, a less-than-ideal device, and high expense make it a difficult product to market well. And although zanamivir was the first neuraminidase inhibitor to the market, it had only a few months lead over the second entrant, oseltamivir (Tamiflu), with an oral formulation much preferred by patients. Faced with this competition, GSK effectively abandoned the product.


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Zanamivir, influenza, and meningococcal disease - Statistical Data Included - Letter to the Editor
From British Medical Journal, 2/5/00 by Stephen T Green

Zanamivir may help to fight potential flu epidemic

EDITOR--The zanamivir issue described by Yamey in his news article[1] and the whole subject of treating influenza have ramifications apart from the potential expense to the British taxpayer (who can easily turn into a patient).

I am keen on any development that might help to reduce the burden of disease in hospital wards. If I were asked to state which single condition will fill up my inpatient beds and send healthcare staff home ill most efficiently, I would always choose influenza. Although it is true that influenza is often a mild illness, its association with the development of potentially lethal sequelae is well recognised. It has been described as the best known model of bacterial-viral coinfection.[2] Influenza is a powerful predisposing factor for invasive meningococcal disease[3] one of the few bacterial conditions still regularly killing otherwise normal healthy young people in the United Kingdom. Hubert et al have stated that when an epidemic of influenza-like syndrome is identified, medical practitioners should be informed of the likelihood of mi increased incidence and severity of meningococcal disease.[4] We cannot currently vaccinate against Neisseria meningitidis type B. Zanamivir has the potential to be useful here. This certainly needs further investigation.

Influenza epidemics result in increased hospital admission rates for bacterial pneumonia,[2] and I have come across many patients who have known the pain and misery of having to have chest drains inserted for the drainage of empyemas as a consequence of having suffered a bout of "not very serious" influenza.

The zanamivir issue merits a broader debate, which should not centre exclusively upon whether or not it will be a helpful agent for groups at high risk. At a recent meeting in Geneva, to mark the 50th anniversary of WHO influenza surveillance, the Director General, Gro Harlem Brundtland, said that, "time to react may be very short--from the first recognition of a new subtype and the onset of a full-blown pandemic, it may be too short to prepare a vaccine and to use it."[5]

We have time to plan now but may not later. Like the little Dutch boy, we may need a finger to stick in the dyke to stop everyone drowning--perhaps zanamivir and similar drugs are that finger.

Stephen T Green consultant physician in infectious diseases and tropical medicine

Royal Hallamshire Hospital, Sheffield S10 2JF

Competing interest: STG has received fees for lecturing from GlaxoWellcome.

[1] Yamey G. NICE to rule on influenza drug zanamivir. BMJ 1999:319;937. (9 October.)

[2] Floret D. Virus-bacteria co-infections. Arch Pediatr 1997;4:1119-24.

[3] Stuart JM, Cartwright K, Andrews NJ. Respiratory syncytial virus infection and meningococcal disease. Epidemiol Infect 1996;117:107-11.

[4] Hubert B, Watier L, Garnerin P, Richardson S. Meningococcal disease and influenza-like syndrome: a new approach to an old question. J Infect Dis 1992;166:542-5.

[5] World Health Organisation. 50 years of influenza surveillance: much still to do to stop a common killer. Geneva: WHO, 1990. (Press release WHO/11.)

NHS regulations are of questionable legality

EDITOR--As Yamey points out in his news article, the National Institute for Clinical Excellence considers that zanamivir (Relenza) is not cost effective and so will very closely monitor its use by doctors in NHS practice.[1] In reality this is a total ban, enforced by threat rather than by legislation. Since general practitioners are not permitted to provide any drug or treatment privately to their NHS patients I wonder what sort of service our patients will receive when this philosophy is taken to its logical conclusion and doctors are required to pay for all the treatments their patients need under the NHS conditions and terms of their service. This is the logical end point of the many recent primary care initiatives.

It may be appropriate to restrict NHS funding for sildenafil (Viagra) as a lifestyle drug, but zanamivir seems to be a potentially lifesaving treatment that might benefit most of the UK's population, particularly when the next influenza epidemic arrives.

All members of our society supposedly have access to free NHS medical care, but this provision is now overtly rationed, and a large number of treatments are simply not available owing to lack of funds. The moderately wealthy, including politicians, can afford medical insurance with instant access to specialist care in sumptuous surroundings. NHS rationing, however, applies to the productive majority of Middle England who are in work but who do not have, or cannot afford, medical insurance or a consultant's private fees. These are the very patients who might wish to pay their doctor a reasonable fee for the many procedures or drugs that the state is no longer prepared to provide for them. They already subsidise the NHS, paying 5.90 [pounds sterling] per item in prescription charges, and they may wish to purchase zanamivir directly from me if it only meant fewer very costly days off work owing to sickness. This is an option apparently denied to them.[2]

I have not abandoned the medical ethic. I believe a doctor's duty is to treat each of his or her patients to the best of his or her ability, and so he or she can take no part in rationing decisions, including the management of the local NHS primary care group. I also consider the prohibition of effective medical treatments to be morally as unacceptable as the Poor Laws of the nineteenth century. It echoes the ethics of an internment camp.

It may even be illegal.

P D Thomas general practitioner and dispensing doctor Gipping Valley Practice, Barham, Suffolk IP6 0AS Competing interest: None declared.

[1] Yamey G. NICE to rule on influenza drug zanamivir. BMJ 1999:319;937. (9 October.)

[2] Thomas PD. NHS Regulations deny patients cheap drugs. BMJ 1993;306:1748-9.

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