Zanamivir
From Wikipedia, the free encyclopedia
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Zanamivir
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| Systematic (IUPAC) name | |
| (2R,3R,4S)- 4-[(diaminomethylidene)amino]- 3-acetamido- 2-[(1R,2R)- 1,2,3-trihydroxypropyl]- 3,4-dihydro- 2H-pyran- 6-carboxylic acid | |
| Identifiers | |
| CAS number | |
| ATC code | J05 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C12H20N4O7 |
| Mol. mass | 332.31 g/mol |
| Synonyms | 5-acetamido- 4-guanidino- 6-(1,2,3-trihydroxypropyl)- 5,6-dihydro- 4H-pyran- 2-carboxylic acid |
| Pharmacokinetic data | |
| Bioavailability | 2% (oral) |
| Protein binding | <10% |
| Metabolism | Negligible |
| Half life | 2.5–5.1 hours |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status |
S4 (Au), POM (UK), ℞-only (U.S.) |
| Routes | Inhalation |
Zanamivir (INN) (pronounced /zəˈnæmɨvɪr/) is a neuraminidase inhibitor used in the treatment of and prophylaxis of both Influenzavirus A and Influenzavirus B. Zanamivir was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline under the trade name Relenza.
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[edit] Development
[edit] Introduction
Relenza was discovered in 1989, and is a neuraminidase inhibitor medication designed to treat Influenza virus A and Influenza virus B. Relenza is the commercial name and only type of zanamivir, and was the first neuraminidase inhibitor commercially developed. It is currently marketed by GlaxoSmithKline.
Relenza was developed by a team of scientists at the Victorian College of Pharmacy at Monash University in Melbourne, Australia. The team was led by Mark von Itzstein in association with the CSIRO. Zanamivir's discovery was a part of the Australian biotechnology company Biota's project to develop antiviral agents via rational drug design.
Both Influenza A and B cause illness. However, Influenza A is the more virulent strain. Influenza A is responsible for both the common ‘seasonal flu’ and notable influenza pandemics such as the Spanish flu (1918), while the Influenza virus B does not cause pandemics. Between 1990 to 2000, there were nine significant outbreaks of influenza A, causing many deaths in England and Wales, whereas only four outbreaks of influenza B occurred.[citation needed]
The approval of Relenza in the United States was controversial. In 1999 a Food and Drug Administration (FDA) advisory committee voted 13 to 4 not to approve the drug because of limited data on efficacy and safety concerns. The drug was approved later in 1999.[1]
[edit] Background
Influenza, commonly known as the flu, is caused by a virus which targets the body's respiratory cells and damages the lining of the respiratory tract, leading to swelling and inflammation of the tract. Influenza spreads rapidly by replicating itself inside the host cell, producing hundreds of copies of the virus in a short period. In approximately an hour the virus can destroy the host cell and propel its replications out into the body to find new host cells. For some people, the flu and its complications can be very serious, even fatal.
Relenza is a part of a range of neuraminidase inhibitor medications. This medication was designed to attack the infected host cells, preventing the virus from spreading throughout other cells in the body and thus reducing the amount of time the virus can survive.
[edit] Influenza A
Influenza A, the seasonal flu, is the common infection which usually outbreaks in the winter months. Typically, the flu is caused when viral particles are transferred between people. Common symptoms include fever, cough, headache, fatigue, body aches, and sore throat. These symptoms may last longer than those of a cold, sometimes for weeks. The most common way to catch the flu is directly from another person. Coughing and sneezing send droplets containing these viral particles from the mouth and nose into the air. If these flu-infected droplets are inhaled by another person, that person may become infected. Another way in which the flu may be caught is by touching something an infected person has transferred these pathogens onto, by sneezing or coughing on the object and a non infected person then touching it.
The reason influenza spreads so rapidly is because a person may be contagious yet show no symptom and thus not know they are infected with the virus and unaware they are spreading it. A person can be contagious for about a week.
[edit] Influenza B
Influenza B has a more complicated presence than Influenza A. In 2008 there were two distinct lineages of influenza B that caused disease (Victoria and Yamagata lineage). These two genetically distinct lineages have caused disease for approximately a dozen years. In any year either the Victoria or the Yamagata lineage may predominate in a particular geographical area.
[edit] Discovery of zanamivir
Zanamivir was discovered in 1989 by scientists led by Mark von Itzstein, at the Victorian College of Pharmacy, Monash University, in collaboration with the CSIRO and scientists at Glaxo, UK. The discovery was funded initially by the Australian biotechnology company Biota and was part of Biota's ongoing program to develop antiviral agents through rational drug design.
That strategy relied on the availability of the structure of influenza neuraminidase, by X-ray crystallography. It was also 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.[2] Sialic acid (N-acetyl neuraminic acid, NANA), the substrate of neuraminidase, is itself a mild inhibitor of the enzyme, but the dehydrated derivative DANA, a transition-state analogue, is a better inhibitor. Computational chemistry techniques were used to probe the active site of the enzyme, in an attempt to design derivatives of DANA that would bind tightly to the aminoacid residues of the catalytic site, and so would be potent and specific inhibitors of the enzyme. The software GRID from Molecular Discovery was used to determine energetically favourable interactions between various functional groups and residues in the catalytic site canyon. This showed there was a negatively charged zone in the neuraminidase active site that aligned with the C4 hydroxyl group of DANA. This hydroxyl was therefore replaced with a positively charged amino group; the 4-amino DANA was 100 times better an inhibitor than DANA, owing to the formation of a salt bridge with a conserved glutamic acid (119) in the active site. It was also noticed that Glu 119 was at the bottom of a conserved pocket in the active site just big enough to accommodate a more basic functional positively charged group, such as a guanidino group, which was also larger than the amino group.(Professor Graeme Laver,2007). Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.[3]
[edit] Limitations
Zanamivir proved to be a potent and effective inhibitor of influenza neuraminidase. It works by binding to the active site of the neuraminidase protein, rendering the influenza virus unable to escape its host cell and infect others (David Cyranoski, 2005). It is also an inhibitor of influenza virus replication in vitro and in vivo. In clinical trials it was found that zanamivir was able to reduce the time to symptom resolution by 1.5 days if therapy was started within 48 hours of the onset of symptoms.
Relenza is a safe and effective treatment for influenza, but must be administered soon after the first symptoms appear. Six to 18 hours is ideal. In most countries the drug can only be obtained with a doctor's prescription, and usually the time taken to get a prescription renders them ineffective (Professor Graeme Laver,2007).
A further limitation is the poor oral bioavailability of zanamivir. This means that oral dosing is ineffective, limiting dosing to the inhaled route. This restricts its usage, as treating asthmatics could induce bronchospasm (F.G. Hayden, 2001). The FDA has issued a Public Health Advisory warning that it has received some reports of respiratory problems following inhalation of Relenza by patients with underlying asthma or chronic obstructive pulmonary disease. The Relenza package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease. [4]
Zanamivir is specific to the influenza virus, has not been known to cause toxic effects, and does not spread around through the body's systemic circulation. It also shows no signs of viral resistance. However, due to a lack of reports or evidence about its toxicity, the FDA does not license it for use in children under 7 years of age.
Most patients prefer taking an oral dosage over inhalation,[citation needed] zanamivir never attained a high popularity, as opposed to oseltamivir that can be taken orally.
Bulk orders of Tamiflu from the United Kingdom, France and other countries to cover 20% or more of their population are pushing Roche's production capacity to the limit. But Relenza, which was the first neuraminidase inhibitor on the market, claims only one percent of the growing flu drug market. The drug has suffered from lackadaisical marketing efforts, according to a lawsuit that Biota, which gets a percentage of sales, brought against GlaxoSmithKline (David Cyranoski, 2005).
Relenza is at least as effective as Tamiflu and has fewer side effects. Adverse events with Tamiflu include nausea, vomiting and headaches, according to an article published 13 August (Lancet 366, 533−534; 2005). The report, based on data compiled from the companies' clinical trials and from subsequent studies, also says there is no evidence of resistance to Relenza, compared with resistance levels of up to 18% in those taking Tamiflu (Lancet 364, 759−765; 2004). The researchers recommend stockpiling both (David Cyranoski, 2005). Tamiflu-resistant strains have also appeared in the European Union, which remain sensitive to Relenza.[5][6]
[edit] Commercial issues
Biota, being only a small company, was not able to bring zanamivir to market by itself. In 1990, zanamivir patent rights were licensed to Glaxo, now GlaxoSmithKline (GSK). In 1999, the product was approved for marketing in the USA and subsequently has been registered by GSK in a total of 70 countries (GlaxoSmithKline News release, 2006). Relenza is delivered via Glaxo's proprietary 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 time course 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 tablet formulation much preferred by patients and physicians.
When first marketed in the USA in 1999/00, Relenza captured only 25% of the influenza anti-viral market, despite a huge promotional campaign. By the end of that season, Tamiflu was outselling Relenza 3:1. During that season, Relenza experienced worldwide safety warnings involving the risk of bronchospasm and death. Glaxo then reduced the marketing of Relenza, and Tamiflu's dominance increased. More than US$20m worth of Relenza sold by Glaxo in the first US season was returned to the company in the next two seasons because Relenza's actual sales to patients were far less than expected, highlighting the fact that the results of the first season were even worse than first thought.
Biota commenced legal proceedings in 2004 alleging that Glaxo's reduced marketing of Relenza was a breach of contract, a charge Glaxo denied. Biota claimed approximately A$700m from Glaxo. After Biota spent four years trying to progress its case, and incurring A$50m in legal costs, the company abandoned the claim in July 2008, recovering only A$20m including legal costs following settlement at mediation. Embarrassingly for Biota's management, it transpired that Biota had refused an earlier tactical offer from Glaxo of A$75m plus legal costs.
Tamiflu, Relenza’s main competitor, was proven in 2006[citation needed] not to be as effective at treating the Influenza viruses as Relenza.
In August 2006, Germany announced that it would buy 1.7 million doses of Relenza, as part of its preparation strategy against bird flu. "Germany's purchase shows that countries are starting to take a balanced view of influenza preparedness," says Simon Tucker, head of research at Melbourne-based Biota, where Relenza was originally developed (David Cyranoski, 2005).
In April 2009 many cases of swine flu (H1N1 type virus) have been reported in USA and Mexico. Zanamavir is one of only two drugs that are prescribed to treat it.
A study published in the June 2009 issue of Nature Biotechnology emphasized the urgent need for augmentation of oseltamivir (Tamiflu) stockpiles, with additional antiviral drugs including zanamivir (Relenza), based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 swine flu neuraminidase (NA) were to acquire the Tamiflu-resistance (His274Tyr) mutation which is currently widespread in seasonal H1N1 strains.[7]
[edit] Developments from zanamivir
Zanamivir was the first of the neuraminidase inhibitors. Despite the limited commercial success of this drug, the work and strategies employed in the development of zanamivir were important first-steps in the development of further members of this class including oseltamivir and the candidate drug RWJ-270201 (Phase I trials).
As a proven anti-influenza drug target, neuraminidase continues to be attractive for the development of new inhibitors. The crystal structure of H5N1 avian influenza neuraminidase (PDB code: 2HTY) provides the three-dimensional structural information and opportunity for finding new inhibitors in this regard, because the existing inhibitors, such as oseltamivir and zanamivir, were developed based on different structures of neuraminidase, such as subtypes N9, N2, and type B genus of influenza virus. Recently, the reported oseltamivir-resistance H5N1 virus neuraminidase still retaining susceptibility to zanamivir indicates that the structure of zanamivir has some more advantages than oseltamivir in binding to the active pocket of H5N1 neuraminidase.(Qi-Shi Du, Shu-Qing Wang and Kuo-Chen Chou, 2007)[5][6]
[edit] Footnotes
- ^ Willman D. (2000). NEW FDA: Relenza Official Asks If One Day Less of Flu Is Worth It. LA Times.
- ^ Meindl P, Bodo G, Palese P, Schulman J, Tuppy H. Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid. Virology 1974;58(2):457-463. PMID 4362431
- ^ von Itzstein M, Wu W-Y, Kok GB, Pegg MS, Dyason JC, Jin B, et al. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature 1993;363(6428):418-423. PMID 8502295
- ^ http://www.fda.gov/cder/drug/advisory/influenza.htm FDA Advisory: Safe and appropriate use of Influenza drugs
- ^ a b Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ, Gamblin SJ. (2008). "Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants". Nature 453: 1258. doi:.
- ^ a b Garcia-Sosa AT, Sild S, Maran U. (2008). "Design of Multi-Binding-Site Inhibitors, Ligand Efficiency, and Consensus Screening of Avian Influenza H5N1 Wild-Type Neuraminidase and of the Oseltamivir-Resistant H274Y Variant". J. Chem. Inf. Model. 48 (10): 2074–2080. doi:. PMID 18847186.
- ^ Venkataramanan Soundararajan, Kannan Tharakaraman, Rahul Raman, S. Raguram, Zachary Shriver, V. Sasisekharan, Ram Sasisekharan (9 June 2009). "Extrapolating from sequence — the 2009 H1N1 'swine' influenza virus". Nature Biotechnology 27 (6). doi:. http://www.nature.com/nbt/journal/v27/n6/full/nbt0609-510.html.
[edit] References
- Venkataramanan Soundararajan, Kannan Tharakaraman, Rahul Raman, S. Raguram, Zachary Shriver, V. Sasisekharan, Ram Sasisekharan, Extrapolating from sequence — the 2009 H1N1 'swine' influenza virus, Nature Biotechnology 27(6), 510-513, June 2009.
- F.G. Hayden, Perspectives on antiviral use during pandemic influenza, Philos. Trans. R. Soc. Lond. B. Biol. Sci. 356 (2001), pp. 1877–1884.
- Qi-Shi Du, Shu-Qing Wang and Kuo-Chen Chou, Analogue inhibitors by modifying oseltamivir based on the crystal neuraminidase structure for treating drug-resistant H5N1 virus, Biochemical and Biophysical Research Communications, Volume 362, Issue 2, Pages 525-531, 19 October 2007
- David Cyranoski, Threat of pandemic brings flu drug back to life,Nature Medicine, Volume 11, doi:10.103831, pages 905-909, August 2005 <http://www.nature.com/nm/journal/v11/n9/full/nm0905-909.html>
- Professor Graeme Laver,Flu drugs - pathway to discovery, Education in Chemistry, March 2007 <http://www.rsc.org/Education/EiC/issues/2007March/FluDrugsPathwayDiscovery.asp>
[edit] External links
- The development of Relenza for treatment of influenza
- Medlineplus drug information for zanamivir
- FDA information page for Relenza
- Relenza Biota Holdings
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