|
|
| Line 1: |
Line 1: |
| {{drugbox | | __NOTOC__ |
| | IUPAC_name = 5-acetamido-4-guanidino-6-(1,2,3-trihydroxypropyl)-<br />5,6-dihydro-4''H''-pyran-2-carboxylic acid
| | {{Zanamivir}} |
| | image = Zanamivir.png
| | {{CMG}} |
| | CAS_number = 139110-80-8
| | |
| | ATC_prefix = J05
| | ==Overview== |
| | ATC_suffix = AH01
| |
| | ATC_supplemental =
| |
| | PubChem = 60855
| |
| | DrugBank = APRD00378
| |
| | C=12 | H=20 | N=4 | O=7
| |
| | molecular_weight = 332.31 g/mol
| |
| | bioavailability = 2% (oral)
| |
| | protein_bound = <10%
| |
| | metabolism = Negligible
| |
| | elimination_half-life = 2.5–5.1 hours
| |
| | excretion = Renal
| |
| | pregnancy_category = B1 ([[Australia|Au]])
| |
| | legal_status = S4 <small>(Au)</small>, POM <small>([[United Kingdom|UK]])</small>, ℞-only <small>(U.S.)</small>
| |
| | routes_of_administration = Inhalation
| |
| }}
| |
| '''Zanamivir''' ([[International Nonproprietary Name|INN]]) ([[International Phonetic Alphabet|IPA]]: {{IPA|[zəˈnæmɪvir]}}) 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'''. '''Relenza''' is the only type of '''Zanamivir'''. | | '''Zanamivir''' ([[International Nonproprietary Name|INN]]) ([[International Phonetic Alphabet|IPA]]: {{IPA|[zəˈnæmɪvir]}}) 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'''. '''Relenza''' is the only type of '''Zanamivir'''. |
|
| |
|
| ==Development== | | ==Category== |
| 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]]. The discovery was funded initially by the Australian biotechnology company [[Biota Holdings|Biota]] and was part of Biota's ongoing program to develop antiviral agents through [[rational drug design]].
| | Antiviral |
| | |
| 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.<ref name="Meindl1974">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</ref> 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 was a better fit for (and therefore inhibited) the active site of neuraminidase. Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.<ref name="vonItzstein1993">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</ref>
| |
| | |
| 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.
| |
|
| |
|
| ==Limitations== | | ==US Brand Names== |
| 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.
| | RELENZA<sup>®</sup> |
|
| |
|
| 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 this route of administration is not acceptable to many in the community.
| | ==FDA Package Insert== |
| | '''[[Zanamivir description|Description]]''' |
| | '''| [[Zanamivir clinical pharmacology|Clinical Pharmacology]]''' |
| | '''| [[Zanamivir microbiology|Microbiology]]''' |
| | '''| [[Zanamivir indications and usage|Indications and Usage]]''' |
| | '''| [[Zanamivir contraindications|Contraindications]]''' |
| | '''| [[Zanamivir warnings and precautions|Warnings and Precautions]]''' |
| | '''| [[Zanamivir adverse reactions|Adverse Reactions]]''' |
| | '''| [[Zanamivir overdosage|Overdosage]]''' |
| | '''| [[Zanamivir clinical studies|Clinical Studies]]''' |
| | '''| [[Zanamivir dosage and administration|Dosage and Administration]]''' |
| | '''| [[Zanamivir compatibility reconstitution and stability|Compatibility, Reconstitution, and Stability]]''' |
| | '''| [[Zanamivir directions for use|Directions For Use]]''' |
| | '''| [[Zanamivir how supplied|How Supplied]]''' |
| | '''| [[Zanamivir labels and packages|Labels and Packages]]''' |
|
| |
|
| The FDA has issued a Public Health Advisory warning that it has received 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. <ref name="fda"> http://www.fda.gov/cder/drug/advisory/influenza.htm FDA Advisory: Safe and appropriate use of Influenza drugs</ref>
| | ==Mechanism of Action== |
| | |
| ==Commercial difficulties== | |
| [[Biota Holdings|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 [[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 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 is of the opinion that Glaxo's reduced marketing of Relenza is a breach of contract, a charge Glaxo denies. Legal proceedings are ongoing.
| |
| | |
| ==Developments from zanamivir== | |
| Zanamivir was the first of the [[neuraminidase inhibitor]]s. 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).
| |
|
| |
|
| ==References== | | ==References== |
| <div class="references-small">{{reflist|2}}</div>
| | {{Reflist|2}} |
| | |
| ==Zanamivir in popular culture==
| |
| A pop song describing zanamivir's role in developing the class of [[neuraminidase inhibitor]]s and somewhat critical of Glaxo's marketing of the drug was written by mantisongs.com.
| |
| | |
| ==External links==
| |
| * [http://www.omedon.co.uk/influenza/ The development of Relenza for treatment of influenza]
| |
| * [http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/500004.html Medlineplus drug information for zanamivir]
| |
| * [http://www.fda.gov/cder/news/relenza/default.htm FDA information page for Relenza]
| |
| * [http://www.biota.com.au/?page=1021002&subpage=1021104 Relenza [[Biota Holdings]]]
| |
| | |
| {{Antivirals}}
| |
| {{Influenza}}
| |
| [[Category:Guanidines]]
| |
| [[Category:Influenza]]
| |
| [[Category:Neuraminidase inhibitors]]
| |
| | |
| [[de:Zanamivir]]
| |
| [[fr:Zanamivir]]
| |
| [[ja:ザナミビル]]
| |
| [[th:ซานามิเวียร์]]
| |
| {{WikiDoc Help Menu}}
| |
| | |
|
| |
|
| {{WikiDoc Sources}}
| | [[Category:Antibiotics]] |
| | [[Category:Wikinfect]] |