Revision as of 01:17, 9 April 2011 editCheMoBot (talk | contribs)Bots141,565 edits Updating {{drugbox}} (changes to verified and watched fields - updated '') per Chem/Drugbox validation (report errors or bugs)← Previous edit |
Latest revision as of 13:03, 22 July 2024 edit undoTamunro (talk | contribs)Extended confirmed users929 editsm →History: corrected grammarTag: Visual edit |
(255 intermediate revisions by 94 users not shown) |
Line 1: |
Line 1: |
|
|
{{Short description|Influenza medication}} |
|
|
{{Use dmy dates|date=October 2022}} |
|
{{Drugbox |
|
{{Drugbox |
|
| Verifiedfields = changed |
|
|
| Watchedfields = changed |
|
| Watchedfields = changed |
|
| verifiedrevid = 402888085 |
|
| verifiedrevid = 470635535 |
|
|
| image = Zanamivir structure.svg |
|
| IUPAC_name = (2R,3R,4S)-4-guanidino-3-(prop-1-en-2-ylamino)-2-((1R,2R)-1,2,3-trihydroxypropyl)-3,4-dihydro-2H-pyran-6-carboxylic acid |
|
|
|
| width = 200 |
|
|synonyms=<small>5-acetamido- 4-guanidino- 6-(1,2,3-trihydroxypropyl)- 5,6-dihydro- 4''H''-pyran- 2-carboxylic acid </small> |
|
|
|
|
|
| image = Zanamivir.png |
|
|
|
<!--Clinical data--> |
|
| CASNo_Ref = {{cascite|correct|CAS}} |
|
|
|
| pronounce = {{IPAc-en|z|ə|ˈ|n|æ|m|ᵻ|v|ɪər}} |
|
|
| tradename = Relenza |
|
|
| Drugs.com = {{drugs.com|monograph|zanamivir}} |
|
|
| DailyMedID = Zanamivir |
|
|
| pregnancy_AU = B1 |
|
|
| pregnancy_category = |
|
|
| routes_of_administration = Inhalation, ] |
|
|
| ATC_prefix = J05 |
|
|
| ATC_suffix = AH01 |
|
|
|
|
|
| legal_AU = S4 |
|
|
| legal_CA = |
|
|
| legal_UK = POM |
|
|
| legal_US = Rx-only |
|
|
| legal_US_comment = <ref>{{cite web | title=Relenza- zanamivir powder | website=DailyMed | date=19 October 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d7c3bcc3-0c0d-4068-fd80-88cf54a376ef | access-date=30 September 2022}}</ref> |
|
|
| legal_EU = Rx-only |
|
|
| legal_EU_comment = <ref>{{Cite web |url=https://www.ema.europa.eu/documents/psusa/zanamivir-except-centrally-authorised-products-list-nationally-authorised-medicinal-products-psusa/00003141/202201_en.pdf |title=List of nationally authorised medicinal products |website=European Medicines Agency}}</ref> |
|
|
| legal_status = |
|
|
|
|
|
<!--Pharmacokinetic data--> |
|
|
| bioavailability = 2% (oral) |
|
|
| protein_bound = <10% |
|
|
| metabolism = Negligible |
|
|
| elimination_half-life = 2.5–5.1 hours |
|
|
| excretion = Kidney |
|
|
|
|
|
<!--Identifiers--> |
|
|
| CAS_number_Ref = {{cascite|correct|??}} |
|
|
| CAS_number = 139110-80-8 |
|
|
| PubChem = 60855 |
|
|
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
|
|
| DrugBank = DB00558 |
|
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
|
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
|
| ChemSpiderID = 54842 |
|
| ChemSpiderID = 54842 |
|
| UNII_Ref = {{fdacite|correct|FDA}} |
|
| UNII_Ref = {{fdacite|correct|FDA}} |
|
| UNII = L6O3XI777I |
|
| UNII = L6O3XI777I |
|
|
| KEGG_Ref = {{keggcite|correct|kegg}} |
|
| InChI = 1/C12H20N4O7/c1-4(18)15-8-5(16-12(13)14)2-7(11(21)22)23-10(8)9(20)6(19)3-17/h2,5-6,8-10,17,19-20H,3H2,1H3,(H,15,18)(H,21,22)(H4,13,14,16)/t5-,6+,8+,9+,10+/m0/s1 |
|
|
|
| KEGG = D00902 |
|
| InChIKey = ARAIBEBZBOPLMB-UFGQHTETBS |
|
|
|
| ChEBI_Ref = {{ebicite|correct|EBI}} |
|
|
| ChEBI = 50663 |
|
|
| ChEMBL_Ref = {{ebicite|correct|EBI}} |
|
|
| ChEMBL = 222813 |
|
|
| PDB_ligand = ZMR |
|
|
|
|
|
<!--Chemical data--> |
|
|
| IUPAC_name = (2''R'',3''R'',4''S'')-4-guanidino-3-(prop-1-en-2-ylamino)-2-((1''R'',2''R'')-1,2,3-trihydroxypropyl)-3,4-dihydro-2''H''-pyran-6-carboxylic acid |
|
|
| C=12 | H=20 | N=4 | O=7 |
|
| smiles = O=C(O)C=1O((O)(O)CO)(NC(=O)C)(/N=C(\N)N)C=1 |
|
| smiles = O=C(O)C=1O((O)(O)CO)(NC(=O)C)(/N=C(\N)N)C=1 |
|
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
|
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
Line 18: |
Line 60: |
|
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
|
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
|
| StdInChIKey = ARAIBEBZBOPLMB-UFGQHTETSA-N |
|
| StdInChIKey = ARAIBEBZBOPLMB-UFGQHTETSA-N |
|
| CAS_number = 139110-80-8 |
|
|
| ATC_prefix = J05 |
|
|
| ATC_suffix = AH01 |
|
|
| ChEMBL_Ref = {{ebicite|changed|EBI}} |
|
|
| ChEMBL = 222813 |
|
|
| ATC_supplemental = |
|
|
| PubChem = 60855 |
|
|
| DrugBank = APRD00378 |
|
|
| KEGG_Ref = {{keggcite|changed|kegg}} |
|
|
| KEGG = D00902 |
|
|
| 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 (]), C (]) |
|
|
| legal_status = S4 <small>(Au)</small>, POM <small>(])</small>, ℞-only <small>(U.S.)</small> |
|
|
| routes_of_administration = Inhalation |
|
|
}} |
|
}} |
|
{{flu}} |
|
|
'''Zanamivir''' (]) ({{pron-en|zəˈnæmɨvɪər}}) is a ] used in the treatment and ] of ] caused by ] and ]. Zanamivir was the first neuraminidase inhibitor commercially developed. It is currently marketed by ] under the ] '''Relenza''' as a powder for oral inhalation. |
|
|
|
|
|
|
|
'''Zanamivir''' is a ] used to treat and prevent ] caused by ] and ]es. It is a ] and was developed by the Australian biotech firm Biota Holdings. It was licensed to Glaxo in 1990 and approved in the US in 1999, only for use as a treatment for influenza. In 2006, it was approved for prevention of influenza A and B.<ref name="fda.gov">{{cite web|title=FDA Approves a Second Drug for the Prevention of Influenza A and B in Adults and Children FDA press release March 29, 2006|url=https://www.fda.gov/newsevents/newsroom/pressannouncements/2006/ucm108622.htm|publisher=FDA|access-date=16 December 2019|archive-date=6 March 2010|archive-url=https://web.archive.org/web/20100306174033/https://www.fda.gov/newsevents/newsroom/pressannouncements/2006/ucm108622.htm|url-status=dead}}</ref> Zanamivir was the first neuraminidase inhibitor commercially developed. It is marketed by ] under the ] '''Relenza''' as a powder for oral inhalation. |
|
According to the ] (CDC), no flu, seasonal or pandemic, has shown any signs of resistance to zanamivir.<ref name="cdc.gov"> |
|
|
{{cite web |
|
|
| url=http://www.cdc.gov/flu/weekly/weeklyarchives2008-2009/weekly32.htm |
|
|
| title=2008-2009 Influenza Season Week 32 ending August 15, 2009 |
|
|
| work=Flu Activity & Surveillance |
|
|
| publisher=] (CDC) |
|
|
| date=August 21, 2009 |
|
|
}}</ref> |
|
|
|
|
|
|
== History == |
|
== Properties == |
|
|
Zanamivir room temperature solubility in water is 36 mg/mL, in ] is 66 mg/mL.'''<ref name=":0">{{Citation |title=Zanamivir |date=2023 |url=https://www.selleckchem.com/datasheet/zanamivir-relenza-S300702-DataSheet.html}}</ref>''' It's insoluble in ethanol.'''<ref name=":0" />''' |
|
|
|
|
|
|
==Medical uses== |
|
Zanamivir was discovered in 1989 by scientists led by Mark von Itzstein at the ], ], in collaboration with the ] and scientists at Glaxo, UK. Zanamivir was the first of the ]s. The discovery was initially funded by the Australian biotechnology company ] and was part of Biota's ongoing program to develop antiviral agents through ]. Its strategy relied on the availability of the structure of influenza ], by ]. It was also known, as far back as 1974, that 2-deoxy-2,3-didehydro-''N''-acetylneuraminic acid (DANA), a ] analogue, was an inhibitor of neuraminidase.<ref name="Meindl1974">{{cite journal | author = Meindl P, Bodo G, Palese P, Schulman J, Tuppy H | title = Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid | journal = Virology | volume = 58 | issue = 2 | pages = 457–63 | year = 1974 | month = April | pmid = 4362431 | accessdate = 2009-07-27 | doi = 10.1016/0042-6822(74)90080-4}}</ref> 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. |
|
|
|
Zanamivir is used for the treatment of infections caused by influenza A and influenza B viruses, but in otherwise-healthy individuals, benefits overall appear to be small. It decreases the risk of one's getting symptomatic, but not asymptomatic influenza. The combination of diagnostic uncertainty, the risk for virus strain resistance, possible side effects and financial cost outweigh the small benefits of zanamivir for the prophylaxis and treatment of healthy individuals.<ref name=Mich2013/> |
|
|
|
|
|
|
Since then, genes expressing resistance to zanamivir were found in Chinese people infected with avian influenza A H7N9 during treatment with zanamivir.<ref name="thelancet.com">{{cite journal | vauthors = Hu Y, Lu S, Song Z, Wang W, Hao P, Li J, Zhang X, Yen HL, Shi B, Li T, Guan W, Xu L, Liu Y, Wang S, Zhang X, Tian D, Zhu Z, He J, Huang K, Chen H, Zheng L, Li X, Ping J, Kang B, Xi X, Zha L, Li Y, Zhang Z, Peiris M, Yuan Z | display-authors = 6 | title = Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance | journal = Lancet | volume = 381 | issue = 9885 | pages = 2273–2279 | date = June 2013 | pmid = 23726392 | doi = 10.1016/S0140-6736(13)61125-3 | s2cid = 7537862 }}</ref> |
|
] 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 GRID software by ] 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 C<sub>4</sub> 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.<ref> |
|
|
{{cite journal |
|
|
|last=Laver |
|
|
|first= Graeme |
|
|
|title=Flu drugs - pathway to discovery |
|
|
|journal=Education in Chemistry |
|
|
|month=March |
|
|
|year=2007 |
|
|
|url=http://www.rsc.org/Education/EiC/issues/2007March/FluDrugsPathwayDiscovery.asp |
|
|
|accessdate = 2009-11-11 |
|
|
}} ISSN 0013-1350</ref> Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.<ref name="vonItzstein1993">{{cite journal | author = von Itzstein M, Wu WY, Kok GB, ''et al.'' | title = Rational design of potent sialidase-based inhibitors of influenza virus replication | journal = Nature | volume = 363 | issue = 6428 | pages = 418–23 | year = 1993 | month = June | pmid = 8502295 | doi = 10.1038/363418a0 | accessdate = 2009-07-27}}</ref> |
|
|
|
|
|
|
|
===Treatment=== |
|
As Biota was a small company, it did not have the resources to bring zanamivir to market by itself. In 1990, zanamivir patent rights were licensed to Glaxo, now ] (GSK). In 1999, the product was approved for marketing in the US and subsequently has been registered by GSK in a total of 70 countries (GlaxoSmithKline News release, 2006). Zanamivir is delivered via Glaxo's proprietary ] inhalation device. The license agreement entitled Biota to receive a 7% royalty on Glaxo's sales of zanamivir. |
|
|
|
In otherwise-healthy individuals, benefits overall appear to be small.<ref name=Mich2013/> Zanamivir shortens the duration of symptoms of influenza-like illness (unconfirmed influenza or 'the flu') by less than a day. In children with asthma there was no clear effect on the time to first alleviation of symptoms.<ref name="cochrane 2014" /> Whether it affects the risk of one's need to be hospitalized or the risk of death is not clear.<ref name=Mich2013/> There is no proof that zanamivir reduced hospitalizations or pneumonia and other complications of influenza, such as ], ], and ].<ref name="cochrane 2014" /> Zanamivir did not reduce the risk of self reported investigator mediated ] or radiologically confirmed pneumonia in adults. The effect on pneumonia in children was also not significant.<ref name="Heneghan syst review">{{cite journal | vauthors = Heneghan CJ, Onakpoya I, Thompson M, Spencer EA, Jones M, Jefferson T | title = Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments | journal = BMJ | volume = 348 | issue = apr09 2 | pages = g2547 | date = April 2014 | pmid = 24811412 | pmc = 3981976 | doi = 10.1136/bmj.g2547 }}</ref> |
|
|
|
|
|
===Developments=== |
|
===Prevention=== |
|
|
Low to moderate evidence indicates it decreases the risk of one's getting influenza by 1 to 12% in those exposed.<ref name=Mich2013>{{cite journal | vauthors = Michiels B, Van Puyenbroeck K, Verhoeven V, Vermeire E, Coenen S | title = The value of neuraminidase inhibitors for the prevention and treatment of seasonal influenza: a systematic review of systematic reviews | journal = PLOS ONE | volume = 8 | issue = 4 | pages = e60348 | year = 2013 | pmid = 23565231 | pmc = 3614893 | doi = 10.1371/journal.pone.0060348 | doi-access = free | bibcode = 2013PLoSO...860348M }}</ref> Prophylaxis trials showed that zanamivir reduced the risk of symptomatic influenza in individuals and households, but there was no evidence of an effect on asymptomatic influenza or on other, influenza-like illnesses. Also there was no evidence of reduction of risk of person-to-person spread of the influenza virus.<ref name="cochrane 2014">{{cite journal | vauthors = Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, Spencer EA, Onakpoya I, Mahtani KR, Nunan D, Howick J, Heneghan CJ | display-authors = 6 | title = Neuraminidase inhibitors for preventing and treating influenza in adults and children | journal = The Cochrane Database of Systematic Reviews | volume = 2014 | issue = 4 | pages = CD008965 | date = April 2014 | pmid = 24718923 | pmc = 6464969 | doi = 10.1002/14651858.CD008965.pub4 }}</ref> |
|
|
The evidence for a benefit in preventing influenza is weak in children, with concerns of ] in the literature.<ref>{{cite journal | vauthors = Wang K, Shun-Shin M, Gill P, Perera R, Harnden A | title = Neuraminidase inhibitors for preventing and treating influenza in children (published trials only) | journal = The Cochrane Database of Systematic Reviews | volume = 2012 | issue = 4 | pages = CD002744 | date = April 2012 | pmid = 22513907 | pmc = 6599832 | doi = 10.1002/14651858.CD002744.pub4 }}</ref> |
|
|
|
|
|
|
===Resistance=== |
|
Recently, the reported oseltamivir-resistance H5N1 virus neuraminidase still retaining susceptibility to zanamivir indicates that the structure of zanamivir has some advantages over oseltamivir in binding to the active pocket of H5N1 neuraminidase.<ref name=collins> |
|
|
|
As of 2009, no influenza had shown any signs of resistance in the US.<ref name="cdc.gov"> |
|
{{cite journal |
|
|
| author=Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ, Gamblin SJ. | title=Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants | journal=Nature | year=2008 | pages=1258 | volume=453 |
|
|
| doi=10.1038/nature06956 |
|
|
| pmid=18480754 |
|
|
| issue=7199 |
|
|
}}</ref><ref name=garcia-sosa> |
|
|
{{cite journal |
|
|
| author=Garcia-Sosa AT, Sild S, Maran U. | title=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| journal=J. Chem. Inf. Model. | year=2008 | pages=2074–2080 | volume=48 | issue=10 | pmid=18847186 | doi=10.1021/ci800242z |
|
|
}}</ref><ref>{{cite journal | author = Du QS, Wang SQ, Chou KC | title = Analogue inhibitors by modifying oseltamivir based on the crystal neuraminidase structure for treating drug-resistant H5N1 virus | journal = Biochemical and Biophysical Research Communications | volume = 362 | issue = 2 | pages = 525–31 | year = 2007 | month = October | pmid = 17707775 | doi = 10.1016/j.bbrc.2007.08.025 | accessdate = 2009-07-27}}</ref><br /> |
|
|
|
|
|
In January 2011, GlaxoSmithKline started a pivotal study testing i.v. zanamivir against p.o. oseltamivir (the Tamiflu pill) as a treatment for patients hospitalised with influenza. |
|
|
|
|
|
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. |
|
|
|
|
|
==Pharmacology== |
|
|
Zanamivir is specifically for the treatment of infections caused by Influenzavirus A and Influenzavirus B. |
|
|
|
|
|
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. |
|
|
|
|
|
Zanamivir works by binding to the ] of the neuraminidase protein, rendering the influenza virus unable to escape its host cell and infect others.<ref name="Cyr">{{cite journal | author = Cyranoski D | title = Threat of pandemic brings flu drug back to life | journal = Nature Medicine | volume = 11 | issue = 9 | pages = 909 | year = 2005 | month = September | pmid = 16145557 | doi = 10.1038/nm0905-909 | accessdate = 2009-07-27}}</ref> 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. |
|
|
|
|
|
===Dosing and side effects=== |
|
|
|
|
|
The ] of zanamivir is 2%. After inhalation, zanamivir is concentrated in the lungs and ], where up to 15% of the dose is absorbed and excreted in urine.<ref name="Moscona">{{cite journal | author = Moscona A | title = Neuraminidase inhibitors for influenza | journal = The New England Journal of Medicine | volume = 353 | issue = 13 | pages = 1363–73 | year = 2005 | month = September | pmid = 16192481 | doi = 10.1056/NEJMra050740 | accessdate = 2009-07-27}}</ref> |
|
|
|
|
|
Dosing is limited to the inhaled route. This restricts its usage, as treating asthmatics could induce ].<ref name="Hayden">{{cite journal | author = Hayden FG | title = Perspectives on antiviral use during pandemic influenza | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 356 | issue = 1416 | pages = 1877–84 | year = 2001 | month = December | pmid = 11779387 | pmc = 1088564 | doi = 10.1098/rstb.2001.1007 | accessdate = 2009-07-27}}</ref> The ] (FDA) has issued a Public Health Advisory warning that it has received some reports of respiratory problems following inhalation of zanamivir by patients with underlying ] or ]. The zanamivir package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease.<ref name="fda"> |
|
|
{{cite web |
|
{{cite web |
|
| url=http://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm052240.htm |
|
| url=https://www.cdc.gov/flu/weekly/weeklyarchives2008-2009/weekly32.htm |
|
|
| title=2008-2009 Influenza Season Week 32 ending August 15, 2009 |
|
| title=Safe and Appropriate Use of Influenza Drugs |
|
|
| work=Public Health Advisories (Drugs) |
|
| work=Flu Activity & Surveillance |
|
| publisher= ] (FDA) |
|
| publisher=] (CDC) |
|
| date=April 30, 2009 |
|
| date=21 August 2009 |
|
|
}}</ref> |
|
| accessdate = 2009-11-11 |
|
|
|
A ] from 2011 found that zanamivir resistance had been rarely reported.<ref name="resistance syst review">{{cite journal | vauthors = Thorlund K, Awad T, Boivin G, Thabane L | title = Systematic review of influenza resistance to the neuraminidase inhibitors | journal = BMC Infectious Diseases | volume = 11 | issue = 1 | pages = 134 | date = May 2011 | pmid = 21592407 | pmc = 3123567 | doi = 10.1186/1471-2334-11-134 | doi-access = free }}</ref> Antiviral resistance can emerge during or after treatment with antivirals in certain people (e.g., ]).<ref>{{cite web|title=Influenza Antiviral Medications: Summary for Clinicians|url=https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm|publisher=CDC|access-date=21 April 2014|date=11 May 2018}}</ref> In 2013 genes expressing resistance to zanamivir (and ]) were found in Chinese patients infected with avian influenza A H7N9.<ref name="thelancet.com"/> |
|
}} {{Dead link|date=September 2010|bot=H3llBot}}</ref> |
|
|
|
|
|
|
|
==Adverse effects== |
|
Zanamivir has not been known to cause toxic effects, does not spread around through the body's systemic circulation and shows no signs of viral resistance from any flu. |
|
|
|
Dosing is limited to the inhalation route. This restricts its usage, as treating asthmatics could induce ]s.<ref name="Hayden">{{cite journal | vauthors = Hayden FG | title = Perspectives on antiviral use during pandemic influenza | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 356 | issue = 1416 | pages = 1877–1884 | date = December 2001 | pmid = 11779387 | pmc = 1088564 | doi = 10.1098/rstb.2001.1007 }}</ref> In 2006 the ] found that breathing problems (bronchospasm), including deaths, were reported in some patients after the initial approval of Relenza. Most of these patients had asthma or chronic obstructive pulmonary disease. Relenza therefore was not recommended for treatment or prophylaxis of seasonal influenza in individuals with asthma or chronic obstructive pulmonary disease.<ref name="FDA 2006">{{cite web|title=FDA Approves a Second Drug for the Prevention of Influenza A and B in Adults and Children|url=https://www.fda.gov/newsevents/newsroom/pressannouncements/2006/ucm108622.htm|publisher=FDA press release}}</ref> In 2009 the zanamivir package insert contains precautionary information regarding risk of bronchospasm in patients with respiratory disease.<ref name="fda">{{cite web | url=https://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm052240.htm | title=Safe and Appropriate Use of Influenza Drugs | work=Public Health Advisories (Drugs) | publisher= ] (FDA) | date=30 April 2009 | access-date = 11 November 2009 | archive-url = https://web.archive.org/web/20091104104758/https://www.fda.gov/Drugs/DrugSafety/PublicHealthAdvisories/ucm052240.htm | archive-date = 4 November 2009}}</ref> |
|
|
GlaxoSmithKline (GSK) and FDA notified healthcare professionals of a report of the death of a patient with influenza having received zanamivir inhalation powder, which was solubilized and administered by mechanical ventilation.<ref>{{cite web |url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm186081.htm |url-status=dead |archive-url=https://web.archive.org/web/20091012032111/http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm186081.htm |archive-date=12 October 2009 |title=Relenza (zanamivir) Inhalation Powder|website=] }}</ref> |
|
|
|
|
|
|
In adults there was no increased risk of reported adverse events in trials. There was little evidence of the possible harms associated with the treatment of children with zanamivir.<ref name="cochrane 2014" /> |
|
GlaxoSmithKline (GSK) and FDA notified healthcare professionals of a report of the death of a patient with influenza who received Relenza (zanamivir) Inhalation Powder which was solubilized and administered by mechanical ventilation.<ref>www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm186081.htm</ref> |
|
|
|
Zanamivir has not been known to cause toxic effects and has low systemic exposure to the human body.<ref>{{cite journal | vauthors = Freund B, Gravenstein S, Elliott M, Miller I | title = Zanamivir: a review of clinical safety | journal = Drug Safety | volume = 21 | issue = 4 | pages = 267–281 | date = October 1999 | pmid = 10514019 | doi = 10.2165/00002018-199921040-00003 | s2cid = 25945928 }}</ref> |
|
|
|
|
|
==Commercial issues== |
|
==Mechanism of action== |
|
|
Zanamivir works by binding to the ] of the ] protein, rendering the influenza virus unable to escape its host cell and infect others.<ref name="Cyr">{{cite journal | vauthors = Cyranoski D | title = Threat of pandemic brings flu drug back to life | journal = Nature Medicine | volume = 11 | issue = 9 | pages = 909 | date = September 2005 | pmid = 16145557 | doi = 10.1038/nm0905-909 | doi-access = free }}</ref> It is also an inhibitor of influenza virus replication ''in vitro'' and ''in vivo''. In clinical trials, zanamivir was found to reduce the time-to-symptom resolution by 1.5 days if therapy was started within 48 hours of the onset of symptoms.{{cn|date=January 2023}} |
|
|
|
|
|
|
The ] of zanamivir is 2%. After inhalation, zanamivir is concentrated in the lungs and ], where up to 15% of the dose is absorbed and excreted in urine.<ref name="Moscona">{{cite journal | vauthors = Moscona A | title = Neuraminidase inhibitors for influenza | journal = The New England Journal of Medicine | volume = 353 | issue = 13 | pages = 1363–1373 | date = September 2005 | pmid = 16192481 | doi = 10.1056/NEJMra050740 | s2cid = 17162678 | doi-access = free }}</ref> |
|
Although zanamivir was the first ] to the market, it had only a few months lead over the second entrant, ] (''Tamiflu''), with an oral tablet formulation. |
|
|
|
|
|
|
|
== History == |
|
According to the CDC, Tamiflu, zanamivir’s main competitor, is not as effective at treating the Influenza viruses as zanamivir, especially in H1N1 Seasonal Flu. In fact, tests showed that 99.6% of the tested strains of seasonal H1N1 flu and 0.5% of 2009 pandemic flu were resistant to Tamiflu while there have been absolutely zero flu samples seasonal or pandemic that show any resistance to zanamivir.<ref name="cdc.gov"/> |
|
|
<ref name=collins>{{cite journal | author=Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ, Gamblin SJ. | title=Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants | journal=Nature | year=2008 | pages=1258 | volume=453 | doi=10.1038/nature06956 | pmid=18480754 | issue=7199}}</ref><ref name=garcia-sosa>{{cite journal | author=Garcia-Sosa AT, Sild S, Maran U. | title=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| journal=J. Chem. Inf. Model. | year=2008 | pages=2074–2080 | volume=48 | issue=10 | pmid=18847186 | doi=10.1021/ci800242z}}</ref> |
|
|
|
|
|
|
|
Zanamivir was first made in 1989 by scientists led by ]<ref>{{cite journal | vauthors = Varghese JN, Laver WG, Colman PM | title = Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 A resolution | journal = Nature | volume = 303 | issue = 5912 | pages = 35–40 | year = 1983 | pmid = 6843658 | doi = 10.1038/303035a0 | s2cid = 4363648 | bibcode = 1983Natur.303...35V }}</ref><ref>{{cite web|url=http://www.csiropedia.csiro.au/display/CSIROpedia/Colman%2C+Peter+Malcolm |title=Colman, Peter Malcolm - CSIROpedia |access-date=2 October 2013 |url-status=dead |archive-url=https://web.archive.org/web/20131004225108/http://www.csiropedia.csiro.au/display/CSIROpedia/Colman%2C+Peter+Malcolm |archive-date=4 October 2013 }}</ref> and Joseph Varghese<ref>{{cite web|url=http://www.csiropedia.csiro.au/display/CSIROpedia/Varghese,+Joseph+Noozhumurry |title=Varghese, Joseph Noozhumurry - CSIROpedia |access-date=2 October 2013 |url-status=dead |archive-url=https://web.archive.org/web/20131005003000/http://www.csiropedia.csiro.au/display/CSIROpedia/Varghese,+Joseph+Noozhumurry |archive-date=5 October 2013 }}</ref> at the Australian ], in collaboration with the ] and ]. Zanamivir was the first of the ]s. The discovery was initially funded by the Australian biotechnology company Biota and was part of Biota's ongoing program to develop antiviral agents through ]. Its strategy relied on the availability of the structure of influenza neuraminidase by ]. It was also known, as far back as 1974, that 2-deoxy-2,3-didehydro-''N''-acetylneuraminic acid (DANA), a ] analogue, is an inhibitor of neuraminidase.<ref name="Meindl1974">{{cite journal | vauthors = Meindl P, Bodo G, Palese P, Schulman J, Tuppy H | title = Inhibition of neuraminidase activity by derivatives of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid | journal = Virology | volume = 58 | issue = 2 | pages = 457–463 | date = April 1974 | pmid = 4362431 | doi = 10.1016/0042-6822(74)90080-4 }}</ref> |
|
When first marketed in the US in 1999/2000, zanamivir captured only 25% of the influenza antiviral market, despite a huge promotional campaign. By the end of that season, Tamiflu was outselling zanamivir 3:1. During that season, zanamivir experienced worldwide safety warnings involving the risk of bronchospasm and death. Glaxo then reduced the marketing of zanamivir, and Tamiflu's dominance increased. More than ]20m worth of zanamivir sold by Glaxo in the first US season was returned to the company in the next two seasons because zanamivir's sales to patients were far less than expected. |
|
|
|
|
|
|
|
] 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 amino acid residues of the catalytic site, so would be potent and specific inhibitors of the enzyme. The GRID software by ] was used to determine energetically favourable interactions between various functional groups and residues in the catalytic site canyon. This investigation showed a negatively charged zone occurs in the neuraminidase active site that aligns with the C<sub>4</sub> hydroxyl group of DANA. This hydroxyl is, therefore, replaced with a positively charged amino group; the 4-amino DANA was shown to be 100 times better as an inhibitor than DANA, owing to the formation of a salt bridge with a conserved glutamic acid (119) in the active site. Glu 119 was also noticed to be at the bottom of a conserved pocket in the active site that is just big enough to accommodate the larger, but more basic ] ].<ref> |
|
Biota commenced legal proceedings in 2004 alleging that Glaxo's reduced marketing of zanamivir was a breach of contract. Biota claimed approximately ]700m from Glaxo. After Biota spent four years trying to progress its case, and incurring ]50m in legal costs, the company abandoned the claim in July 2008, recovering only ]20m including legal costs following settlement at mediation. Biota had refused an earlier tactical offer from Glaxo of ]75m plus legal costs. |
|
|
|
{{cite magazine | vauthors = Laver G |date= 1 March 2007 |title= Flu drugs - pathway to discovery |url= https://eic.rsc.org/feature/flu-drugs-pathway-to-discovery/2020145.article |magazine= ] |volume= 44 |issue= 2 |pages= 48–52 |issn=0013-1350 |publisher= ] |access-date= 19 June 2018 }}</ref> Zanamivir, a transition-state analogue inhibitor of neuraminidase, was the result.<ref name="vonItzstein1993">{{cite journal | vauthors = von Itzstein M, Wu WY, Kok GB, Pegg MS, Dyason JC, Jin B, Van Phan T, Smythe ML, White HF, Oliver SW | display-authors = 6 | title = Rational design of potent sialidase-based inhibitors of influenza virus replication | journal = Nature | volume = 363 | issue = 6428 | pages = 418–423 | date = June 1993 | pmid = 8502295 | doi = 10.1038/363418a0 | s2cid = 4359333 | bibcode = 1993Natur.363..418V }}</ref> |
|
|
|
|
|
|
In 1999, the product was approved for marketing in the US and Europe for treatment of influenza A and B. The FDA advisory committee had recommended by a vote 13 to 4 that it should not be approved, because it lacked efficacy and was no more effective than placebo when the patients were on other drugs such as paracetamol. But the FDA leadership overruled the committee and criticised its reviewer, biostatistician Michael Elashoff. The review of oseltamivir, which was also in approval process at that time, was taken away from him, and reassigned to someone else.<ref name="cohen 2010">{{cite journal | vauthors = Cohen D, Carter P | title = Conflicts of interest. WHO and the pandemic flu "conspiracies" | journal = BMJ | volume = 340 | issue = jun03 4 | pages = c2912 | date = June 2010 | pmid = 20525679 | doi = 10.1136/bmj.c2912 | s2cid = 35959611 }}</ref> In 2006 zanamivir was approved in the US and Europe for prevention of influenza A and B.<ref name="fda.gov"/> |
|
In August 2006, Germany announced that it would buy 1.7 million doses of zanamivir, 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 zanamivir was originally developed.<ref name="Cyr"/> |
|
|
|
|
|
|
|
== References == |
|
In April 2009 many cases of ] (H1N1 type virus) were reported in US and Mexico. Zanamivir is one of only two drugs that are prescribed to treat it. A study published in June 2009 emphasized the urgent need for augmentation of ] (Tamiflu) stockpiles, with additional antiviral drugs including zanamivir, 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 99.6% of all tested seasonal H1N1 strains.<ref> |
|
|
|
{{Reflist}} |
|
{{cite journal |
|
|
| author = Soundararajan V, Tharakaraman K, Raman R, Raguram S, Sasisekharan V, Sasisekharan R |
|
|
| title = Extrapolating from sequence--the 2009 H1N1 'swine' influenza virus |
|
|
| journal = Nature Biotechnology |
|
|
| volume = 27 |
|
|
| issue = 6 |
|
|
| pages = 510–3 |
|
|
| year = 2009 |
|
|
| month = June |
|
|
| pmid = 19513050 |
|
|
| doi = 10.1038/nbt0609-510 |
|
|
| accessdate = 2009-07-27 |
|
|
}}</ref> |
|
|
|
|
|
In January 2011, GSK announced it was commencing Phase III trials for Intravenous zanamivir in a study which will span 20 countries in the Northern and Southern hemispheres. <ref>{{cite news| url=http://www.reuters.com/article/idUSTRE70I1RU20110119 | work=Reuters | first=Ben | last=Hirschler | title=GSK tests intravenous flu drug vs Roche's Tamiflu | date=2011-01-19}}</ref> |
|
|
|
|
|
==Legal status== |
|
|
The drug is approved for use for the prevention and treatment of influenza in those over the age of 7 in the United States, Canada, European Union and many other countries. |
|
|
It is not recommended for people with respiratory problems and ailments. |
|
|
|
|
|
==Chemistry== |
|
|
] |
|
|
{{Break}}After Scheigetz et al.<ref name="Scheigetz">{{cite journal|url=http://www.informaworld.com/smpp/content~db=all~content=a908779823~frm=titlelink|author=Scheigetz, J.; Zamboni, R.; Bernstein, M. A.;Roy, B.|title=A syntheses of 4-a-guanidino-2-deoxy-2,3-didehydro n-acetylneuraminic acid |date=December 1995|volume=27|issue=6|pages=637–644|work=]: The New Journal for Organic Synthesis |doi=10.1021/ol901511x |accessdate=2010-11-14}}</ref> |
|
|
|
|
|
==References== |
|
|
{{Reflist|2}} |
|
|
|
|
|
|
==External links== |
|
== External links == |
|
|
* MedlinePlus drug |
|
* {{Dead link|date=November 2009}} |
|
|
* MedlinePlus drug |
|
|
* ] (FDA) |
|
|
* ]] |
|
|
* ] |
|
|
|
|
|
|
{{RNA antivirals}} |
|
{{RNA antivirals}} |
|
{{Influenza}} |
|
{{Influenza}} |
|
|
{{GlaxoSmithKline}} |
|
|
{{Portal bar | Medicine}} |
|
|
|
|
|
] |
|
] |
|
] |
|
] |
|
] |
|
|
] |
|
] |
|
|
] |
|
] |
|
] |
|
] |
|
] |
|
|
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|
|
] |
|