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Revision as of 16:31, 10 January 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 469931785 of page Zanamivir for the Chem/Drugbox validation project (updated: 'DrugBank').		Latest revision as of 13:03, 22 July 2024 edit Tamunro (talk | contribs)Extended confirmed users904 editsm →History: corrected grammarTag: Visual edit
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			{{Short description|Influenza medication}}
	{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
			{{Use dmy dates|date=October 2022}}
	{{Drugbox		{{Drugbox
	| Verifiedfields = changed		| Watchedfields = changed
	| verifiedrevid = 423109522		| 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
	| image = Zanamivir.png		| width = 200
	<!--Clinical data-->		<!--Clinical data-->
			| pronounce = {{IPAc-en|z|ə|ˈ|n|æ|m|ᵻ|v|ɪər}}
	| tradename = Relenza		| tradename = Relenza
	| Drugs.com = {{drugs.com|monograph|zanamivir}}		| Drugs.com = {{drugs.com|monograph|zanamivir}}
			| DailyMedID = Zanamivir
	| pregnancy_category = B1 (]), C (])
			| pregnancy_AU = B1
	| legal_status = S4 <small>(Au)</small>, POM <small>(])</small>, ℞-only <small>(U.S.)</small>
			| pregnancy_category =
	| routes_of_administration = Inhalation
			| 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-->		<!--Pharmacokinetic data-->
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	| metabolism = Negligible		| metabolism = Negligible
	| elimination_half-life = 2.5–5.1 hours		| elimination_half-life = 2.5–5.1 hours
	| excretion = Renal		| excretion = Kidney
	<!--Identifiers-->		<!--Identifiers-->
	| CASNo_Ref = {{cascite|correct|CAS}}
	| CAS_number_Ref = {{cascite|correct|??}}		| CAS_number_Ref = {{cascite|correct|??}}
	| CAS_number = 139110-80-8		| CAS_number = 139110-80-8
	| ATC_prefix = J05
	| ATC_suffix = AH01
	| PubChem = 60855		| PubChem = 60855
	| DrugBank_Ref = {{drugbankcite|correct|drugbank}}		| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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	| KEGG_Ref = {{keggcite|correct|kegg}}		| KEGG_Ref = {{keggcite|correct|kegg}}
	| KEGG = D00902		| KEGG = D00902
	| ChEBI_Ref = {{ebicite|changed|EBI}}		| ChEBI_Ref = {{ebicite|correct|EBI}}
	| ChEBI = 50663		| ChEBI = 50663
	| ChEMBL_Ref = {{ebicite|correct|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 222813		| ChEMBL = 222813
			| PDB_ligand = ZMR
	<!--Chemical data-->		<!--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
			| C=12 | H=20 | N=4 | O=7
	| molecular_weight = 332.31 g/mol
	| 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
	| 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
	| InChIKey = ARAIBEBZBOPLMB-UFGQHTETBS
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/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		| StdInChI = 1S/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
	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}		| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey = ARAIBEBZBOPLMB-UFGQHTETSA-N		| StdInChIKey = ARAIBEBZBOPLMB-UFGQHTETSA-N
	| synonyms = <small>5-acetamido- 4-guanidino- 6-(1,2,3-trihydroxypropyl)- 5,6-dihydro- 4''H''-pyran- 2-carboxylic acid </small>
	}}		}}
			'''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.
			== 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 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>
			===Treatment===
			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>
			===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===
			As of 2009, no influenza had shown any signs of resistance in the US.<ref name="cdc.gov">
			{{cite web
			| url=https://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=21 August 2009
			}}</ref>
			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"/>
			==Adverse effects==
			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" />
			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>
			==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>
			== History ==
			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>
			] 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>
			{{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"/>
			== References ==
			{{Reflist}}
			== External links ==
			* MedlinePlus drug
			{{RNA antivirals}}
			{{Influenza}}
			{{GlaxoSmithKline}}
			{{Portal bar | Medicine}}
			]
			]
			]
			]
			]
			]