Zilpaterol: Difference between revisions

{{Short description|Chemical compound}}

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 455101716

| IUPAC_name = (±)-''trans''-4,5,6,7-Tetrahydro-7-hydroxy-6-(isopropylamino)-imidazo[4,5,1-jk]-[1]benzazepin-2(1''H'')-one

| image = Zilpaterol enantiomers.svg

| width = 165

| tradename = Zilmax

| pregnancy_category =

| routes_of_administration = [[Oral administration|Oral]]

| ATC_prefix = None

| ATC_suffix =

| legal_AU = S4

| legal_CA = Rx-only

| legal_CA_comment =

| legal_status =

| bioavailability =

| metabolism =

| elimination_half-life = 11.9–13.2 hours (first phase)

| excretion = [[Urine]] (88.2–84.3%) and [[feces]] (8.6–8.7%) (in cattle)<ref name="FAO">{{cite web| vauthors = Boison J, Ramos F, Sanders P, Chicoine A, Scheid S |title=Residue Evaluation of Certain Veterinary Drugs (78th meeting). 10. Zilpaterol hydrochloride|url=http://www.fao.org/3/a-i3745e.pdf|website=Food and Agriculture Organization of the United Nations|publisher=Joint FAO/WHO Expert Committee on Food Additives|access-date=22 February 2016|pages=133–59|date=2013}}</ref>

| CAS_number_Ref = {{cascite|correct|CAS}}

| CAS_number = 119520-05-7

| PubChem = 9992825

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = S384A1Y12J

| synonyms = RU 42173

| C = 14

| H = 19

| N = 3

| O = 2

| smiles = CC(C)N[C@@H]1CCN2C3=C([C@H]1O)C=CC=C3NC2=O

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 2343170

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C14H19N3O2/c1-8(2)15-11-6-7-17-12-9(13(11)18)4-3-5-10(12)16-14(17)19/h3-5,8,11,13,15,18H,6-7H2,1-2H3,(H,16,19)/t11-,13-/m1/s1

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = ZSTCZWJCLIRCOJ-DGCLKSJQSA-N

'''Zilpaterol''' is a [[Beta2-adrenergic agonist|β₂ adrenergic agonist]].<ref>{{cite web|title=Zilmax (zilpaterol hydrochloride 4.8%) Type A Medicated Article|url=https://intervetus.naccvp.com/product/view/1047465?e=d97b22ed63e734e84c1a5910a9c8f531z1688|website=Compendium of Veterinary Products — Merck Animal Health|publisher=Intervet/Merck Animal Health|access-date=22 February 2016|archive-date=27 April 2017|archive-url=https://web.archive.org/web/20170427084723/https://intervetus.naccvp.com/product/view/1047465?e=d97b22ed63e734e84c1a5910a9c8f531z1688|url-status=dead}}</ref><ref name="pmid16332507">{{cite journal | vauthors = Verhoeckx KC, Doornbos RP, Witkamp RF, van der Greef J, Rodenburg RJ | title = Beta-adrenergic receptor agonists induce the release of granulocyte chemotactic protein-2, oncostatin M, and vascular endothelial growth factor from macrophages | journal = International Immunopharmacology | volume = 6 | issue = 1 | pages = 1–7 | date = January 2006 | pmid = 16332507 | doi = 10.1016/j.intimp.2005.05.013 }}</ref> Under its brand name, '''Zilmax''', it is used to increase the size of cattle and the efficiency of feeding them.<ref name="chronicle1">{{cite web| vauthors = Petersen M |url=http://chronicle.com/article/As-Beef-Cattle-Become/131480/ |title=As Beef Cattle Become Behemoths, Who Are Animal Scientists Serving? | work = The Chronicle Review - The Chronicle of Higher Education |date=15 April 2012 |publisher=Chronicle.com |access-date=2012-04-16}}</ref> Zilmax is produced by Intervet, a subsidiary of [[Merck & Co.]],<ref name="chronicle1"/><ref name="merck">{{cite web |url=http://www.merck-animal-health-usa.com/products/zilmax/overview.aspx |title=Zilmax - Overview |publisher=Merck-animal-health-usa.com |access-date=2012-04-16 |archive-date=2020-04-21 |archive-url=https://web.archive.org/web/20200421000321/https://www.merck-animal-health-usa.com/products/zilmax/overview.aspx |url-status=dead }}</ref> and marketed as a "beef-improvement technology".<ref>{{cite web|title=Zilmax® Post-Approval Research Nears Completion Intervet's New Performance Technology Offers Value throughout Beef Industry|url=http://www.merck-animal-health-usa.com/news/2008-05-07_zilmax_post-approval_research_nears_completion.aspx|publisher=Merck Animal Health USA|access-date=29 July 2015|date=July 19, 2007|quote=This is the first beef-improvement technology to add value all the way through the beef system.|archive-date=2015-09-26|archive-url=https://web.archive.org/web/20150926055823/http://www.merck-animal-health-usa.com/news/2008-05-07_zilmax_post-approval_research_nears_completion.aspx|url-status=dead}}</ref> Zilpaterol is typically fed [[feedlot|in the last three to six weeks]] of cattle's lives, with a brief period (three days in the US) before death for [[Drug withdrawal|withdrawal]], which allows the drug to mostly leave the animal's tissues.

Concerns have been raised on the impact of zilpaterol on flavor;<ref>{{cite web | url = http://www.slate.com/articles/health_and_science/food/2013/02/zilmax_the_cattle_growth_drug_that_s_making_beef_more_like_chicken.html | title = Why Beef Is Becoming More Like Chicken | publisher = Slate.com | date = Feb 14, 2013}}</ref> however, studies have confirmed that overall tenderness, juiciness, flavor intensity, and beef flavor remain within the normal variation observed in the beef industry and differences are smaller than what can be detected by the consumer.<ref>{{cite journal | url = https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm051412.pdf | title = ZILMAX (Zilpaterol Hydrochloride): Type A Medicated Article for Cattle Fed in Confinement for Slaughter | journal = Freedom of Information Summary, Original New Animal Drug Application, NADA 141-258 | publisher = Food and Drug Administration}}</ref>

In the meantime, several studies have shown the use of zilpaterol leads to increased size, feed efficiency, and value.<ref>{{cite journal | journal = Proceedings, Western Section, American Society of Animal Science | volume = 50 | year = 1999 | title = Influence of the β-Agonist, Zilpaterol, on Growth Performance and Carcass Characteristics of Feedlot Steers | vauthors = Plascencia A, Torrentera N, Zinn RA | url = http://animalscience.ucdavis.edu/faculty/zinn/pdf/20.Pdf | pages = 331–334 | access-date = 2012-04-16 | archive-date = 2012-07-22 | archive-url = https://web.archive.org/web/20120722040450/http://animalscience.ucdavis.edu/faculty/zinn/pdf/20.Pdf | url-status = dead }}</ref><ref name="animsci2009">{{cite journal | vauthors = Montgomery JL, Krehbiel CR, Cranston JJ, Yates DA, Hutcheson JP, Nichols WT, Streeter MN, Bechtol DT, Johnson E, TerHune T, Montgomery TH | display-authors = 6 | title = Dietary zilpaterol hydrochloride. I. Feedlot performance and carcass traits of steers and heifers | journal = Journal of Animal Science | volume = 87 | issue = 4 | pages = 1374–1383 | date = April 2009 | pmid = 19098247 | doi = 10.2527/jas.2008-1162 | doi-access = free }}</ref><ref name="perspectives">{{cite journal | vauthors = Delmore RJ, Hodgen JM, Johnson BJ | title = Perspectives on the application of zilpaterol hydrochloride in the United States beef industry | journal = Journal of Animal Science | volume = 88 | issue = 8 | pages = 2825–2828 | date = August 2010 | pmid = 20382871 | doi = 10.2527/jas.2009-2473 | url = https://digitalcommons.calpoly.edu/cgi/viewcontent.cgi?article=1013&context=asci_fac }}</ref><ref>{{cite journal | vauthors = Lawrence TE, Gasch CA, Hutcheson JP, Hodgen JM | title = Zilpaterol improves feeding performance and fabrication yield of concentrate-finished cull cows | journal = Journal of Animal Science | volume = 89 | issue = 7 | pages = 2170–2175 | date = July 2011 | pmid = 21278106 | doi = 10.2527/jas.2010-3422 | doi-access = free }}</ref>

Merck reported Zilmax-fed cattle do not produce beef with a difference in taste or quality compared to cattle not fed the drug, but elsewhere, concerns have been raised about the beef's tenderness.<ref name="chronicle1"/><ref name="merck"/> Studies have variously found a slight reduction in tenderness,<ref name=animsci2009/><ref name=Holstein/> an increase in [[shear force]],<ref name=perspectives/> and a lower percentage of intramuscular fat ([[marbled meat|marbling]]).<ref name="Holstein">{{cite journal | vauthors = Holmer SF, Fernández-Dueñas DM, Scramlin SM, Souza CM, Boler DD, McKeith FK, Killefer J, Delmore RJ, Beckett JL, Lawrence TE, VanOverbeke DL, Hilton GG, Dikeman ME, Brooks JC, Zinn RA, Streeter MN, Hutcheson JP, Nichols WT, Allen DM, Yates DA | display-authors = 6 | title = The effect of zilpaterol hydrochloride on meat quality of calf-fed Holstein steers | journal = Journal of Animal Science | volume = 87 | issue = 11 | pages = 3730–3738 | date = November 2009 | pmid = 19648490 | doi = 10.2527/jas.2009-1838 | doi-access = free | hdl = 2346/95089 | hdl-access = free }}</ref>

==Prohibitions and processor adoption==

As of October 2017, Zilmax was approved in 17 countries, notably the US, Canada, South Africa, South Korea, Ukraine and Brazil.<ref name=blb>{{cite news | vauthors = Le Bizec B |title=A General Perspective on the Use of Wada Prohibited Substances for Animal Husbandry |url=https://www.wada-ama.org/sites/default/files/bruno_le_bizec_animal_husbandry_symposium_oct2017.pdf |publisher=WADA |date=October 2017}}</ref>

As of 2013, Zilmax was banned in China, Taiwan, Russia, and many countries in the European Union.<ref>{{Cite web|url=https://www.npr.org/blogs/thesalt/2013/08/09/210538430/did-tyson-drop-zilmax-fed-beef-to-appease-foreign-buyers|title=Did Tyson Ban Doping Cows with Zilmax to Boost Foreign Sales?|website=NPR.org}}</ref><ref>{{cite news | title = Taiwan detects more U.S. beef with banned feed additive | url = https://www.reuters.com/article/us-beef-usa-taiwan-idUSBRE99S0IO20131029 | work = Reuters | date = 29 October 2013 }}</ref>

===In the US===

[[Tyson Foods]] was the first among the largest U.S. meatpackers to adopt Zilmax. Because of concerns about tenderness and loss of marbling, Cargill and other meatpackers resisted the practice. The next adopters were [[JBS S.A.|JBS]] and [http://www.nationalbeef.com National Beef], with [[Cargill]] finally joining them in mid-2012.<ref name="leonard">{{cite book| vauthors = Leonard C |title=The meat racket : the secret takeover of America's food business|date=2014|publisher=Simon & Schuster|location=New York|isbn=9781451645811}}</ref>

On August 6, 2013, Tyson Foods banned Zilmax-fed cattle from its processing plants after cattle began arriving with missing hooves in large numbers during hot weather.<ref>{{Cite web|url=http://www.businessinsider.com/why-merck-halted-sales-of-zilmax-2013-12|title = Cattle Feet Were 'Basically Coming Apart' Before Merck Halted Sales of a Muscle-Building Drug|website = [[Business Insider]]}}</ref>

==Origin and formulation==

Zilmax is produced by Merck in France, a country in which the substance is prohibited. As of October 2017, its commercial formulation was 4.8% zilpaterol hydrochloride, 8% polyoxyl [[castor oil]], 4.3% [[polyvinyl pyrrolidone]] and 82.9% ground [[corn cob]].<ref name=blb/>

== Chemistry ==

Zilpaterol has two [[Chirality (chemistry)|chiral]] carbons and consequently four optical [[enantiomer]]s. These enantiomers are: (6''R'',7''R'')-, (6''R'',7''S'')-, (6''S'',7''R'')- and (6''S'',7''S'')-. RU 42173 corresponds to racemic ''trans''-zilpaterol hydrochloride, a mixture of the (6''R'',7''R'')-(−)- and (6''S'',7''S'')-(+)-enantiomers.<ref name="FAO" />

== External links ==

* [http://www.zilmax.com Zilmax (zilpaterol hydrochloride) — Consumer Information Center] {{Webarchive|url=https://web.archive.org/web/20160304173628/http://www.zilmax.com/ |date=2016-03-04 }}

{{Reflist|2}}

[[Category:Phenylethanolamines]]

[[Category:Benzazepanes]]

[[Category:Beta2-adrenergic agonists]]

[[Category:Drugs developed by Merck & Co.]]

[[Category:Heterocyclic compounds with 3 rings]]

[[Category:Ureas]]

[[Category:Veterinary drugs]]

[[Category:Isopropylamino compounds]]

[[Category:Medicated feed]]