Editing Paracetamol (section)

==History==
[[Image:Axelrod.jpg|thumb|[[Julius Axelrod]] ''(pictured)'' and [[Bernard Brodie (biochemist)|Bernard Brodie]] demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better-tolerated analgesic.]]

[[Acetanilide]] was the first [[aniline]] derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of [[Antifebrin]] by Cahn & Hepp in 1886.<ref>{{cite journal |vauthors=Cahn A, Hepp P |title=Das Antifebrin, ein neues Fiebermittel |trans-title=Antifebrin, a new antipyretic |journal=Centralblatt für klinische Medizin |year=1886 |volume=7 |pages=561–4 |url=https://babel.hathitrust.org/cgi/pt?num=561&u=1&seq=5&view=image&size=100&id=mdp.39015009239362 |language=de |access-date=21 February 2019 |archive-date=1 September 2020 |archive-url= https://web.archive.org/web/20200901204651/https://babel.hathitrust.org/cgi/pt?num=561&u=1&seq=5&view=image&size=100&id=mdp.39015009239362 |url-status=live }}</ref> But its unacceptable toxic effects{{emdash}}the most alarming being [[cyanosis]] due to [[methemoglobinemia]], an increase of hemoglobin in its ferric [Fe<sup>3+</sup>] state, called [[methemoglobin]], which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissue{{emdash}}prompted the search for less toxic aniline derivatives.<ref name=Bertolini2006rev>{{cite journal |vauthors=Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S |title=Paracetamol: New vistas of an old drug |journal= CNS Drug Reviews |volume=12 |issue=3–4 |pages=250–75 |year=2006 |pmid=17227290 |doi =10.1111/j.1527-3458.2006.00250.x|pmc=6506194 }}</ref> Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.<ref name="ourarchive.otago.ac.nz"/><ref name="Roy_2011"/>

[[Harmon Northrop Morse]] synthesized paracetamol at [[Johns Hopkins University]] via the reduction of [[4-Nitrophenol|''p''-nitrophenol]] with [[tin]] in glacial [[acetic acid]] in 1877,<ref>{{cite journal |title=Ueber eine neue Darstellungsmethode der Acetylamidophenole |trans-title=On a new method of preparing acetylamidophenol |pages=232–233 |vauthors=Morse HN |year=1878 |doi=10.1002/cber.18780110151 |journal=[[Berichte der deutschen chemischen Gesellschaft]] |volume=11 |issue=1 |url=https://zenodo.org/record/1425148 |archive-url=https://web.archive.org/web/20230928132132/https://zenodo.org/record/1425148/files/article.pdf |url-status=live |archive-date=28 September 2023 |language=de |access-date=28 December 2023 }}</ref><ref name=badmed/> but it was not until 1887 that clinical pharmacologist [[Joseph von Mering]] tried paracetamol on humans.<ref name=Bertolini2006rev/> In 1893, von Mering published a paper reporting on the clinical results of paracetamol with [[phenacetin]], another aniline derivative.<ref>{{cite journal |vauthors = von Mering J |year=1893 |title=Beitrage zur Kenntniss der Antipyretica |journal=Ther Monatsch |volume=7 |pages=577–587 }}</ref> Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce [[methemoglobinemia]]. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established [[Bayer]] as a leading pharmaceutical company.<ref name=drugdiscov>{{cite book |title=Drug Discovery: A History |vauthors = Sneader W |publisher=Wiley |year=2005 |isbn=978-0471899808 |page=439 |location=Hoboken, NJ |url=https://books.google.com/books?id=jglFsz5EJR8C&pg=PA439 |url-status=live |archive-url=https://web.archive.org/web/20160818021904/https://books.google.com/books?id=jglFsz5EJR8C&pg=PA439 |archive-date=18 August 2016 }}</ref>

Von Mering's claims remained essentially unchallenged for half a century until two teams of researchers from the United States analyzed the metabolism of acetanilide and phenacetin.<ref name=drugdiscov/> In 1947, [[David Lester (biochemist)|David Lester]] and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.<ref>{{cite journal|vauthors = Lester D, Greenberg LA, Carroll RP|title = The metabolic fate of acetanilid and other aniline derivatives: II. Major metabolites of acetanilid appearing in the blood|journal = J. Pharmacol. Exp. Ther.|year = 1947|volume = 90|pages = 68–75|url = http://jpet.aspetjournals.org/cgi/reprint/90/1/68|pmid = 20241897|issue = 1| doi=10.1016/S0022-3565(25)05394-7 |url-status=live|archive-url = https://web.archive.org/web/20081202161015/http://jpet.aspetjournals.org/cgi/reprint/90/1/68|archive-date = 2 December 2008}}</ref> In 1948, [[Bernard Brodie (biochemist)|Bernard Brodie]], [[Julius Axelrod]] and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans, and established that it was just as efficacious an analgesic as its precursor.<ref>{{cite journal| vauthors=Brodie BB, Axelrod J |author-link2=Julius Axelrod |title = The estimation of acetanilide and its metabolic products, aniline, ''N''-acetyl ''p''-aminophenol and ''p''-aminophenol (free and total conjugated) in biological fluids and tissues|journal = J. Pharmacol. Exp. Ther.|year = 1948|volume = 94|issue = 1|pages = 22–28|doi=10.1016/S0022-3565(25)03461-5 |pmid = 18885610}}</ref><ref>{{cite journal | vauthors = Brodie BB, Axelrod J | author-link2 = Julius Axelrod | title = The fate of acetanilide in man | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 94 | issue = 1 | pages = 29–38 | date = September 1948 | doi = 10.1016/S0022-3565(25)03462-7 | pmid = 18885611 | url = http://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdf | url-status = live | archive-url = https://web.archive.org/web/20080907110847/http://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdf | archive-date = 7 September 2008 }}</ref><ref>{{cite journal| vauthors=Flinn FB, Brodie BB |title = The effect on the pain threshold of ''N''-acetyl ''p''-aminophenol, a product derived in the body from acetanilide|journal = J. Pharmacol. Exp. Ther.|year = 1948|volume = 94|issue = 1|pages = 76–77| doi=10.1016/S0022-3565(25)03471-8 |pmid = 18885618}}</ref> They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, [[phenylhydroxylamine]]. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.<ref>{{cite journal | vauthors = Brodie BB, Axelrod J | title = The fate of acetophenetidin in man and methods for the estimation of acetophenetidin and its metabolites in biological material | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 97 | issue = 1 | pages = 58–67 | date = September 1949 | doi = 10.1016/S0022-3565(25)03631-6 | pmid = 18140117 | url = https://jpet.aspetjournals.org/content/97/1/58 }}</ref> This led to a "rediscovery" of paracetamol.<ref name=Bertolini2006rev/>

Paracetamol was first marketed in the United States in 1950 under the name Trigesic, a combination of paracetamol, aspirin, and caffeine.<ref name=badmed/> Reports in 1951 of three users stricken with the blood disease [[agranulocytosis]] led to its removal from the marketplace, and it took several years until it became clear that the disease was unconnected.<ref name=badmed/> The following year, 1952, paracetamol returned to the U.S. market as a prescription drug.<ref name="pmid329728"/> In the United Kingdom, marketing of paracetamol began in 1956 by [[Sterling-Winthrop Co.]] as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers.<ref name="pmid799998">{{cite journal |vauthors=Spooner JB, Harvey JG |title=The history and usage of paracetamol |journal=J Int Med Res |volume=4 |issue=4 Suppl |pages=1–6 |date=1976 |pmid=799998 |doi=10.1177/14732300760040S403 |s2cid=11289061}}</ref><ref name="LandauAchilladelis1999">{{cite book| vauthors = Landau R, Achilladelis B, Scriabine A |title=Pharmaceutical Innovation: Revolutionizing Human Health|url=https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA248|year=1999|publisher=Chemical Heritage Foundation|isbn=978-0-941901-21-5|pages=248–249|url-status=live|archive-url= https://web.archive.org/web/20160817194009/https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA248|archive-date=17 August 2016 }}</ref> In 1963, paracetamol was added to the ''[[British Pharmacopoeia]]'', and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.<ref name="pmid799998"/><ref name=badmed>{{cite book|title=Bad Medicine: The Prescription Drug Industry in the Third World |vauthors = Silverman M, Lydecker M, Lee PR |publisher= Stanford University Press |year=1992 |isbn=978-0804716697 |pages=[https://archive.org/details/badmedicinepresc0000silv/page/88 88]–90 |url= https://archive.org/details/badmedicinepresc0000silv |url-access=registration}}</ref>

Concerns about paracetamol's safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause of [[analgesic nephropathy]] and hematological toxicity.<ref name=Bertolini2006rev/> Available in the U.S. without a prescription since 1955<ref name="pmid329728">{{cite journal |vauthors=Ameer B, Greenblatt DJ |title=Acetaminophen |journal=Ann Intern Med |volume=87 |issue=2 |pages=202–9 |date=August 1977 |pmid=329728 |doi=10.7326/0003-4819-87-2-202}}</ref> (1960, according to another source<ref>{{cite web |url=http://www.tylenol.com/news/about-us |title=Our Story |publisher=McNEIL-PPC, Inc. |access-date=8 March 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140308090216/http://www.tylenol.com/news/about-us |archive-date=8 March 2014 }}</ref>), paracetamol has become a common household drug.<ref>{{cite news |url=http://www.medicinenet.com/acetaminophen/article.htm |title=Medication and Drugs |date=1996–2010 |work=MedicineNet |access-date=22 April 2010 |url-status=live |archive-url=https://web.archive.org/web/20100422200526/http://www.medicinenet.com/acetaminophen/article.htm |archive-date=22 April 2010}}</ref> In 1988, Sterling Winthrop was acquired by [[Eastman Kodak]] which sold the over the counter drug rights to [[SmithKline Beecham]] in 1994.<ref>{{cite web| url=http://www.secinfo.com/dUGc.bs.htm |title=SEC Info – Eastman Kodak Co – '8-K' for 6/30/94 |access-date=3 March 2016|url-status=dead|archive-url= https://web.archive.org/web/20160304061947/http://www.secinfo.com/dUGc.bs.htm|archive-date=4 March 2016}}</ref>

In June 2009, an FDA advisory committee recommended that new restrictions be placed on paracetamol use in the United States to help protect people from the potential toxic effects. The maximum single adult dosage would be decreased from 1000{{nbsp}}mg to 650{{nbsp}}mg, while combinations of paracetamol and other products would be prohibited. Committee members were particularly concerned by the fact that the then-present maximum dosages of paracetamol had been shown to produce alterations in liver function.<ref name="WebMD">{{cite web |url=http://www.webmd.com/pain-management/news/20090701/fda-may-restrict-acetaminophen |title=FDA May Restrict Acetaminophen |publisher=Webmd |date=1 July 2009 |access-date=19 March 2011 |url-status=live |archive-url=https://web.archive.org/web/20110321075108/http://www.webmd.com/pain-management/news/20090701/fda-may-restrict-acetaminophen |archive-date=21 March 2011 }}</ref>

In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325{{nbsp}}mg per tablet or capsule and began requiring manufacturers to update the labels of all prescription combination paracetamol products to warn of the potential risk of severe liver damage.<ref name="FDA_20110113">{{cite press release| url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm| date = 13 January 2011| title = FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings| publisher = U.S. [[Food and Drug Administration]] (FDA)| access-date = 13 January 2011| url-status=live| archive-url = https://web.archive.org/web/20110115151630/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm| archive-date = 15 January 2011}}{{PD-notice}}</ref><ref name="FDA_CDER">{{cite web| url = https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-prescription-acetaminophen-products-be-limited-325-mg-dosage-unit |title = FDA Drug Safety Communication: Prescription Acetaminophen Products to be Limited to 325 mg Per Dosage Unit; Boxed Warning Will Highlight Potential for Severe Liver Failure| date = 13 January 2011| publisher = U.S. [[Food and Drug Administration]] (FDA)| access-date = 13 January 2011| url-status=live| archive-url = https://web.archive.org/web/20110118040527/https://www.fda.gov/Drugs/DrugSafety/ucm239821.htm| archive-date = 18 January 2011}}{{PD-notice}}</ref><ref>{{cite news| url = https://www.boston.com/lifestyle/health/articles/2011/01/13/fda_orders_lowering_pain_reliever_in_vicodin/| title = FDA orders lowering pain reliever in Vicodin |vauthors = Perrone M |agency = Associated Press| date = 13 January 2011| work = [[The Boston Globe]]| access-date = 13 January 2011| url-status= live| archive-url = https://web.archive.org/web/20121102211431/http://www.boston.com/lifestyle/health/articles/2011/01/13/fda_orders_lowering_pain_reliever_in_vicodin/ |archive-date = 2 November 2012 }}</ref><ref name="NYT_Harris">{{cite news| url = https://www.nytimes.com/2011/01/14/health/policy/14fda.html| title = F.D.A. Plans New Limits on Prescription Painkillers |vauthors = Harris G |work = [[The New York Times]]| date = 13 January 2011| access-date = 13 January 2011| url-status=live| archive-url = https://web.archive.org/web/20120609101901/http://www.nytimes.com/2011/01/14/health/policy/14fda.html| archive-date = 9 June 2012 }}</ref><ref>{{cite press release |title=FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings |website=U.S. [[Food and Drug Administration]] (FDA) |date=15 January 2011 |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm |archive-url= https://web.archive.org/web/20110115151630/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm |archive-date=15 January 2011 |url-status=dead |access-date=23 February 2014}}{{PD-notice}}</ref> Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325{{nbsp}}mg per dosage unit.<ref name="FDA_CDER" /><ref name="NYT_Harris" />

In November 2011, the [[Medicines and Healthcare products Regulatory Agency]] revised UK dosing of liquid paracetamol for children.<ref>{{cite web |date=14 November 2011 |url=http://www.mhra.gov.uk/home/groups/s-par/documents/websiteresources/con134921.pdf |archive-url= https://web.archive.org/web/20191028074131/http://www.mhra.gov.uk/home/groups/s-par/documents/websiteresources/con134921.pdf |url-status=dead |archive-date=28 October 2019 |title=Liquid paracetamol for children: revised UK dosing instructions introduced |publisher=[[Medicines and Healthcare products Regulatory Agency]] (MHRA) |access-date=27 October 2019}}</ref>

In September 2013, "Use Only as Directed", an episode of the radio program ''[[This American Life]]''<ref>{{cite episode |title=Use Only as Directed |url= http://www.thisamericanlife.org/radio-archives/episode/505/use-only-as-directed |access-date=24 September 2013 |series=This American Life |series-link=This American Life |network=[[Public Radio International]] |station=[[WBEZ]] |location=Chicago |date=20 September 2013 |number=505 |url-status=live |archive-url= https://web.archive.org/web/20130927121525/http://www.thisamericanlife.org/radio-archives/episode/505/use-only-as-directed |archive-date=27 September 2013 }}</ref> highlighted deaths from paracetamol overdose. This report was followed by two reports by [[ProPublica]] alleging that the "FDA has long been aware of studies showing the risks of acetaminophen. So has the maker of Tylenol, McNeil Consumer Healthcare, a division of Johnson & Johnson"<ref>{{cite web |vauthors = Gerth J, Miller TC |title=Use Only as Directed |url=https://www.propublica.org/article/tylenol-mcneil-fda-use-only-as-directed |publisher=[[ProPublica]] |date=20 September 2013 |access-date=24 September 2013 |url-status=live |archive-url=https://web.archive.org/web/20130924034013/http://www.propublica.org/article/tylenol-mcneil-fda-use-only-as-directed |archive-date=24 September 2013 }}</ref> and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug."<ref>{{cite web| vauthors = Miller TC, Gerth J |title=Dose of Confusion |url=https://www.propublica.org/article/tylenol-mcneil-fda-kids-dose-of-confusion |publisher=[[ProPublica]] |date=20 September 2013 |access-date=24 September 2013 |url-status=live |archive-url= https://web.archive.org/web/20130924033315/http://www.propublica.org/article/tylenol-mcneil-fda-kids-dose-of-confusion |archive-date=24 September 2013 }}</ref>