Quinine: Difference between revisions

{{Short description|Medication used to treat malaria and babesiosis}}

{{distinguish|quinidine|quinone|quinoline|chloroquine}}

{{for|the Nine album|Quinine (album)}}

{{for|the flowering herb known as wild quinine|Parthenium integrifolium}}

{{Use dmy dates|date=March 2022}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox drug

| Watchedfields = changed

| verifiedrevid = 441980057

| image = Quinine structure.png

| width = 200

| alt =

| width2 = 180

| alt2 =

<!--Clinical data-->

| pronounce = {{IPAc-en|US|ˈ|k|w|aɪ|n|aɪ|n}}, {{IPAc-en|k|w|ɪ|ˈ|n|iː|n}} or {{IPAc-en|UK|ˈ|k|w|ɪ|n|iː|n}} {{respell|KWIN|een}}

| tradename = Qualaquin, Quinbisul, others<ref>{{cite web | title=Quinine International | website=Drugs.com | date=2 November 2020 | url=https://www.drugs.com/international/quinine.html | access-date=8 November 2020}}</ref>

| Drugs.com = {{drugs.com|monograph|quinine-sulfate}}

| MedlinePlus = a682322

| DailyMedID = Quinine

| licence_US = Quinine

| pregnancy_AU = D

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Quinine Use During Pregnancy | website=Drugs.com | date=25 March 2020 | url=https://www.drugs.com/pregnancy/quinine.html | access-date=13 August 2020}}</ref>

| pregnancy_US = N

| pregnancy_US_comment = <ref name="Drugs.com pregnancy" />

| legal_AU = S4

| legal_CA = Rx-only

| legal_UK = POM

| legal_US = Rx-only

| legal_status =

| routes_of_administration = [[Oral administration|By mouth]], [[intramuscular]], [[intravenous]], [[rectal administration|rectal]]

| ATC_prefix = M09

| ATC_suffix = AA01

| ATC_supplemental = {{ATC|P01|BC01}}

<!--Pharmacokinetic data-->

| bioavailability =

| protein_bound = 70–95%<ref name=MSR>{{cite web|title=Qualaquin (quinine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=29 January 2014|url=http://reference.medscape.com/drug/qualaquin-quinine-342696#showall|url-status=live|archive-url=https://web.archive.org/web/20140202183809/http://reference.medscape.com/drug/qualaquin-quinine-342696#showall|archive-date=2 February 2014}}</ref>

| metabolism = [[Liver]] (mostly [[CYP3A4]] and [[CYP2C19]]-mediated)

| elimination_half-life = 8–14 hours (adults), 6–12 hours (children)<ref name = MSR/>

| excretion = [[Kidney]] (20%)

<!--Identifiers-->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 130-95-0

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 15854

| PubChem = 8549

| IUPHAR_ligand = 2510

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00468

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 84989

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D08460

<!--Chemical data-->

| IUPAC_name = (''R'')-(6-Methoxyquinolin-4-yl)[(1''S'',2''S'',4''S'',5''R'')-5-vinylquinuclidin-2-yl]methanol

| C=20 | H=24 | N=2 | O=2

| SMILES = [H] [C@@]1([C@@H](C2=CC=NC3=CC=C(C=C23)OC)O)C[C@@H]4CC[N@]1C[C@@H]4C=C

<!-- Definition and uses -->

'''Quinine''' is a medication used to treat [[malaria]] and [[babesiosis]].<ref name=AHFS2020>{{Cite web|title=Quinine sulfate|url=https://www.drugs.com/monograph/quinine-sulfate.html|publisher=Drugs.com|date=20 February 2020|access-date=14 May 2020}}</ref> This includes the treatment of malaria due to ''[[Plasmodium falciparum]]'' that is resistant to [[chloroquine]] when [[artesunate]] is not available.<ref name=AHFS2020/><ref>{{cite journal | vauthors = Esu EB, Effa EE, Opie ON, Meremikwu MM | title = Artemether for severe malaria | journal = The Cochrane Database of Systematic Reviews | volume = 6 | pages = CD010678 | date = June 2019 | issue = 6 | pmid = 31210357 | pmc = 6580442 | doi = 10.1002/14651858.CD010678.pub3 }}</ref> While sometimes used for [[nocturnal leg cramps]], quinine is not recommended for this purpose due to the risk of serious [[side effect]]s.<ref name=AHFS2020/> It can be taken by mouth or [[intravenously]].<ref name=AHFS2020/> Malaria resistance to quinine occurs in certain areas of the world.<ref name=AHFS2020/> Quinine is also used as an ingredient in [[tonic water]] and other beverages to impart a bitter taste.<ref name="olmsted">{{cite book | vauthors = Olmsted J, Williams GM |title=Chemistry: The Molecular Science |date=1997 |publisher=Jones & Bartlett Learning |isbn=978-0-815-18450-8 |page=137 |url=https://books.google.com/books?id=1vnk6J8knKkC&pg=PA137 |url-status=live |archive-url=https://web.archive.org/web/20160915152729/https://books.google.com/books?id=1vnk6J8knKkC&pg=PA137 |archive-date=15 September 2016}}</ref>

<!-- Side effects and mechanism -->

Common side effects include headache, [[tinnitus|ringing in the ears]], vision issues, and [[sweating]].<ref name=AHFS2020/> More severe side effects include [[deafness]], [[thrombocytopenia|low blood platelets]], and an [[irregular heartbeat]].<ref name=AHFS2020/> Use can make one more prone to [[sunburn]].<ref name=AHFS2020/> While it is unclear if use during pregnancy carries potential for fetal harm, treating malaria during pregnancy with quinine when appropriate is still recommended.<ref name=AHFS2020/> Quinine is an [[alkaloid]], a naturally occurring chemical compound.<ref name=AHFS2020/> How it works as a medicine is not entirely clear.<ref name=AHFS2020/>

<!-- History, society, and culture -->

Quinine was first isolated in 1820 from the bark of a [[cinchona]] tree, which is native to [[Peru]],<ref name=AHFS2020/><ref>{{cite book | vauthors = Willcox M |date=28 June 2004 |title=Traditional Medicinal Plants and Malaria |url=https://books.google.com/books?id=L3lZiwsCZoYC&pg=PA23|publisher=CRC Press |page=231 |isbn=9780203502327}}</ref><ref>{{cite book | vauthors = Cechinel-Filho V |title= Plant bioactives and drug discovery : principles, practice, and perspectives|date=2012|publisher=John Wiley & Sons|location=Hoboken, N.J.|isbn=9780470582268|page=2|url=https://books.google.com/books?id=hhraBwhymOUC&pg=PA2|url-status=live|archive-url=https://web.archive.org/web/20160304073629/https://books.google.com/books?id=hhraBwhymOUC&pg=PA2|archive-date=4 March 2016}}</ref> and its molecular formula was determined by [[Adolph Strecker]] in 1854.<ref>{{Cite journal| vauthors = Strecker A |date=1854|title=Ueber einen neuen aus Aldehyd - Ammoniak und Blausäure entstehenden Körper |journal=Liebigs Ann. Chem.|volume=91|issue=3|pages=349–351|doi=10.1002/jlac.18540910309|url=https://zenodo.org/record/1427060 }}</ref> The class of chemical compounds to which it belongs is thus called the cinchona alkaloids. Bark extracts had been used to treat malaria since at least 1632 and it was introduced to Spain as early as 1636 by [[Jesuit missionaries]] returning from the [[New World]].<ref>{{cite book| vauthors = Staines HM, Krishna S |title=Treatment and Prevention of Malaria : Antimalarial Drug Chemistry, Action and Use.|date=2011|publisher=Springer Verlag|location=[S.l.]|isbn=9783034604796|page=45|url=https://books.google.com/books?id=cNuY6tyyyrUC&pg=PA45}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> Treatment of malaria with quinine marks the first known use of a chemical compound to treat an infectious disease.<ref>{{cite web |title=Quinine |url=https://www.britannica.com/science/quinine |website=Encyclopedia Britannica |access-date=12 November 2021}}</ref>

{{TOC limit}}

== Uses ==

=== Medical ===

As of 2006, quinine is no longer recommended by the [[World Health Organization]] (WHO) as a first-line treatment for [[malaria]], because there are other substances that are equally effective with fewer side effects. They recommend that it be used only when [[artemisinin#Artemisinin derivatives|artemisinins]] are not available.{{why|reason=Because of increasing malaria resistance to the drug?|date=March 2024}}<ref>{{cite web|author=World Health Organization|title=Guidelines for the treatment of malaria|publisher=World Health Organization|url=http://apps.who.int/malaria/docs/TreatmentGuidelines2006.pdf|year=2006|access-date=10 August 2009|url-status=dead|archive-url=https://web.archive.org/web/20090805225019/http://apps.who.int/malaria/docs/TreatmentGuidelines2006.pdf|archive-date=5 August 2009}}</ref><ref>{{cite journal | vauthors = Dondorp A, Nosten F, Stepniewska K, Day N, White N | title = Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial | journal = Lancet | volume = 366 | issue = 9487 | pages = 717–725 | year = 2005 | pmid = 16125588 | doi = 10.1016/S0140-6736(05)67176-0 | s2cid = 173027 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Reyburn H, Mtove G, Hendriksen I, von Seidlein L | title = Oral quinine for the treatment of uncomplicated malaria | journal = BMJ | volume = 339 | pages = b2066 | date = July 2009 | pmid = 19622550 | doi = 10.1136/bmj.b2066 | s2cid = 206891479 | url = https://researchonline.lshtm.ac.uk/id/eprint/5019/1/Oral%20quinine%20for%20the%20treatment%20of%20uncomplicated%20malaria%20_%20The%20BMJ.pdf }}</ref><ref>{{cite journal | vauthors = Achan J, Tibenderana JK, Kyabayinze D, Wabwire Mangen F, Kamya MR, Dorsey G, D'Alessandro U, Rosenthal PJ, Talisuna AO | title = Effectiveness of quinine versus artemether-lumefantrine for treating uncomplicated falciparum malaria in Ugandan children: randomised trial | journal = BMJ | volume = 339 | pages = b2763 | date = July 2009 | pmid = 19622553 | pmc = 2714631 | doi = 10.1136/bmj.b2763 }}</ref> Quinine is also used to treat [[Systemic lupus erythematosus|lupus]] and [[arthritis]].

Quinine was frequently prescribed as an [[off-label]] treatment for [[Cramps#Nocturnal leg cramps|leg cramps at night]], but this has become less common since 2010 due to a warning from the US [[Food and Drug Administration]] (FDA) that such practice is associated with life-threatening side effects.<ref name="FDA Safety Communication">{{cite web | url = https://www.fda.gov/drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm218202.htm | title = FDA Drug Safety Communication: New risk management plan and patient Medication Guide for Qualaquin (quinine sulfate) | access-date = 21 February 2011 | date = 7 August 2010 | publisher = U.S. [[Food and Drug Administration]] (FDA) | url-status = live | archive-url = https://web.archive.org/web/20110219065903/https://www.fda.gov/drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm218202.htm | archive-date = 19 February 2011}}</ref><ref name="FDA risks">{{cite web | title=Serious risks associated with using Quinine to prevent or treat nocturnal leg cramps (September 2012) | website=U.S. [[Food and Drug Administration]] (FDA)| date=31 August 2012 | url=https://www.fda.gov/ForHealthProfessionals/LearningActivities/ucm317811.htm | archive-url=https://web.archive.org/web/20161022135438/https://www.fda.gov/ForHealthProfessionals/LearningActivities/ucm317811.htm | archive-date=22 October 2016 | url-status=dead | access-date=19 January 2020}}</ref><ref>{{Cite web|url=https://www.consumerreports.org/cro/2012/04/quinine-for-night-time-leg-cramps-no-longer-recommended/index.htm|title=Quinine for Night-Time Leg Cramps |website=[[Consumer Reports]]|access-date=20 January 2020}}</ref> Quinine can also act as a competitive inhibitor of [[monoamine oxidase]] (MAO), an enzyme that removes neurotransmitters from the brain. As an [[Monoamine oxidase inhibitor|MAO inhibitor]], it has potential to serve as a treatment for individuals with psychological disorders, similar to antidepressants that inhibit MAO.<ref>{{cite journal | vauthors = Mitsui N, Noro T, Kuroyanagi M, Miyase T, Umehara K, Ueno A | title = Monoamine oxidase inhibitors from Cinchonae Cortex | journal = Chemical & Pharmaceutical Bulletin | volume = 37 | issue = 2 | pages = 363–366 | date = February 1989 | pmid = 2743481 | doi = 10.1248/cpb.37.363 | doi-access = free }}</ref>

====Available forms====

Quinine is a basic [[amine]] and is usually provided as a salt. Various existing preparations include the [[hydrochloride]], dihydrochloride, [[sulfate]], bisulfate and [[gluconate]]. In the United States, quinine sulfate is commercially available in 324&nbsp;mg tablets under the brand name Qualaquin.

All quinine salts may be given orally or [[Intravenous therapy|intravenous]]ly (IV); quinine gluconate may also be given [[intramuscular injection|intramuscular]]ly (IM) or rectally (PR).<ref name="Barennes1996">{{cite journal | vauthors = Barennes H, Pussard E, Mahaman Sani A, Clavier F, Kahiatani F, Granic G, Henzel D, Ravinet L, Verdier F | title = Efficacy and pharmacokinetics of a new intrarectal quinine formulation in children with Plasmodium falciparum malaria | journal = British Journal of Clinical Pharmacology | volume = 41 | issue = 5 | pages = 389–395 | date = May 1996 | pmid = 8735679 | pmc = 2042609 | doi = 10.1046/j.1365-2125.1996.03246.x }}</ref><ref name="Barennes2006">{{cite journal | vauthors = Barennes H, Balima-Koussoubé T, Nagot N, Charpentier JC, Pussard E | title = Safety and efficacy of rectal compared with intramuscular quinine for the early treatment of moderately severe malaria in children: randomised clinical trial | journal = BMJ | volume = 332 | issue = 7549 | pages = 1055–1059 | date = May 2006 | pmid = 16675812 | pmc = 1458599 | doi = 10.1136/bmj.332.7549.1055 }}</ref> The main problem with rectal administration is that the dose can be expelled before it is completely absorbed; in practice, this is corrected by giving a further half dose. No injectable preparation of quinine is licensed in the US; [[quinidine]] is used instead.<ref>{{cite journal | vauthors = ((Centers for Disease Control and Prevention)) | title = Treatment with quinidine gluconate of persons with severe Plasmodium falciparum infection: discontinuation of parenteral quinine from CDC Drug Service | journal = MMWR. Recommendations and Reports | volume = 40 | issue = RR-4 | pages = 21–23 | date = April 1991 | pmid = 1850497 | url = https://www.cdc.gov/mmwr/preview/mmwrhtml/00043932.htm }}</ref><ref>{{cite journal | vauthors = Magill A, Panosian C | title = Making antimalarial agents available in the United States | journal = The New England Journal of Medicine | volume = 353 | issue = 4 | pages = 335–337 | date = July 2005 | pmid = 16000347 | doi = 10.1056/NEJMp058167 | author-link2 = Claire Panosian | doi-access = free }}</ref>

{| class="wikitable"

|+'''Quinine base in various salts'''

!Name

!Amount equivalent to 100&nbsp;mg quinine base

|-

|Quinine base

|100&nbsp;mg

|-

|Quinine bisulfate

|169&nbsp;mg

|-

|Quinine dihydrochloride

|122&nbsp;mg

|-

|Quinine gluconate

|160&nbsp;mg

|-

|Quinine hydrochloride

|111&nbsp;mg

|-

|Quinine sulfate dihydrate [(quinine)₂H₂SO₄∙2H₂O]

|121&nbsp;mg

|}

===Beverages===

{{See also|Tonic water}}

[[File:Tonic water uv.jpg|thumb|[[Tonic water]], in normal light and ultraviolet "[[black light]]". The quinine content of tonic water causes it to [[fluorescence|fluoresce]] under black light.]]

Quinine is a flavor component of [[tonic water]] and [[bitter lemon]] [[drink mixer]]s. On the [[soda gun]] behind many bars, tonic water is designated by the letter "Q" representing quinine.<ref>{{cite book | vauthors = Charming C |title=Miss Charming's Guide for Hip Bartenders and Wayout Wannabes |page=189 |year=2006 |publisher=Sourcebooks, Inc. |location=USA |isbn=978-1-4022-0804-1 }}</ref>

Tonic water was initially marketed as a means of delivering quinine to consumers in order to offer anti-malarial protection. According to tradition, because of the bitter taste of anti-[[malaria]]l quinine tonic, British colonials in India mixed it with [[gin]] to make it more palatable, thus creating the [[gin and tonic]] cocktail, which is still popular today.<ref>{{cite web | vauthors = Khosla S |title=Gin and Tonic: The fascinating story behind the invention of the classic English cocktail |url=https://www.india.com/lifestyle/gin-and-tonic-the-fascinating-story-behind-the-invention-of-the-classic-english-cocktail-1934782/ |website=India.com |access-date=8 June 2019|date=17 March 2017 }}</ref> While it is possible to drink enough tonic water to temporarily achieve quinine levels that offer anti-malarial protection, it is not a sustainable long-term means of protection.<ref>{{cite journal | vauthors = Meyer CG, Marks F, May J | title = Editorial: Gin tonic revisited | journal = Tropical Medicine & International Health | volume = 9 | issue = 12 | pages = 1239–1240 | date = December 2004 | pmid = 15598254 | doi = 10.1111/j.1365-3156.2004.01357.x | s2cid = 24261782 | doi-access = free }}</ref>

In France, quinine is an ingredient of an {{lang|fr|[[apéritif]]}} known as {{lang|fr|[[quinquina]]}}, or ''"Cap Corse"'', and the wine-based {{lang|fr|apéritif}} [[Dubonnet]]. In Spain, quinine (also known as "Peruvian bark" for its origin from the native cinchona tree) is sometimes blended into sweet [[Malaga (wine)|Malaga wine]], which is then called ''"Malaga Quina"''. In Italy, the traditional flavoured wine [[Barolo#Barolo Chinato|Barolo Chinato]] is infused with quinine and local herbs, and is served as a {{Lang|fr|[[digestif]]}}. In Britain, the company [[A.G. Barr]] uses quinine as an ingredient in the carbonated and [[caffeinated beverage]] [[Irn-Bru]]. In Uruguay and Argentina, quinine is an ingredient of a [[PepsiCo]] tonic water named [[Paso de los Toros (drink)|Paso de los Toros]]. In Denmark, it is used as an ingredient in the carbonated sports drink [[Faxe Kondi]] made by [[Royal Unibrew]].

As a flavouring agent in drinks, quinine is limited to 83&nbsp;[[Parts per million|ppm]] ({{nowrap|100 mg/L}}) in the United States, and in the European Union.<ref>{{cite journal | vauthors = Ballestero JA, Plazas PV, Kracun S, Gómez-Casati ME, Taranda J, Rothlin CV, Katz E, Millar NS, Elgoyhen AB | title = Effects of quinine, quinidine, and chloroquine on alpha9alpha10 nicotinic cholinergic receptors | journal = Molecular Pharmacology | volume = 68 | issue = 3 | pages = 822–829 | date = September 2005 | pmid = 15955868 | doi = 10.1124/mol.105.014431 | s2cid = 26907917 }}</ref><ref>{{cite web|title=Food Additive Status List|url=https://www.fda.gov/food/ingredientspackaginglabeling/foodadditivesingredients/ucm091048.htm|website=U.S. Food and Drug Administration|publisher=U.S. Department of Health and Human Services|access-date=9 October 2017}}</ref><ref>{{cite web|title=COMMISSION IMPLEMENTING REGULATION (EU) No 872/2012|url=http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1507509835974&uri=CELEX:32012R0872|website=EUR-Lex|publisher=Official Journal of the European Union|access-date=9 October 2017}}</ref>

===Scientific===

Quinine (and [[quinidine]]) are used as the [[chirality (chemistry)|chiral]] [[Moiety (chemistry)|moiety]] for the [[ligand]]s used in [[Sharpless asymmetric dihydroxylation]] as well as for numerous other chiral catalyst backbones. Because of its relatively constant and well-known [[fluorescence]] [[quantum yield]], quinine is used in [[photochemistry]] as a common fluorescence [[Standard (metrology)|standard]].<ref name="books.google.co.in">{{cite book| vauthors = Lakowicz JR |authorlink=Joseph R. Lakowicz|title=Principles of Fluorescence Spectroscopy|url=https://books.google.com/books?id=-PSybuLNxcAC|edition=3rd|year=2006|publisher=Springer Science & Business Media|isbn=978-0-387-46312-4|page=54|chapter=2. Instrumentation for Fluorescence Spectroscopy}}</ref><ref name="Quinine sulfate">{{cite web | vauthors = Prahl S |title=Quinine sulfate |url=https://omlc.org/spectra/PhotochemCAD/html/081.html |website=OMLC |access-date=16 August 2013}}</ref>

==Contraindications==

Because of the narrow difference between its therapeutic and toxic effects, quinine is a common cause of drug-induced disorders, including [[thrombocytopenia]] and [[thrombotic microangiopathy]].<ref name="liles">{{cite journal | vauthors = Liles NW, Page EE, Liles AL, Vesely SK, Raskob GE, George JN | title = Diversity and severity of adverse reactions to quinine: A systematic review | journal = American Journal of Hematology | volume = 91 | issue = 5 | pages = 461–466 | date = May 2016 | pmid = 26822544 | doi = 10.1002/ajh.24314 | doi-access = free }}</ref> Even from minor levels occurring in common beverages, quinine can have severe [[adverse event|adverse effects]] involving multiple organ systems, among which are [[immune system]] effects and [[fever]], [[hypotension]], [[hemolytic anemia]], [[acute kidney injury]], liver toxicity, and blindness.<ref name=liles/> In people with [[atrial fibrillation]], [[Electrical conduction system of the heart|conduction defect]]s, or [[heart block]], quinine can cause [[heart arrhythmia]]s, and should be avoided.<ref>{{Cite journal|date=2017|title=Off-label use of sildenafil in valvular heart disease should be avoided|journal=Clinical Pharmacist|doi=10.1211/cp.2017.20203778|issn=2053-6178}}</ref>{{Failed verification|date=June 2023}}

Quinine can cause [[hemolysis]] in [[G6PD deficiency]] (an inherited deficiency), but this risk is small and the physician should not hesitate to use quinine in people with G6PD deficiency when there is no alternative.<ref name=USlabel2013>{{cite web|title=US label: quinine sulfate|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021799s023lbl.pdf|publisher=FDA|date=April 2013|url-status=live|archive-url=https://web.archive.org/web/20170120063419/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021799s023lbl.pdf|archive-date=20 January 2017}}</ref>

While not necessarily an absolute contraindication, concomitant administration of quinine with drugs primarily metabolized by [[CYP2D6]] may lead to higher than expected plasma concentrations of the drug, due to quinine's strong inhibition of the enzyme.<ref name=PMID27618912/>

==Adverse effects==

Quinine can cause unpredictable serious and life-threatening blood and cardiovascular reactions including [[thrombocytopenia|low platelet count]] and [[hemolytic–uremic syndrome]]/[[thrombotic thrombocytopenic purpura]] (HUS/TTP), [[long QT syndrome]] and other serious cardiac arrhythmias including ''[[torsades de pointes]]'', [[blackwater fever]], [[disseminated intravascular coagulation]], [[leukopenia]], and [[neutropenia]].<ref name=AHFS2020/> Some people who have developed TTP due to quinine have gone on to develop [[kidney failure]].<ref name=AHFS2020/><ref name=USlabel2013/> It can also cause serious hypersensitivity reactions including anaphylactic shock, [[urticaria]], serious skin rashes, including [[Stevens–Johnson syndrome]] and [[toxic epidermal necrolysis]], [[angioedema]], facial edema, [[bronchospasm]], [[Idiopathic granulomatous hepatitis|granulomatous hepatitis]], and itchiness.<ref name=AHFS2020/><ref name=USlabel2013/>

The most common adverse effects involve a group of symptoms called [[cinchonism]], which can include headache, vasodilation and sweating, nausea, [[tinnitus]], hearing impairment, [[vertigo]] or dizziness, blurred vision, and disturbance in color perception.<ref name=AHFS2020/><ref name=liles/><ref name=USlabel2013/> More severe cinchonism includes vomiting, diarrhea, abdominal pain, deafness, blindness, and disturbances in heart rhythms.<ref name=USlabel2013/> Cinchonism is much less common when quinine is given by mouth, but oral quinine is not well tolerated (quinine is exceedingly bitter and many people will vomit after ingesting quinine tablets).<ref name=AHFS2020/> Other drugs, such as Fansidar ([[sulfadoxine]] with [[pyrimethamine]]) or Malarone ([[proguanil]] with [[atovaquone]]), are often used when oral therapy is required. Quinine ethyl carbonate is tasteless and odourless,<ref>{{cite journal |vauthors = Jamaludin A, Mohamad M, Navaratnam V, Selliah K, Tan SC, Wernsdorfer WH, Yuen KH |title = Relative bioavailability of the hydrochloride, sulphate and ethyl carbonate salts of quinine |journal = British Journal of Clinical Pharmacology |volume = 25 |issue = 2 |pages = 261–263 |date = February 1988 |pmid = 3358888 |pmc = 1386482 |doi = 10.1111/j.1365-2125.1988.tb03299.x }}</ref> but is available commercially only in Japan. Blood glucose, electrolyte and cardiac monitoring are not necessary when quinine is given by mouth.

Quinine has diverse [[Drug interaction|unwanted interactions]] with numerous [[prescription drug]]s, such as potentiating the [[anticoagulant]] effects of [[warfarin]].<ref name=AHFS2020/> It is a strong inhibitor of [[CYP2D6]],<ref name="PMID27618912">{{cite journal | vauthors = Fasinu PS, Tekwani BL, Avula B, Chaurasiya ND, Nanayakkara NP, Wang YH, Khan IA, Walker LA | title = Pathway-specific inhibition of primaquine metabolism by chloroquine/quinine | journal = Malaria Journal | volume = 15 | issue = 1 | pages = 466 | date = September 2016 | pmid = 27618912 | pmc = 5020452 | doi = 10.1186/s12936-016-1509-x | doi-access = free }}</ref> an enzyme involved in the metabolism of many drugs.

==Mechanism of action==

{{missing information|section|cramp mechanism; MAOI action aforementioned|date=December 2022}}

Quinine is used for its [[toxicity]] to the malarial pathogen, ''[[Plasmodium falciparum]]'', by interfering with its ability to dissolve and metabolize [[hemoglobin]].<ref name=AHFS2020/><ref>{{Cite DrugBank |drug=Quinine|id=DB00468 }}</ref> As with other quinoline antimalarial drugs, the precise [[mechanism of action]] of quinine has not been fully resolved, although [[in vitro]] studies indicate it inhibits [[nucleic acid]] and protein synthesis, and inhibits [[glycolysis]] in ''P. falciparum''.<ref name=AHFS2020/> The most widely accepted hypothesis of its action is based on the well-studied and closely related quinoline drug, [[chloroquine]]. This model involves the inhibition of [[hemozoin]] [[biocrystallization]] in the [[Heme ligase|heme detoxification]] pathway, which facilitates the aggregation of [[cytotoxic]] [[heme]].{{medcn|date=May 2020}} Free cytotoxic heme accumulates in the parasites, causing their deaths.<ref>{{cite journal | vauthors = Foley M, Tilley L | title = Quinoline antimalarials: mechanisms of action and resistance | journal = International Journal for Parasitology | volume = 27 | issue = 2 | pages = 231–240 | date = February 1997 | pmid = 9088993 | doi = 10.1016/s0020-7519(96)00152-x }}</ref> Quinine may target the malaria [[purine nucleoside phosphorylase]] enzyme.<ref>{{cite journal |url=https://www.science.org/content/blog-post/quinine-s-target |title=Quinine's Target | vauthors = Lowe D |author-link=Derek Lowe |journal=[[Science (journal)|Science]] |date=22 January 2019 |access-date=28 January 2019 }}</ref>

==Chemistry==

The [[Ultraviolet|UV]] absorption of quinine peaks around 350&nbsp;nm (in [[Ultraviolet A|UVA]]). Fluorescent emission peaks at around 460&nbsp;nm (bright blue/cyan hue).<ref>{{cite web |url=http://www.olympusmicro.com/primer/techniques/fluorescence/fluorescenceintro.html |title=Basic Concepts in Fluorescence |url-status=live |archive-url=https://web.archive.org/web/20120913065648/http://www.olympusmicro.com/primer/techniques/fluorescence/fluorescenceintro.html |archive-date=13 September 2012}}</ref> Quinine is highly [[fluorescence|fluorescent]] ([[quantum yield]] ~0.58) in 0.1&nbsp;[[Molar concentration|M]] [[sulfuric acid]] solution.<ref name="books.google.co.in"/><ref name="Quinine sulfate"/>

===Synthesis===

{{Main|Quinine total synthesis}}

[[Cinchona|Cinchona trees]] remain the only economically practical source of quinine. However, under wartime pressure during World War II, research towards its synthetic production was undertaken. A formal chemical synthesis was accomplished in 1944 by American chemists [[Robert Burns Woodward|R.B. Woodward]] and [[W.E. Doering]].<ref name="Woodward1944">

{{cite journal |vauthors=Woodward R, Doering W | title = The Total Synthesis of Quinine | journal = [[Journal of the American Chemical Society|J Am Chem Soc]] | volume = 66 | issue = 849 | pages = 849 | year = 1944| doi = 10.1021/ja01233a516 }}</ref> Since then, several more efficient [[quinine total synthesis|quinine total syntheses]] have been achieved,<ref>{{cite journal | vauthors = Kaufman TS, Rúveda EA |year=2005 |title=Die Jagd auf Chinin: Etappenerfolge und Gesamtsiege |language=de|journal=Angewandte Chemie International Edition |volume=117 |issue=6 |pages=876–907 |doi=10.1002/ange.200400663 |bibcode=2005AngCh.117..876K }}</ref> but none of them can compete in economic terms with isolation of the alkaloid from natural sources. The first synthetic [[organic chemistry|organic]] [[dye]], [[mauveine]], was discovered by [[William Henry Perkin]] in 1856 while he was attempting to synthesize quinine.

===Biosynthesis===

[[File:Quinine Biosynthesis.png|thumb|Quinine biosynthesis]]

In the first step of quinine [[biosynthesis]], the enzyme strictosidine synthase catalyzes a stereoselective [[Pictet–Spengler reaction]] between [[tryptamine]] and [[secologanin]] to yield [[strictosidine]].<ref>{{cite journal | vauthors = Treimer JF, Zenk MH | title = Purification and properties of strictosidine synthase, the key enzyme in indole alkaloid formation | journal = European Journal of Biochemistry | volume = 101 | issue = 1 | pages = 225–233 | date = November 1979 | pmid = 510306 | doi = 10.1111/j.1432-1033.1979.tb04235.x | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mizukami H, Nordlöv H, Lee SL, Scott AI | title = Purification and properties of strictosidine synthetase (an enzyme condensing tryptamine and secologanin) from Catharanthus roseus cultured cells | journal = Biochemistry | volume = 18 | issue = 17 | pages = 3760–3763 | date = August 1979 | pmid = 476085 | doi = 10.1021/bi00584a018 }}</ref> Suitable modification of [[strictosidine]] leads to an aldehyde. Hydrolysis and decarboxylation would initially remove one carbon from the iridoid portion and produce corynantheal. Then the [[tryptamine]] side-chain were cleaved adjacent to the nitrogen, and this nitrogen was then bonded to the acetaldehyde function to yield cinchonaminal. Ring opening in the indole heterocyclic ring could generate new amine and keto functions. The new quinoline heterocycle would then be formed by combining this amine with the aldehyde produced in the [[tryptamine]] side-chain cleavage, giving cinchonidinone. For the last step, hydroxylation and methylation gives quinine.<ref>{{cite book |title=Medicinal natural products : a biosynthetic approach |publisher=Wiley |isbn=9780470742761 |pages=380–381 |edition=3rdition}}</ref><ref>{{cite journal | vauthors = O'Connor SE, Maresh JJ | title = Chemistry and biology of monoterpene indole alkaloid biosynthesis | journal = Natural Product Reports | volume = 23 | issue = 4 | pages = 532–547 | date = August 2006 | pmid = 16874388 | doi = 10.1039/b512615k }}</ref>

===Catalysis===

Quinine and other [[Cinchona alkaloid|''Cinchona'' alkaloids]] can be used as [[organocatalysis|catalysts]] for [[stereoselective]] reactions in [[organic synthesis]].<ref name="Reyes-et-al-2016">{{citation | vauthors = Reyes E, Uria U, Vicario JL, Carrillo L | chapter = The Catalytic, Enantioselective Michael Reaction | title = Organic Reactions | publisher=John Wiley & Sons, Inc. | publication-place=[[Hoboken]], New Jersey, US | date=2016-09-13 | doi=10.1002/0471264180.or090.01 | pages=1–898 | isbn=978-0-471-26418-7}}</ref>{{rp|at=Table 3B Plate 560}} For example, the quinine-catalyzed [[Michael addition]] of a [[malononitrile]] to [[α,β-enone]]s gives a high degree of sterechemical control.<ref name="Reyes-et-al-2016" />

==History==

{{see also|History of malaria}}

[[Image:Cinchona calisaya - Köhler–s Medizinal-Pflanzen-179.jpg|thumb|19th-century illustration of ''Cinchona calisaya'']]

Quinine was used as a muscle relaxant by the [[Quechuas|Quechua]] people, who are indigenous to [[Peru]], [[Bolivia]] and [[Ecuador]], to halt shivering.<ref>{{cite book| vauthors = Flückiger FA, Hanbury D |authorlink1=Friedrich August Flückiger |authorlink2=Daniel Hanbury|title=Pharmacographia: A History of the Principal Drugs of Vegetable Origin, Met with in Great Britain and British India|chapter-url=https://books.google.com/books?id=ATQbAAAAYAAJ&pg=PA302|year=1874|publisher=Macmillan and Co.|location=London|pages=302–331|chapter=Cortex Cinchonæ}}</ref> The Quechua would mix the ground bark of [[cinchona]] trees with sweetened water to offset the bark's bitter taste, thus producing something similar to [[tonic water]].<ref>{{cite book | vauthors = Hobbs K, West D |title=The Story of Trees : and how they changed the way we live |date=2020 |others=illustrated by Thibaud Hérem |publisher=Laurence King |location=London |isbn=978-1-7862-7522-6 |page=148}}</ref>

Spanish [[Society of Jesus|Jesuit]] missionaries were the first to bring cinchona to Europe. The Spanish had observed the Quechua's use of cinchona and were aware of the medicinal properties of cinchona bark by the 1570s or earlier: [[Nicolás Monardes]] (1571) and Juan Fragoso (1572) both described a tree, which was subsequently identified as the cinchona tree, whose bark was used to produce a drink to treat [[diarrhea]].<ref>See:

* {{cite journal | vauthors = Ortiz Crespo FI |title=Fragoso, Monardes and pre-Chinchonian knowledge of Cinchona |journal=Archives of Natural History |date=1995 |volume=22 |issue=2 |pages=169–181 |doi=10.3366/anh.1995.22.2.169 |issn=0260-9541 |url=https://www.reumatologiaclinica.org/en-pdf-S2173574307702460}}

* {{cite book| vauthors = Stuart DC |title=Dangerous Garden: The Quest for Plants to Change Our Lives|url=https://books.google.com/books?id=Ze0n0yeqsXUC&pg=PA28 |year=2004 |publisher=Harvard University Press |location=Cambridge, MA |isbn=978-0-674-01104-5 |page=28}}

* {{cite book| vauthors = Monardes N |authorlink=Nicolás Monardes |title=Primera y segunda y tercera partes de la Historia medicinal, de las cosas que se traen de nuestras Indias Occidentales, que sirven en Medicina |url=https://books.google.com/books?id=BMiaWiCqFCMC&pg=RA1-PA75-IA2 |year=1580 |publisher=Fernando Díaz |location=Seville, Spain |language=es |pages=74–75 |trans-title=First and second and third parts of medicinal History, of the things that are brought from our West Indies, which are used in Medicine |quote=Del nuevo Reyno, traen una corteza, que dizen ser de un arbol, que es de mucha grandeza: el qual dizen que lleva unas hojas en forma de coraçon, y que no lleva fruto. Este arbol tiene una corteza gruessa, muy solida y dura, que en esto y en el color parece mucho a la corteza del palo que llaman Guayacan: en la superficie tiene una pelicula delgada blanquisca, quebrada por toda ella: tiene la corteza mas de un dedo de gruesso, solida y pesada: la qual gustada tiene notable amargor, como el de la Genciana: tiene en el gusto notable astriction, con alguna aromaticidad, porque al fin de mascar la respica della buen olor. Tienen los Indios esta corteza en mucho, y usan della en todo genero de camaras, que sean con sangre, o sin ella. Los Españoles fatigados de aquesta enfermedad, por aviso de los Indios, han usado de aquesta corteza y han sanado muchos dellos con ella.<br />Toman della tanto como una haba pequeña hecha polvos, tomase en vino tinto, o en agua apropiada, como tienen la calentura, o mal: hase de tomar por la mañana en ayunas, tres o quatro vezes: usando en lo demas, la orden y regimiento que conviene a los que tienen camaras. |trans-quote=From the new kingdom, there is brought a bark, which is said to be from a tree, which is very large: it is said that it bears leaves in the form of a heart, and that it bears no fruit. This tree has a thick bark, very solid and hard, that in this and in its color looks much like the bark of the tree that is called ''[[lignum vitae|guayacán]]'': on the surface, it has a thin, discontinuous whitish film throughout it: it has bark more than one finger thick, solid and heavy: which, when tasted, has a considerable bitterness, like that of the gentian: it has in its taste a considerable astringency, with some aromaticity, because at the end of chewing it, one breathes with a sweet odor. The Indians hold this bark in high regard, and use it for all sorts of diarrhea, that are with blood [i.e., bloody] and without it. The Spanish [who are] tired of this disease, on the advice of the Indians, have used this bark and have healed many of those with it. They take as much as a small bean, make [it into] powder, take it in red wine or in appropriate water, if they have fever or illness: it must be taken in the morning on an empty stomach, three or four times: otherwise, using the order and regimen that suits those who have diarrhea.}}

* {{cite book| vauthors = Fragoso J |title=Discursos de las cosas aromaticas, arboles y frutales, y de otras muchas medicinas simples que se traen de la India Oriental y que sirven al uso de medicina |url=https://books.google.com/books?id=ZGpIEb3BRfAC |year=1572 |publisher=Francisco Sánchez |location=Madrid, Spain |language=es |page=35 |trans-title=Discourse on fragrant things, trees and fruits, as well as many other ordinary medicines that have been brought from India and the Orient and are of use to medicine |quote=En el nuevo mundo ay un grande arbol que lleva las hojas a forma de coraçon, y carece de fruto. Tiene dos cortezas, la una gruessa muy solida y dura, que assi en la sustancia como en el color es muy semejante al Guayacan: la otra es mas delgada y blanquezina, la qual es amarga con alguna estipticidad: y demas desto es aromatica. Tienenla en mucho nuestros Indios, porque la usan contra qualesquier camaras, tomando del polvo peso de una drama o poco mas, desatado en agua azerada, o vino tinto. |trans-quote=In the new world, there is a big tree that bears leaves in the form of a heart, and lacks fruit. It has two barks, one [is] thick, very solid, [and] hard, which in substance as well as in color is much like ''guayacan'' [i.e., ''lignum vitae'']: the other is thinner and whitish, which is bitter with some styptic [i.e., astringent] quality: and besides this, it is aromatic. Our Indians regard it highly, because they use it against any diarrheas, taking a weight of a dram or a bit more of the powder, mixing it in mineral water, or red wine.}}</ref> Quinine has been used in unextracted form by Europeans since at least the early 17th century.<ref>{{cite journal | vauthors = Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, Rosenthal PJ, D'Alessandro U | title = Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria | journal = Malaria Journal | volume = 10 | pages = 144 | date = May 2011 | pmid = 21609473 | pmc = 3121651 | doi = 10.1186/1475-2875-10-144 | doi-access = free }}</ref>

A popular story of how it was brought to Europe by the [[Countess of Chinchon]] was debunked by medical historian [[Alec Haggis]] around 1941.<ref>{{cite journal | vauthors = Pain S |title=The Countess and the cure |journal=New Scientist |date=15 September 2001 |url=https://www.newscientist.com/article/mg17123085-200-the-countess-and-the-cure/}}</ref> During the 17th century, malaria was endemic to the [[swamp]]s and [[marsh]]es surrounding the city of [[Rome]]. It had caused the deaths of several [[pope]]s, many [[Cardinal (Catholicism)|cardinal]]s and countless common Roman citizens. Most of the Catholic [[priest]]s trained in Rome had seen malaria patients and were familiar with the [[shivering]] brought on by the [[wikt:febrile|febrile]] phase of the disease.

The [[Jesuit]] Agostino Salumbrino (1564–1642),<ref>{{cite book| vauthors = de Andrade A |authorlink=Alonso Andrada |others=Original series by [[Juan Eusebio Nieremberg]] |title=Varones ilustres en santidad, letras y zelo de las almas de la Compañía de Jesús |url=https://books.google.com/books?id=paaIyIGye1gC&pg=PA612 |series=Varones ilustres de la Compañía de Jesús |volume=5 |date=3 August 1642 |publication-date=1666 |publisher=José Fernandez de Buendía |location=Madrid, Spain |language=es |pages=612–628 |chapter=Vida del Devoto Hermano Agustin Salumbrino |trans-title=Illustrious men in holiness, letters, and zeal for souls of the [[Society of Jesus]] |trans-chapter=The life of the devout Brother Agustin Salumbrino |quote-page=612 |quote=Naciò el Hermano Agustin Salumbrino el año de mil y quinientos y sesenta y quatro en la Ciudad de Fḷọṛi en la Romania […] |trans-quote=Brother Agustino Salumbrino was born in the year 1564 in the city of [[Forlì]] in [[Romagna]]}}</ref> an [[apothecary]] by training who lived in [[Lima]] (now in present-day [[Peru]]), observed the Quechua using the bark of the cinchona tree to treat such shivering. While its effect in treating malaria (and malaria-induced shivering) was unrelated to its effect in controlling shivering from [[rigors]], it was a successful medicine against malaria. At the first opportunity, Salumbrino sent a small quantity to Rome for testing as a malaria treatment.<ref>See:

* {{cite journal | vauthors = Medina Rodríguez F, Aceves Ávila FJ, Moreno Rodríguez J |title=Precisions on the History of Quinine |journal=Reumatología Clínica |date=2007 |volume=3 |issue=4 |pages=194–196 |doi=10.1016/S2173-5743(07)70246-0 |series=Letters to the Editor |issn=2173-5743 |quote=In fact, though the last wordon this has not yet been spoken, there are Jesuit texts thatmention that quinine reached Rome in 1632, with theprovincial of the Jesuit missions in Peru, father AlonsoMessia Venegas, as its introducer, when he brought asample of the bark to present it as a primacy, and whohad left Lima 2 years earlier, because evidence of his stayin Seville 1632 has been registered, publishing one of hisbooks there and following his way to Rome as a procurator. |url=https://www.reumatologiaclinica.org/en-pdf-S2173574307702460}}

* {{cite book | vauthors = Torres Saldamando E |title=Los antiguos jesuitas del Perú |date=June 1882 |publisher=Imprenta Liberal |location=Lima, Peru |pages=180–181 |chapter-url=https://archive.org/details/losantiguosjesui00torr/page/180/mode/2up |language=es |chapter=El P. Diego de Torres Vazquez |quote=Al siguiente año se dirigieron á Europa los Procuradores P. Alonso Messía Venegas y P. Hernando de Leon Garavito, llevando gran cantidad de la corteza de la quina, cuyo conocimiento extendieron por el mundo los jesuitas. |quote-page=181 |trans-quote=In the following year [i.e., 1631] there went to Europe the procurators Father Alonso Messia Venegas and Father Hernando de Leon Garavito, taking a great quantity of cinchona bark, knowledge of which the Jesuits spread throughout the world.}}

* {{cite web | vauthors = Bailetti A |title=Capítulo 10: La Condesa de Chinchón |url=http://lamalariayelarboldequina.blogspot.com/2013/11/capitulo-9-proximamente.html |website=LA MISIÓN DEL JESUITA AGUSTÍN SALUMBRINO, la malaria y el árbol de quina |quote=A últimas horas de la tarde del treinta y uno de mayo de 1631 se hizo a la vela la Armada Real con dirección a Panamá llevando el precioso cargamento de oro y plata.<br />En una de las naves viajaban los procuradores jesuitas padres Alonso Messia y Hernando León Garavito custodiando los fardos con la corteza de quina en polvo preparados por Salumbrino. Después de casi veinte días de navegación el inapreciable medicamento llegó a la ciudad de Panamá, donde fue descargado para cruzar en mulas el agreste camino del itsmo palúdico hasta Portobelo para seguir a Cartagena y la Habana, cruzar el Atlántico y llegar a Sanlúcar de Barrameda en Sevilla. […] Finalmente siguió su camino a Roma y a su destino final el Hospital del Espíritu Santo. |trans-quote=Late in the afternoon of 31 May 1631, the royal armada set sail in the direction of Panama, carrying its multimillion [dollar] cargo of gold and silver.<br />On one of the ships traveled the Jesuit procurators Fathers Alonso Messia and Hernando León Garavito, guarding the cases of powdered cinchona bark, prepared by Salumbrino. After almost 20 days of sailing, medicine arrived in the city of Panama, where it was transloaded onto mules. It then traveled the malarial isthmus as far as Portobelo, thence to Cartagena [in Colombia] and Havana. It then traveled to Sanlúcar de Barrameda in Seville, [Spain]. […] Finally it followed the road to Rome and to its final destination, the Hospital of the Holy Spirit}}</ref> In the years that followed, cinchona bark, known as [[Jesuit's bark]] or Peruvian bark, became one of the most valuable commodities shipped from Peru to Europe. When [[Charles II of England|King Charles II]] was cured of malaria at the end of the 17th Century with quinine, it became popular in [[London]].<ref>{{cite book| vauthors = Rocco F |title=Quinine: malaria and the quest for a cure that changed the world |year=2004 |publisher=Perennial |location=New York, NY }}</ref> It remained the antimalarial drug of choice until the 1940s, when other drugs took over.<ref>{{cite book| vauthors = Humphrey L |title=Quinine and Quarantine|year=2000 | location = Columbia, Missouri | publisher = University of Missouri Press }}</ref>

The form of quinine most effective in treating malaria was found by [[Charles Marie de La Condamine]] in 1737.<ref>{{cite book | vauthors = Marie de la Condamine C |authorlink=Charles Marie de La Condamine |title=Histoire de l'Académie royale des sciences |chapter-url=https://books.google.com/books?id=yOAEAAAAQAAJ&pg=PA226 |date=29 May 1737 |publisher=Imprimerie Royale |pages=226–243 |chapter=Sur l'arbre du quinquina |publication-date=1740}}</ref><ref>De Jussieu accompanied de la Condamine on the latter's expedition to Peru: {{cite book | vauthors = de Jussieu J |author1-link=Joseph de Jussieu |title=Description de l'arbre à quinquina |date=1737 |publisher=Société du traitement des quinquinas |location=Paris |url=https://gallica.bnf.fr/view3if/ga/ark:/12148/bpt6k90339p |publication-date=1934}}</ref> In 1820, French researchers [[Pierre Joseph Pelletier]] and [[Joseph Bienaimé Caventou]] first isolated quinine from the bark of a tree in the genus ''[[Cinchona]]'' – probably ''[[Cinchona pubescens]]'' – and subsequently named the substance.<ref>{{cite journal | vauthors = Pelletier PJ, Caventou JB | title = Recherches Chimiques sur les Quinquinas | trans-title = Continuation: Chemical Research on Quinquinas | language = fr | publisher = Crochard | date = 1820 | journal = Annales de Chimie et de Physique | volume = 15 | pages = 337–365 | url = https://books.google.com/books?id=veE3AAAAMAAJ&pg=PA337 |quote=The authors name quinine on page 348: ''" …, nous avons cru devoir la nommer ''quinine'', pour la distinguer de la cinchonine par un nom qui indique également son origine."'' |trans-quote=…, we thought that we should name it "quinine" in order to distinguish it from cinchonine by means of a name that also indicates its origin.}}</ref> The name was derived from the original [[Quechua languages|Quechua]] (Inca) word for the cinchona tree bark, ''quina'' or ''quina-quina'', which means "bark of bark" or "holy bark". Prior to 1820, the bark was dried, ground to a fine powder, and mixed into a liquid (commonly wine) in order to be drunk. Large-scale use of quinine as a malaria [[prophylaxis]] started around 1850. In 1853 [[Paul Briquet]] published a brief history and discussion of the literature on "quinquina".<ref>{{cite book | vauthors = Briquet P |author1-link=Paul Briquet |title=Traité thérapeutique du quinone et de ses préparations |date=1853 |publisher= L. Martinet |location=Paris |url=https://archive.org/details/b23982135 |language=fr}}</ref>

Quinine played a significant role in the colonization of Africa by Europeans. The availability of quinine for treatment had been said to be the prime reason Africa ceased to be known as the "white man's grave". A historian said, "it was quinine's efficacy that gave colonists fresh opportunities to swarm into the [[Gold Coast (region)|Gold Coast]], [[Nigeria]] and other parts of west Africa".<ref name="clifford">{{cite book |title=A People's History of Science: Miners, Midwives, and 'Low Mechanicks' | vauthors = Conner CD |year=2005 |publisher=Nation Books |location=New York |isbn=978-1-56025-748-6 |pages=[https://archive.org/details/peopleshistoryof0000conn/page/95 95–96] |url=https://archive.org/details/peopleshistoryof0000conn|url-access=registration }} Also cites {{cite book |title=The Greatest Benefit to Mankind: A Medical History of Humanity | vauthors = Porter R |year=1998 |publisher=W. W. Norton |location=New York |isbn=978-0-393-04634-2 |pages=[https://archive.org/details/greatestbenefitt00port/page/465 465–466] |url=https://archive.org/details/greatestbenefitt00port/page/465 }}</ref>

To maintain their monopoly on cinchona bark, Peru and surrounding countries began outlawing the export of cinchona seeds and saplings in the early 19th century. In 1865, [[Manuel Incra Mamani]] collected seeds from a plant particularly high in quinine and provided them to [[Charles Ledger]]. Ledger sent them to his brother, who sold them to the Dutch government. Mamani was arrested on a seed collecting trip in 1871, and beaten so severely, likely because of providing the seeds to foreigners, that he died soon afterwards.<ref>{{Cite web | vauthors = Canales NA |date=7 April 2022 |title=Hunting lost plants in botanical collections |url=https://wellcomecollection.org/articles/YjyPpREAAB8AhS-R |access-date=2022-05-09 |website=Wellcome Collection |language=en}}</ref>

By the late 19th century the Dutch grew the plants in Indonesian plantations. Soon they became the main suppliers of the tree. In 1913 they set up the Kina Bureau, a cartel of cinchona producers charged with controlling price and production.<ref name="Shah-2010">{{Cite book|title=The Fever: How Malaria Has Ruled Humankind for 500,000 Years| vauthors = Shah S |publisher=Farrar, Straus and Giroux|year=2010|pages=94}}</ref> By the 1930s Dutch plantations in [[Java]] were producing 22 million pounds of cinchona bark, or 97% of the world's quinine production.<ref name="clifford" /> U.S. attempts to prosecute the Kina Bureau proved unsuccessful.<ref name="Shah-2010" />

During [[World War II]], Allied powers were cut off from their supply of quinine when Germany conquered the Netherlands, and Japan controlled the [[Philippines]] and [[Indonesia]]. The US had obtained four million cinchona seeds from the Philippines and began operating cinchona plantations in [[Costa Rica]]. Additionally, they began harvesting wild cinchona bark during the [[Cinchona Missions]]. Such supplies came too late. Tens of thousands of US troops in Africa and the South Pacific died of malaria due to the lack of quinine.<ref name=clifford/> Despite controlling the supply, the Japanese did not make effective use of quinine, and thousands of Japanese troops in the southwest Pacific died as a result.<ref>{{cite book | vauthors = Morton L | title = The Fall of the Philippines | location = Washington, D.C. | publisher = United States Army | year = 1953 | chapter-url = http://www.history.army.mil/books/wwii/5-2/5-2_29.htm | chapter = 29 | page = 524 | url-status = live | archive-url = https://web.archive.org/web/20170525032120/http://www.history.army.mil/books/wwii/5-2/5-2_29.htm | archive-date = 25 May 2017}}</ref><ref>{{cite web | vauthors = Hawk A | url = http://ajrp.awm.gov.au/AJRP/remember.nsf/Web-Printer/1989A520D772FE7ECA256B5A0011AF2B?OpenDocument | title = Remembering the war in New Guinea: Japanese Medical Corps – malaria | url-status = live | archive-url = https://web.archive.org/web/20111122234912/http://ajrp.awm.gov.au/AJRP/remember.nsf/Web-Printer/1989A520D772FE7ECA256B5A0011AF2B?OpenDocument | archive-date = 22 November 2011}}</ref><ref>{{cite book | veditors = Heaton LD | title = Preventive Medicine in World War II: Volume VI, Communicable Diseases: Malaria | location = Washington, D.C. | publisher = Department of the Army | year = 1963 | chapter = 8 | chapter-url = http://history.amedd.army.mil/booksdocs/wwii/Malaria/chapterVIII.htm | pages = 401 and 434 | url-status = live | archive-url = https://web.archive.org/web/20120129130700/http://history.amedd.army.mil/booksdocs/wwii/Malaria/chapterVIII.htm | archive-date = 29 January 2012}}</ref><ref>{{cite journal | url = http://www.lonesentry.com/articles/ttt/japanese_medical_services.html | title = Notes on Japanese Medical Services | journal = Tactical and Technical Trends | issue = 36 | year = 1943 | url-status = live | archive-url = https://web.archive.org/web/20111014082451/http://lonesentry.com/articles/ttt/japanese_medical_services.html | archive-date = 14 October 2011}}</ref>

Quinine remained the antimalarial drug of choice until after World War II. Since then, other drugs that have fewer side effects, such as [[chloroquine]], have largely replaced it.<ref>{{Cite book|title=The Fever: How Malaria Has Ruled Humankind for 500,000 Years| vauthors = Shah S |publisher=Farrar, Straus and Giroux|year=2010|pages=102}}</ref>

''Bromo Quinine'' were [[brand name]] [[Cough medicine|cold tablets]] containing quinine, manufactured by Grove Laboratories. They were first marketed in 1889 and available until at least the 1960s.<ref>{{cite news |url=http://www.time.com/time/magazine/article/0,9171,939616,00.html |title=Medicine: What's Good for a Cold? |magazine=Time |access-date=27 April 2010 |date=22 February 1960 |url-status=dead |archive-url=https://web.archive.org/web/20100726032511/http://www.time.com/time/magazine/article/0,9171,939616,00.html |archive-date=26 July 2010}}</ref>

Conducting research in central Missouri, [[John Sappington|John S. Sappington]] independently developed an anti-malaria pill from quinine. Sappington began importing cinchona bark from Peru in 1820. In 1832, using quinine derived from the cinchona bark, Sappington developed a pill to treat a variety of fevers, such as scarlet fever, yellow fever, and influenza in addition to malaria. These illnesses were widespread in the Missouri and Mississippi valleys. He manufactured and sold "Dr. Sappington's Anti-Fever Pills" across Missouri. Demand became so great that within three years, Sappington founded a company known as Sappington and Sons to sell his pills nationwide.<ref>{{cite web|url=https://historicmissourians.shsmo.org/historicmissourians/name/s/sappington/ |title= John. S Sappington|work=Historic Missourians| publisher= State Historical Society of Missouri }}</ref>

==Society and culture==

===Natural occurrence===

The bark of ''[[Remijia]]'' contains 0.5–2% of quinine. The bark is cheaper than bark of ''[[Cinchona]]''. As it has an intense taste, it is used for making [[tonic water]].<ref name="Hobhouse">{{cite book |title=Šest rostlin, které změnily svět | vauthors = Hobhouse H |year=2004 |publisher=Akademie věd České republiky |location=Prague |isbn=978-80-200-1179-4 |pages=59 |language=cs }}</ref>

==={{anchor|Regulation in the US}} Regulation in the US===

From 1969, to 1992, the US [[Food and Drug Administration]] (FDA) received 157 reports of health problems related to quinine use, including 23 which had resulted in death.<ref>{{cite web|url=https://www.fda.gov/fdac/departs/695_updates.html |title=FDA Orders Stop to Marketing of Quinine for Night Leg Cramps |access-date=31 July 2009 |date=July–August 1995 |work=FDA Consumer Magazine |publisher=U.S. [[Food and Drug Administration]] (FDA) |archive-url=https://web.archive.org/web/20080115020839/https://www.fda.gov/fdac/departs/695_updates.html |archive-date=15 January 2008 |url-status=dead }}</ref> In 1994, the FDA banned the marketing of [[Over-the-counter drug|over-the-counter]] quinine as a treatment for nocturnal leg cramps. [[Pfizer]] [[Pharmaceuticals]] had been selling the brand name Legatrin for this purpose. It is also sold as a softgel (by SmithKlineBeecham) as Q-vel.{{Citation needed|date=January 2016}} Doctors may still prescribe quinine, but the FDA has ordered firms to stop marketing unapproved drug products containing quinine. The FDA is also cautioning consumers about [[off-label use]] of quinine to treat leg cramps.<ref name="FDA Safety Communication" /><ref name="FDA risks" /> Quinine is approved for treatment of malaria, but was also commonly prescribed to treat leg cramps and similar conditions. Because malaria is life-threatening, the risks associated with quinine use are considered acceptable when used to treat that condition.<ref>{{cite press release | publisher=U.S. [[Food and Drug Administration]] (FDA) | date=11 December 2006 | title=FDA Orders Unapproved Quinine Drugs from the Market and Cautions Consumers About Off-Label Use of Quinine to Treat Leg Cramps | url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108799.htm | access-date=31 July 2009 | url-status=dead | archive-url=https://web.archive.org/web/20090728012040/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108799.htm | archive-date=28 July 2009}}</ref>

Though Legatrin was banned by the FDA for the treatment of leg cramps, the drug manufacturer URL Mutual has branded a quinine-containing drug named Qualaquin. It is marketed as a treatment for malaria and is sold in the United States only by prescription. In 2004, the CDC reported only 1,347 confirmed cases of malaria in the United States.<ref>{{cite journal | vauthors = Skarbinski J, James EM, Causer LM, Barber AM, Mali S, Nguyen-Dinh P, Roberts JM, Parise ME, Slutsker L, Newman RD | title = Malaria surveillance--United States, 2004 | journal = Morbidity and Mortality Weekly Report. Surveillance Summaries | volume = 55 | issue = 4 | pages = 23–37 | date = May 2006 | pmid = 16723971 | url = https://www.cdc.gov/mmwr/PDF/ss/ss5301.pdf }}</ref>

=== Termination of pregnancy ===

For much of the 20th century, women's use of an overdose of quinine to deliberately terminate a pregnancy was a relatively common [[abortion]] method in various parts of the world, including China.<ref>{{Cite book | vauthors = Rodriguez SM |url= |title=Reproductive realities in modern China : birth control and abortion, 1911-2021 |date=2023 |publisher=[[Cambridge University Press]] |isbn=978-1-009-02733-5 |location=Cambridge, United Kingdom |pages=1 |oclc=1366057905}}</ref>

===Cutting agent===

Quinine is sometimes detected as a [[cutting agent]] in [[Illegal drug trade|street drugs]] such as [[cocaine]] and [[heroin]].<ref>{{cite web |url=https://www.justice.gov/dea/pr/micrograms/2009/mg1009.pdf | title = Dimethyltryptamine and Ecstasy Mimic Tablets (Actually Containing 5-Methoxy-Methylisopropyltryptamine) in Oregon |date=October 2009 |publisher=Drug Enforcement Administration, U.S. Department of Justice |archive-url=https://web.archive.org/web/20121017234110/http://www.justice.gov/dea/pr/micrograms/2009/mg1009.pdf |archive-date=17 October 2012 |page=79|access-date=22 September 2012}}</ref>

==Other animals==

Quinine is used as a treatment for ''[[Cryptocaryon irritans]]'' (commonly referred to as white spot, crypto or marine ich) infection of [[marine aquarium]] fish.<ref>{{cite magazine| vauthors = Porritt M |url=http://www.reefculturemagazine.com.au/cryptocaryon.html|title= Cryptocaryon irritans|archive-url=https://web.archive.org/web/20091024035340/http://www.reefculturemagazine.com.au/cryptocaryon.html |archive-date=24 October 2009 |magazine=Reef Culture Magazine |edition=1 |access-date=9 July 2009|url-status=dead}}</ref>

== References ==

{{Reflist}}

{{refbegin}}

* {{cite book | vauthors = Schroeder-Lein G |title=The encyclopedia of Civil War medicine|year=2008|publisher=Sharpe, Inc.|location=Armonk, NY|ref=none}}

* {{cite book | vauthors = Hobhouse H |author1-link=Henry Hobhouse (author) |title=Seeds of Change: Six Plants That Transformed Mankind |date=2005 |publisher=Counterpoint |location=Berkeley, CA |isbn=978-1-59376-049-6 |orig-date=1986}}

* {{cite journal | vauthors = Stockwell JR | title = Aeromedical considerations of malaria prophylaxis with mefloquine hydrochloride | journal = Aviation, Space, and Environmental Medicine | volume = 53 | issue = 10 | pages = 1011–1013 | date = October 1982 | pmid = 6983345 | ref = none | title-link = malaria prophylaxis }}

* {{cite journal | vauthors = Wolff RS, Wirtschafter D, Adkinson C | title = Ocular quinine toxicity treated with hyperbaric oxygen | journal = Undersea & Hyperbaric Medicine | volume = 24 | issue = 2 | pages = 131–134 | date = June 1997 | pmid = 9171472 | url = http://archive.rubicon-foundation.org/2278 | ref = none | access-date = 13 August 2008 | url-status = usurped | archive-url = https://web.archive.org/web/20110811180033/http://archive.rubicon-foundation.org/2278 | archive-date = 11 August 2011 }}

* {{cite book | vauthors = Slater L |title=War and disease : biomedical research on malaria in the twentieth century|year=2009|publisher=Rutgers University Press|location=New Brunswick, NJ|ref=none}}

* {{cite journal | vauthors = Lloyd HD |author1-link=Henry Demarest Lloyd |title=Lords of Industry |journal=The North American Review |date=June 1884 |volume=138 |issue=331 |pages=535–553 |publisher=University of Northern Iowa |issn=0029-2397 |jstor=25118388}}

* {{cite book | vauthors=((World Health Organization)) | year=2015 | title=Guidelines for the treatment of malaria | edition=3rd | publisher=[[World Health Organization]] (WHO) | hdl=10665/162441 | isbn=9789241549127 |ref=none}}

{{refend}}

== External links ==

{{Wiktionary}}

* [https://druginfo.nlm.nih.gov/drugportal/name/quinine|publisher=U.S. Quinine] at the Drug Information Portal

* [http://www.inchem.org/documents/pims/pharm/pim464.htm Quinine] at the International Programme on Chemical Safety

* {{cite web| url = https://www.chemwatch.net/resource-center/quinine/ | publisher = Chemwatch | work = Resource Center | title = Quinine}}

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