Chloroquine: Difference between revisions

{{short description|Medication used to treat malaria}}

{{Distinguish|Hydroxychloroquine}}

<!-- there is currently confusion between these two drugs as a result of comments around the coronavirus pandemic -->

{{Use dmy dates|date=August 2023}}

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{{Infobox drug

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| image2 = Chloroquine-ligand-CLQ-A-from-PDB-xtal-4FGL-Mercury-3D-balls.png

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<!-- Clinical data -->

| pronounce = {{IPAc-en|ˈ|k|l|ɔː|r|ə|k|w|iː|n}}

| tradename = Aralen, other

| Drugs.com = {{drugs.com|monograph|chloroquine-phosphate}}

| MedlinePlus =

| DailyMedID = Chloroquine

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_AU_comment =

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| routes_of_administration = [[By mouth]]

| class =

| ATC_prefix = P01

| ATC_suffix = BA01

| ATC_supplemental = {{ATC|P01|BB52}}

<!-- Legal status -->

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->

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| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->

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| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->

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| legal_DE = <!-- Anlage I, II, III or Unscheduled-->

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| legal_UK = P

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| legal_status = Rx only

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<!-- Identifiers -->

| CAS_supplemental =

| IUPHAR_ligand = 5535

| NIAID_ChemDB = 000733

| PDB_ligand =

| synonyms = Chloroquine phosphate

<!-- Chemical and physical data -->

| IUPAC_name = (''RS'')-''N'''-(7-chloroquinolin-4-yl)-''N'',''N''-diethylpentane-1,4-diamine

| C=18 | H=26 | Cl=1 | N=3

| SMILES = Clc1cc2nccc(c2cc1)NC(C)CCCN(CC)CC

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<!-- Definition and medical uses -->

'''Chloroquine''' is a medication primarily used to prevent and treat [[malaria]] in areas where malaria remains sensitive to its effects.<ref name=AHFS2015>{{cite web|title=Aralen Phosphate|url=https://www.drugs.com/monograph/chloroquine-phosphate.html|publisher=The American Society of Health-System Pharmacists|access-date=2 December 2015|url-status=live|archive-url=https://web.archive.org/web/20151208200339/http://www.drugs.com/monograph/aralen-phosphate.html|archive-date=8 December 2015}}</ref> Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication.<ref name=AHFS2015 /> Chloroquine is also occasionally used for [[amebiasis]] that is occurring outside the [[intestines]], [[rheumatoid arthritis]], and [[lupus erythematosus]].<ref name=AHFS2015 /> While it has not been formally studied in pregnancy, it appears safe.<ref name=AHFS2015 /><ref>{{cite web |title=Chloroquine Use During Pregnancy |url=https://www.drugs.com/pregnancy/chloroquine.html |website=Drugs.com |access-date=16 April 2019 |quote=There are no controlled data in human pregnancies. |archive-url=https://web.archive.org/web/20190416201619/https://www.drugs.com/pregnancy/chloroquine.html |archive-date=16 April 2019 |url-status=live }}</ref> It was studied to treat [[COVID-19]] early in the [[COVID-19 pandemic|pandemic]], but these studies were largely halted in the summer of 2020, and the [[National Institutes of Health|NIH]] does not recommend its use for this purpose.<ref name=":1">{{cite web | date=|title=Chloroquine or Hydroxychloroquine|url=https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/chloroquine-or-hydroxychloroquine-with-or-without-azithromycin/|url-status=live|archive-url=https://web.archive.org/web/20200828170647/https://www.covid19treatmentguidelines.nih.gov/antiviral-therapy/chloroquine-or-hydroxychloroquine-with-or-without-azithromycin/ |archive-date=28 August 2020 |access-date=14 February 2021|website=COVID-19 Treatment Guidelines|publisher=[[National Institutes of Health]]|language=en}}</ref> It is taken by mouth.<ref name=AHFS2015 />

<!-- Side effects and mechanism-->

Common side effects include muscle problems, loss of appetite, diarrhea, and skin rash.<ref name=AHFS2015 /> Serious side effects include problems with vision, muscle damage, [[seizures]], and [[aplastic anemia|low blood cell levels]].<ref name=AHFS2015 /><ref>{{cite book | vauthors = Mittra RA, Mieler WG |title=Retina | edition = Fifth |date=2013 |publisher=W.B. Saunders |isbn=978-1-4557-0737-9 |pages=1532–1554 |doi = 10.1016/B978-1-4557-0737-9.00089-8 |access-date=25 March 2020 |language=en |chapter=Chapter 89 – Drug Toxicity of the Posterior Segment |chapter-url= https://entokey.com/drug-toxicity-of-the-posterior-segment/ }}</ref> Chloroquine is a member of the drug class [[4-Aminoquinoline|4-aminoquinoline]].<ref name=AHFS2015 /> As an antimalarial, it works against the asexual form of the [[malaria parasite]] in the stage of its life cycle within the [[red blood cell]].<ref name=AHFS2015 /> How it works in rheumatoid arthritis and lupus erythematosus is unclear.<ref name=AHFS2015 /><!-- Quote = mechanism(s) of action in the treatment of rheumatoid arthritis and lupus erythematosus not determined -->

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

Chloroquine was discovered in 1934 by [[Hans Andersag]].<ref>{{cite book |veditors=Manson P, Cooke G, Zumla A |title=Manson's tropical diseases. |date=2009 |publisher=Saunders |location=[Edinburgh] |isbn=978-1-4160-4470-3 |page=1240 |edition=22nd |url=https://books.google.com/books?id=CF2INI0O6l0C&pg=PA1240 |access-date=9 September 2017 |archive-url=https://web.archive.org/web/20181102004125/https://books.google.com/books?id=CF2INI0O6l0C&pg=PA1240 |archive-date=2 November 2018 |url-status=live }}</ref><ref>{{cite book | vauthors = Bhattacharjee M |title=Chemistry of Antibiotics and Related Drugs |date=2016 |publisher=Springer |isbn=978-3-319-40746-3 |page=184 |url=https://books.google.com/books?id=vgXWDAAAQBAJ&pg=PA184 |access-date=9 September 2017 |archive-url=https://web.archive.org/web/20181101204139/https://books.google.com/books?id=vgXWDAAAQBAJ&pg=PA184 |archive-date=1 November 2018 |url-status=live }}</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| hdl-access=free }}</ref> It is available as a [[generic medication]].<ref name=AHFS2015 />

{{TOC limit}}

== Medical uses ==

=== Malaria ===

[[File:Paludisme.png|thumb|upright=1.6|Distribution of malaria in the world:<ref name="CDC Malaria">{{cite web |url=https://www.cdc.gov/malaria/about/faqs.html#treatment |title=Frequently Asked Questions (FAQs): If I get malaria, will I have it for the rest of my life? |publisher=US Centers for Disease Control and Prevention |date=8 February 2010 |access-date=14 May 2012 |url-status=live |archive-url=https://web.archive.org/web/20120513112631/http://www.cdc.gov/malaria/about/faqs.html#treatment |archive-date=13 May 2012 }}</ref>

<br /><span style="color:#7e0000; font-size:120%;">♦</span>&nbsp;Elevated occurrence of chloroquine- or multi-resistant malaria

<br /><span style="color:#f00; font-size:120%;">♦</span>&nbsp;Occurrence of chloroquine-resistant malaria

<br /><span style="color:#e08040; font-size:120%;">♦</span>&nbsp;No ''Plasmodium falciparum'' or chloroquine-resistance

<br /><span style="color:silver; font-size:120%;">♦</span>&nbsp;No malaria

]]

Chloroquine has been used in the treatment and prevention of [[malaria]] from ''[[Plasmodium vivax]]'', ''[[Plasmodium ovale|P. ovale]]'', and ''[[Plasmodium malariae|P. malariae]]''. It is generally not used for ''[[Plasmodium falciparum]]'' as there is widespread resistance to it.<ref>{{cite book | vauthors = Plowe CV | title = Malaria: Drugs, Disease and Post-genomic Biology | chapter = Antimalarial drug resistance in Africa: strategies for monitoring and deterrence | volume = 295 | pages = 55–79 | year = 2005 | pmid = 16265887 | doi = 10.1007/3-540-29088-5_3 | chapter-url = https://archive.org/details/malariadrugsdise0000unse/page/55 | isbn = 3-540-25363-7 | series = Current Topics in Microbiology and Immunology | publisher = Springer }}</ref><ref>{{cite book |doi=10.1007/3-540-29088-5_2 |chapter=Antimalarial Multi-Drug Resistance in Asia: Mechanisms and Assessment |title=Malaria: Drugs, Disease and Post-genomic Biology |series=Current Topics in Microbiology and Immunology |year=2005 | vauthors = Uhlemann AC, Krishna S |volume=295 |pages=39–53 |publisher=Springer |pmid=16265886 |isbn=978-3-540-25363-1 }}</ref>

Chloroquine has been extensively used in [[mass drug administration]]s, which may have contributed to the emergence and spread of resistance. It is recommended to check if chloroquine is still effective in the region prior to using it.<ref>{{cite web|title = Chloroquine phosphate tablet – chloroquine phosphate tablet, coated|url = http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9b585ad5-ae86-4403-b83f-8d8363d43da5|website = dailymed.nlm.nih.gov|access-date = 4 November 2015|url-status = live|archive-url = https://web.archive.org/web/20151208164343/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9b585ad5-ae86-4403-b83f-8d8363d43da5|archive-date = 8 December 2015}}</ref> In areas where resistance is present, other [[Antimalarial drug|antimalarials]], such as [[mefloquine]] or [[atovaquone]], may be used instead. The [[Centers for Disease Control and Prevention]] recommend against treatment of malaria with chloroquine alone due to more effective combinations.<ref>CDC. Health information for international travel 2001–2002. Atlanta, Georgia: U.S. Department of Health and Human Services, Public Health Service, 2001.</ref>

=== Amebiasis ===

In treatment of [[amoebic liver abscess]], chloroquine may be used instead of or in addition to other medications in the event of failure of improvement with [[metronidazole]] or another [[nitroimidazole]] within five days or intolerance to metronidazole or a nitroimidazole.<ref>{{EMedicine|article|183920|Amebic Hepatic Abscesses|treatment}}</ref>

=== Rheumatic disease ===

As it mildly suppresses the [[immune system]], chloroquine is used in some [[autoimmune disorder]]s, such as [[rheumatoid arthritis]] and has an off-label indication for [[lupus erythematosus]].<ref name=AHFS2015 />

== Side effects ==

[[adverse drug reaction|Side effects]] include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhea, swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness, easy bruising/bleeding, hearing and mental problems.<ref name=":3">{{cite web|url=https://www.webmd.com/drugs/2/drug-8633/chloroquine-oral/details|title=Drugs & Medications|website=www.webmd.com|access-date=22 March 2020}}</ref><ref name=":4">{{cite web|url=https://www.drugs.com/sfx/chloroquine-side-effects.html|title=Chloroquine Side Effects: Common, Severe, Long Term|website=Drugs.com|access-date=22 March 2020}}</ref>

* Unwanted/uncontrolled movements (including tongue and face twitching, [[diskenesia]], and [[dystonia]])<ref name=":3" /><ref name=FDA2018Label />

* Deafness or [[tinnitus]]<ref name=":3" />

* Nausea, vomiting, diarrhea, abdominal cramps<ref name=":4" />

* Headache<ref name=":3" />

* Mental/mood changes (such as confusion, personality changes, unusual thoughts/behavior, depression, feeling being watched, hallucinating)<ref name=":3" /><ref name=":4" />

* Signs of serious infection (such as high fever, severe chills, persistent sore throat)<ref name=":3" />

* Skin [[itch]]iness, skin color changes, hair loss, and skin rashes<ref name=":4" /><ref>{{cite web|url=https://medlineplus.gov/druginfo/meds/a682318.html|title=Chloroquine: MedlinePlus Drug Information|website=medlineplus.gov|access-date=22 March 2020}}</ref>

** Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever; its severity is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.<ref>{{cite journal | vauthors = Ajayi AA | title = Mechanisms of chloroquine-induced pruritus | journal = Clinical Pharmacology and Therapeutics | volume = 68 | issue = 3 | pages = 336 | date = September 2000 | pmid = 11014416 }}</ref>

* Triggering of a severe psoriasis attack in those with [[psoriasis]]<ref name=FDA2018Label />

* Unpleasant metallic taste

** This could be avoided by "taste-masked and controlled release" formulations such as multiple emulsions.<ref>{{cite journal | vauthors = Vaziri A, Warburton B | title = Slow release of chloroquine phosphate from multiple taste-masked W/O/W multiple emulsions | journal = Journal of Microencapsulation | volume = 11 | issue = 6 | pages = 641–648 | year = 1994 | pmid = 7884629 | doi = 10.3109/02652049409051114 }}</ref>

* [[Chloroquine retinopathy]] (irreversible retinal damage)<ref name=FDA2018Label />

* Electrocardiographic changes<ref name="Tönnesmann2013">{{cite journal | vauthors = Tönnesmann E, Kandolf R, Lewalter T | title = Chloroquine cardiomyopathy - a review of the literature | journal = Immunopharmacology and Immunotoxicology | volume = 35 | issue = 3 | pages = 434–442 | date = June 2013 | pmid = 23635029 | doi = 10.3109/08923973.2013.780078 | s2cid = 37926477 }}</ref>

** This manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or [[cardiomyopathy]] — often with hypertrophy, restrictive physiology, and congestive [[heart failure]]. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies.

* [[Pancytopenia]], [[aplastic anemia]], reversible [[agranulocytosis]], [[thrombocytopenia|low blood platelets]], [[neutropenia]]<ref name=FDA2018Label>{{cite web | title=Chloroquine phosphate tablet | website=DailyMed | date=8 October 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ee944d28-f596-4163-a502-e779c0d622bc | access-date=7 April 2020}}</ref>

* Worsening of the condition for those with [[porphyria]]<ref name=FDA2018Label />

=== Pregnancy ===

Chloroquine has not been shown to have any harmful effects on the fetus when used in the recommended doses for malarial prophylaxis.<ref name=":2">{{cite web|title = Malaria – Chapter 3 – 2016 Yellow Book |url = http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/malaria|website = wwwnc.cdc.gov|access-date = 11 November 2015|url-status = live|archive-url = https://web.archive.org/web/20160114185552/http://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/malaria|archive-date = 14 January 2016}}</ref> Small amounts of chloroquine are excreted in the breast milk of lactating women. However, this drug can be safely prescribed to infants, the effects are not harmful. Studies with mice show that [[Radioactive tracer|radioactively tagged]] chloroquine passed through the [[placenta]] rapidly and accumulated in the fetal eyes which remained present five months after the drug was cleared from the rest of the body.<ref name=FDA2018Label /><ref>{{cite journal | vauthors = Ullberg S, Lindquist NG, Sjòstrand SE | title = Accumulation of chorio-retinotoxic drugs in the foetal eye | journal = Nature | volume = 227 | issue = 5264 | pages = 1257–1258 | date = September 1970 | pmid = 5452818 | doi = 10.1038/2271257a0 | s2cid = 4191322 | bibcode = 1970Natur.227.1257U }}</ref> Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.<ref name=":2" />

===Elderly===

There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney functions, as is more likely to be the case in the elderly.<ref name=FDA2018Label />

== Drug interactions ==

Chloroquine has a number of [[drug–drug interaction]]s that might be of clinical concern:{{citation needed|date=March 2020}}

* [[Ampicillin]]{{snd}} levels may be reduced by chloroquine;<ref name=FDA2018Label />

* [[Antacids]]{{snd}} may reduce absorption of chloroquine;<ref name=FDA2018Label />

* [[Cimetidine]]{{snd}} may inhibit metabolism of chloroquine; increasing levels of chloroquine in the body;<ref name=FDA2018Label />

* [[Cyclosporine]]{{snd}} levels may be increased by chloroquine;<ref name=FDA2018Label /> and

* [[Mefloquine]]{{snd}} may increase risk of convulsions.<ref name=FDA2018Label />

== Overdose ==

<!-- Definition and symptoms -->

Chloroquine, in overdose, has a risk of death of about 20%.<ref name=Ling2008>{{cite journal | vauthors = Ling Ngan Wong A, Tsz Fung Cheung I, Graham CA | title = Hydroxychloroquine overdose: case report and recommendations for management | journal = European Journal of Emergency Medicine | volume = 15 | issue = 1 | pages = 16–18 | date = February 2008 | pmid = 18180661 | doi = 10.1097/MEJ.0b013e3280adcb56 | s2cid = 41205035 }}</ref> It is rapidly absorbed from the gut with an onset of symptoms generally within an hour.<ref name=Smith2005/> Symptoms of overdose may include sleepiness, vision changes, [[seizures]], [[apnea|stopping of breathing]], and heart problems such as [[ventricular fibrillation]] and [[low blood pressure]].<ref name=Ling2008/><ref name=Smith2005/> [[Low blood potassium]] may also occur.<ref name=Ling2008/>

<!-- Cause -->

While the usual dose of chloroquine used in treatment is 10&nbsp;mg/kg, toxicity begins to occur at 20&nbsp;mg/kg, and death may occur at 30&nbsp;mg/kg.<ref name=Ling2008/> In children as little as a single tablet can be fatal.<ref name=Smith2005>{{cite journal | vauthors = Smith ER, Klein-Schwartz W | title = Are 1-2 dangerous? Chloroquine and hydroxychloroquine exposure in toddlers | journal = The Journal of Emergency Medicine | volume = 28 | issue = 4 | pages = 437–443 | date = May 2005 | pmid = 15837026 | doi = 10.1016/j.jemermed.2004.12.011 }}</ref><ref name=FDA2018Label/>

<!-- Treatment -->

Treatment recommendations include early [[mechanical ventilation]], cardiac monitoring, and [[activated charcoal]].<ref name=Ling2008/> [[Intravenous fluids]] and [[vasopressor]]s may be required with [[epinephrine (medication)|epinephrine]] being the vasopressor of choice.<ref name=Ling2008/> Seizures may be treated with [[benzodiazepines]].<ref name=Ling2008/> Intravenous [[potassium chloride]] may be required, however this may result in [[high blood potassium]] later in the course of the disease.<ref name=Ling2008/> [[Kidney dialysis|Dialysis]] has not been found to be useful.<ref name=Ling2008/>

== Pharmacology ==

{{more sources needed section|date=March 2024}}

Absorption of chloroquine is rapid and primarily happens in the gastrointestinal tract.<ref>{{cite web |url=http://www.inchem.org/documents/pims/pharm/chloroqu.htm#SectionTitle:6.1%20Absorption%20by%20route%20of%20exposure |title=Chloroquine |at=§6.1 Absorption by route of exposure |access-date=24 April 2020}}</ref> It is widely distributed in body tissues.<ref>{{cite journal | vauthors = Adelusi SA, Salako LA | title = Tissue and blood concentrations of chloroquine following chronic administration in the rat | journal = The Journal of Pharmacy and Pharmacology | volume = 34 | issue = 11 | pages = 733–735 | date = November 1982 | pmid = 6129306 | doi = 10.1111/j.2042-7158.1982.tb06211.x | s2cid = 35269419 }}</ref> Protein binding in plasma ranges from 46% to 79%.<ref>{{cite journal | vauthors = Walker O, Birkett DJ, Alván G, Gustafsson LL, Sjöqvist F | title = Characterization of chloroquine plasma protein binding in man | journal = British Journal of Clinical Pharmacology | volume = 15 | issue = 3 | pages = 375–377 | date = March 1983 | pmid = 6849768 | pmc = 1427768 | doi = 10.1111/j.1365-2125.1983.tb01513.x | doi-access = free }}</ref> Its metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine.<ref>{{cite journal | vauthors = Projean D, Baune B, Farinotti R, Flinois JP, Beaune P, Taburet AM, Ducharme J | title = In vitro metabolism of chloroquine: identification of CYP2C8, CYP3A4, and CYP2D6 as the main isoforms catalyzing N-desethylchloroquine formation | journal = Drug Metabolism and Disposition | volume = 31 | issue = 6 | pages = 748–754 | date = June 2003 | pmid = 12756207 | doi = 10.1124/dmd.31.6.748 | s2cid = 2115928 }}</ref> Its excretion is ≥50% as unchanged drug in urine, where acidification of urine increases its elimination.{{citation needed|date=July 2015}} It has a very high volume of distribution, as it diffuses into the body's [[adipose tissue]].{{citation needed|date=July 2015}}

Accumulation of the drug may result in deposits that can lead to blurred vision and [[blindness]].<ref name="Handzel_2021">{{cite journal | vauthors = Handzel DM, Romanou-Papadopoulou V, Briesen S | title = [Visual loss under chloroquine treatment-and not (only) due to bull's eye maculopathy!] | language = German | journal = Der Ophthalmologe | volume = 118 | issue = 9 | pages = 953–955 | date = September 2021 | pmid = 33300096 | pmc = | doi = 10.1007/s00347-020-01288-y | s2cid = 228089310 | trans-title = Visual loss under chloroquine treatment-and not (only) due to bull's eye maculopathy! }}</ref> It and related [[quinine]]s have been associated with cases of [[retina]]l toxicity, particularly when provided at higher doses for longer times.{{citation needed|date=July 2015}} With long-term doses, routine visits to an [[ophthalmologist]] are recommended.{{citation needed|date=July 2015}}

Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the [[lysosomes]] of cells in the body.{{citation needed|date=July 2015}} The pK_a for the quinoline nitrogen of chloroquine is 8.5, meaning it is about 10% deprotonated at physiological pH (per the [[Henderson-Hasselbalch equation]]).{{citation needed|date=July 2015}} This decreases to about 0.2% at a lysosomal pH of 4.6.{{citation needed|date=July 2015}} Because the deprotonated form is more membrane-permeable than the protonated form, a quantitative "trapping" of the compound in lysosomes results.{{citation needed|date=July 2015}}

== Mechanism of action ==

[[File:Medical quinolines pathway.png|thumb|300px|Medical quinolines]]

=== Malaria ===

[[File:Birefringence of malaria pigment.jpg|thumb |[[Hemozoin]] formation in ''P. falciparum'': many antimalarials are strong inhibitors of hemozoin crystal growth.]]

The [[wiktionary:lysosomotropic|lysosomotropic]] character of chloroquine is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for ''in vitro'' experiments pertaining to intracellular lipid related diseases,<ref>{{cite journal | vauthors = Chen PM, Gombart ZJ, Chen JW | title = Chloroquine treatment of ARPE-19 cells leads to lysosome dilation and intracellular lipid accumulation: possible implications of lysosomal dysfunction in macular degeneration | journal = Cell & Bioscience | volume = 1 | issue = 1 | pages = 10 | date = March 2011 | pmid = 21711726 | pmc = 3125200 | doi = 10.1186/2045-3701-1-10 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kurup P, Zhang Y, Xu J, Venkitaramani DV, Haroutunian V, Greengard P, Nairn AC, Lombroso PJ | title = Abeta-mediated NMDA receptor endocytosis in Alzheimer's disease involves ubiquitination of the tyrosine phosphatase STEP61 | journal = The Journal of Neuroscience | volume = 30 | issue = 17 | pages = 5948–5957 | date = April 2010 | pmid = 20427654 | pmc = 2868326 | doi = 10.1523/JNEUROSCI.0157-10.2010 }}</ref> autophagy, and apoptosis.<ref>{{cite journal | vauthors = Kim EL, Wüstenberg R, Rübsam A, Schmitz-Salue C, Warnecke G, Bücker EM, Pettkus N, Speidel D, Rohde V, Schulz-Schaeffer W, Deppert W, Giese A | title = Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells | journal = Neuro-Oncology | volume = 12 | issue = 4 | pages = 389–400 | date = April 2010 | pmid = 20308316 | pmc = 2940600 | doi = 10.1093/neuonc/nop046 }}</ref>

Inside [[red blood cell]]s, the malarial [[parasite]], which is then in its asexual [[apicomplexa life cycle stage|lifecycle]] stage, must degrade [[hemoglobin]] to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.{{citation needed|date=July 2015}}

Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases the toxic and soluble molecule [[heme]]. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form [[hemozoin]], a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.{{citation needed|date=July 2015}}

Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole. Chloroquine (CQ) then becomes protonated (to CQ²⁺), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further [[biocrystallization]] of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion.<ref>{{cite journal | vauthors = Hempelmann E | title = Hemozoin biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors | journal = Parasitology Research | volume = 100 | issue = 4 | pages = 671–676 | date = March 2007 | pmid = 17111179 | doi = 10.1007/s00436-006-0313-x | s2cid = 30446678 }}</ref> Parasites that do not form hemozoin are therefore resistant to chloroquine.<ref name="Lin2015">{{cite journal | vauthors = Lin JW, Spaccapelo R, Schwarzer E, Sajid M, Annoura T, Deroost K, Ravelli RB, Aime E, Capuccini B, Mommaas-Kienhuis AM, O'Toole T, Prins F, Franke-Fayard BM, Ramesar J, Chevalley-Maurel S, Kroeze H, Koster AJ, Tanke HJ, Crisanti A, Langhorne J, Arese P, Van den Steen PE, Janse CJ, Khan SM | title = Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance | journal = The Journal of Experimental Medicine | volume = 212 | issue = 6 | pages = 893–903 | date = June 2015 | pmid = 25941254 | pmc = 4451122 | doi = 10.1084/jem.20141731 | url = https://lirias.kuleuven.be/bitstream/123456789/500975/3/2015113.pdf | access-date = 4 November 2018 | url-status = live | archive-url = https://web.archive.org/web/20170922103013/https://lirias.kuleuven.be/bitstream/123456789/500975/3/2015113.pdf | archive-date = 22 September 2017 }}</ref>

==== Resistance in malaria ====

Since the first documentation of ''P. falciparum'' chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against ''P. falciparum'' has declined as resistant strains of the parasite evolved.

Resistant parasites are able to rapidly remove chloroquine from the digestive vacuole using a transmembrane pump. Chloroquine-resistant parasites pump chloroquine out at 40 times the rate of chloroquine-sensitive parasites; the pump is coded by the ''P. falciparum'' chloroquine resistance transporter (''PfCRT'') gene.<ref>{{cite journal | vauthors = Martin RE, Marchetti RV, Cowan AI, Howitt SM, Bröer S, Kirk K | title = Chloroquine transport via the malaria parasite's chloroquine resistance transporter | journal = Science | volume = 325 | issue = 5948 | pages = 1680–1682 | date = September 2009 | pmid = 19779197 | doi = 10.1126/science.1175667 | s2cid = 206520905 | bibcode = 2009Sci...325.1680M }}</ref> The natural function of the chloroquine pump is to transport peptides: mutations to the pump that allow it to pump chloroquine out impairs its function as a peptide pump and comes at a cost to the parasite, making it less fit.<ref>{{cite journal | vauthors = Shafik SH, Cobbold SA, Barkat K, Richards SN, Lancaster NS, Llinás M, Hogg SJ, Summers RL, McConville MJ, Martin RE | title = The natural function of the malaria parasite's chloroquine resistance transporter | journal = Nature Communications | volume = 11 | issue = 1 | pages = 3922 | date = August 2020 | pmid = 32764664 | pmc = 7413254 | doi = 10.1038/s41467-020-17781-6 | bibcode = 2020NatCo..11.3922S }}</ref>

Resistant parasites also frequently have mutation in the [[ABC transporter]] ''P. falciparum'' multidrug resistance (''PfMDR1'') gene, although these mutations are thought to be of secondary importance compared to ''PfCRT''. An altered chloroquine-transporter protein, ''CG2'' has been associated with chloroquine resistance, but other mechanisms of resistance also appear to be involved.<ref>{{cite book | vauthors = Tripathi KD | title = Essentials of Medical Pharmacology | edition = fifth | date = 2003 | publisher = Jaypee Brothers Medical Publisher Ltd | pages = 739–740 }}</ref>

[[Verapamil]], a Ca²⁺ channel blocker, has been found to restore both the chloroquine concentration ability and sensitivity to this drug. Other agents which have been shown to reverse chloroquine resistance in malaria are [[chlorpheniramine]], [[gefitinib]], [[imatinib]], [[tariquidar]] and [[zosuquidar]].<ref name=Alcantara2013>{{cite journal | vauthors = Alcantara LM, Kim J, Moraes CB, Franco CH, Franzoi KD, Lee S, Freitas-Junior LH, Ayong LS | title = Chemosensitization potential of P-glycoprotein inhibitors in malaria parasites | journal = Experimental Parasitology | volume = 134 | issue = 2 | pages = 235–243 | date = June 2013 | pmid = 23541983 | doi = 10.1016/j.exppara.2013.03.022 }}</ref>

{{As of|2014}} chloroquine is still effective against [[poultry malaria]] in [[Thailand]]. Sohsuebngarm et al. 2014 test ''[[Plasmodium gallinaceum|P. gallinaceum]]'' at [[Chulalongkorn University]] and find the parasite is not resistant.<ref name="McDougald-et-al-2019">{{cite book | vauthors = McDougald LR, Cervantes HM, Jenkins MC, Hess M, Beckstead R | title=Diseases of Poultry | edition=14 | chapter=Protozoal Infections | publisher=[[Wiley (publisher)|Wiley]] | date=22 November 2019 | isbn=9781119371199}}</ref>{{rp|1237}} [[Sertraline]], [[fluoxetine]] and [[paroxetine]] reverse chloroquine resistance, making resistant biotypes susceptible if used in a cotreatment.<ref name="Bellido-et-al-2000">{{cite journal | vauthors = Munoz-Bellido JL, Munoz-Criado S, Garcìa-Rodrìguez JA | title = Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors | journal = International Journal of Antimicrobial Agents | volume = 14 | issue = 3 | pages = 177–180 | date = April 2000 | pmid = 10773485 | doi = 10.1016/s0924-8579(99)00154-5 | publisher = [[International Society of Chemotherapy]] ([[Elsevier]]) }}</ref>

=== Antiviral ===

Chloroquine has [[antiviral]] effects against some viruses.<ref>{{cite journal | vauthors = Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R | title = Effects of chloroquine on viral infections: an old drug against today's diseases? | journal = The Lancet. Infectious Diseases | volume = 3 | issue = 11 | pages = 722–727 | date = November 2003 | pmid = 14592603 | pmc = 7128816 | doi = 10.1016/s1473-3099(03)00806-5 }}</ref> It increases late endosomal and lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome — release of the virus requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.<ref name="Al‐Bari 2020 p.">{{cite journal | vauthors = Al-Bari MA | title = Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases | journal = Pharmacology Research & Perspectives | volume = 5 | issue = 1 | pages = e00293 | date = February 2017 | pmid = 28596841 | pmc = 5461643 | doi = 10.1002/prp2.293 }}</ref><ref name="Fredericksen Wei Yao Luo p.">{{cite journal | vauthors = Fredericksen BL, Wei BL, Yao J, Luo T, Garcia JV | title = Inhibition of endosomal/lysosomal degradation increases the infectivity of human immunodeficiency virus | journal = Journal of Virology | volume = 76 | issue = 22 | pages = 11440–11446 | date = November 2002 | pmid = 12388705 | pmc = 136743 | doi = 10.1128/JVI.76.22.11440-11446.2002 }}</ref>

Chloroquine also seems to act as a zinc [[ionophore]] that allows extracellular zinc to enter the cell and inhibit viral RNA-dependent [[RNA polymerase]].<ref>{{cite journal | vauthors = Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ | title = Chloroquine is a zinc ionophore | journal = PLOS ONE | volume = 9 | issue = 10 | pages = e109180 | date = 1 October 2014 | pmid = 25271834 | pmc = 4182877 | doi = 10.1371/journal.pone.0109180 | doi-access = free | bibcode = 2014PLoSO...9j9180X }}</ref><ref>{{cite journal | vauthors = te Velthuis AJ, van den Worm SH, Sims AC, Baric RS, Snijder EJ, van Hemert MJ | title = Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture | journal = PLOS Pathogens | volume = 6 | issue = 11 | pages = e1001176 | date = November 2010 | pmid = 21079686 | pmc = 2973827 | doi = 10.1371/journal.ppat.1001176 | doi-access = free }}</ref>

=== Other ===

Chloroquine inhibits [[thiamine]] uptake.<ref name=Huang2012>{{cite journal | vauthors = Huang Z, Srinivasan S, Zhang J, Chen K, Li Y, Li W, Quiocho FA, Pan X | title = Discovering thiamine transporters as targets of chloroquine using a novel functional genomics strategy | journal = PLOS Genetics | volume = 8 | issue = 11 | pages = e1003083 | year = 2012 | pmid = 23209439 | pmc = 3510038 | doi = 10.1371/journal.pgen.1003083 | doi-access = free }}</ref> It acts specifically on the transporter [[SLC19A3]].

Against [[rheumatoid arthritis]], it operates by inhibiting [[lymphocyte]] proliferation, [[phospholipase A2]], antigen presentation in dendritic cells, release of [[enzyme]]s from [[lysosome]]s, release of [[reactive oxygen species]] from [[macrophage]]s, and production of [[Interleukin 1|IL-1]].{{medcn|date=March 2024}}

== History ==

In [[Peru]], the indigenous people extracted the bark of the ''[[Cinchona]]'' tree (''[[Cinchona officinalis]]'')<ref>{{cite web|url=https://pfaf.org/user/Plant.aspx?LatinName=Cinchona+officinalis|title=Cinchona officinalis – L.| vauthors = Fern K |date=2010–2020|website=Plans for a Future|url-status=live|archive-url= https://web.archive.org/web/20170825212410/http://www.pfaf.org/user/Plant.aspx?LatinName=Cinchona+officinalis |archive-date=25 August 2017|access-date=2 February 2020}}</ref> and used the extract to fight chills and fever in the seventeenth century. In 1633, this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria. The quinoline antimalarial drug [[quinine]] was isolated from the extract in 1820.<ref name=Arrow>{{cite book |isbn=9780309092180 |doi=10.17226/11017|doi-access=free| veditors = Arrow KJ, Panosian C, Gelband H |title=Saving lives, buying time : economics of malaria drugs in an age of resistance|date=2004|publisher=National Academies Press|pmid=25009879|author1=Institute of Medicine (US) Committee on the Economics of Antimalarial Drug}}</ref>{{rp|130–131}}

After World War I, the German government sought alternatives to quinine. Chloroquine, a synthetic analogue with the same [[mechanism of action]] was discovered in 1934, by [[Hans Andersag]] and coworkers at the [[Bayer]] laboratories, who named it Resochin.<ref>{{cite journal | vauthors = Kouznetsov VV, Amado Torres DF |title=Antimalarials: construction of molecular hybrids based on chloroquine |journal=Universitas Scientiarum |date=September 2008 |volume=13 |issue=3 |pages=306–320 |url=http://www.scielo.org.co/scielo.php?pid=S0122-74832008000300010&script=sci_arttext }}</ref><ref>{{cite journal | vauthors = Krafts K, Hempelmann E, Skórska-Stania A | title = From methylene blue to chloroquine: a brief review of the development of an antimalarial therapy | journal = Parasitology Research | volume = 111 | issue = 1 | pages = 1–6 | date = July 2012 | pmid = 22411634 | doi = 10.1007/s00436-012-2886-x | s2cid = 54526057 }}</ref> It was ignored for a decade, because it was considered too toxic for human use. Instead, in World War II, the [[German Africa Corps]] used the chloroquine analogue 3-methyl-chloroquine, known as Sontochin. After Allied forces arrived in Tunis, Sontochin fell into the hands of Americans, who sent the material back to the United States for analysis, leading to renewed interest in chloroquine.<ref>{{cite book | vauthors = Sneader W | title = Drug Discovery. A History. | publisher = Wiley | date = 2005 | isbn = 0471899801}}</ref><ref name="pmid22508305">{{cite journal | vauthors = Pou S, Winter RW, Nilsen A, Kelly JX, Li Y, Doggett JS, Riscoe EW, Wegmann KW, Hinrichs DJ, Riscoe MK | title = Sontochin as a guide to the development of drugs against chloroquine-resistant malaria | journal = Antimicrobial Agents and Chemotherapy | volume = 56 | issue = 7 | pages = 3475–3480 | date = July 2012 | pmid = 22508305 | pmc = 3393441 | doi = 10.1128/AAC.00100-12 | s2cid = 32186437 }}</ref> United States government-sponsored clinical trials for antimalarial [[drug development]] showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug.<ref name=Arrow />{{rp|61–66}} It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.<ref>{{cite web | url = https://www.cdc.gov/malaria/history/index.htm#chloroquine | title = The History of Malaria, an Ancient Disease | publisher = Centers for Disease Control | url-status = live | archive-url = https://web.archive.org/web/20100828183012/http://www.cdc.gov//malaria//history//index.htm#chloroquine | archive-date = 28 August 2010| date = 29 July 2019 }}</ref>

=== Chemical synthesis ===

The first synthesis of chloroquine was disclosed in a patent filed by [[IG Farben]] in 1937.<ref>{{cite patent |country=DE |number=683692 |status=patent |gdate=1939-11-13 |fdate=1937-10-08 |pridate=1937-10-08 |invent1 =Andersag, Hans |invent2 = Breitner, Stefan |invent3 = Jung, Heinrich |title=Process for the preparation of quinoline compounds containing amino groups with basic substituents in the 4-position |assign1= IG Farbenindustrie AG}}</ref> In the final step, [[4,7-dichloroquinoline]] was reacted with 1-diethylamino-4-aminopentane.

: [[File:Chloroquin Synthese.svg|650px]]

By 1949, chloroquine manufacturing processes had been established to allow its widespread use.<ref>{{cite journal|doi=10.1021/ie50472a002| vauthors = Kenyon RL, Wiesner JA, Kwartler CE |title=Chloroquine manufacture|date=1 April 1949|journal=Industrial & Engineering Chemistry|volume=41|issue=4|pages=654–662 }}</ref>

== Society and culture ==

[[File:Esochin® Tabletten (Rückseite).jpg|thumb|Resochin tablet package]]

=== Formulations ===

Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.<ref>{{cite web |title=Chloroquine |url=https://pubchem.ncbi.nlm.nih.gov/compound/chloroquine#section=U-S-Imports |website=nih.gov |publisher=National Institutes of Health |access-date=24 March 2020}}</ref>

=== Names ===

Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.<ref>{{cite web|url=https://www.ipca.com/pharmaceutical-formulations-manufacturers-india.html|title=Ipca Laboratories: Formulations – Branded|url-status=live|archive-url=https://web.archive.org/web/20190406132110/https://ipca.com/pharmaceutical-formulations-manufacturers-india.html|archive-date=6 April 2019|access-date=14 March 2020}}</ref>

== Other animals ==

Chloroquine, in various chemical forms, is used to treat and control surface growth of anemones and algae, and many protozoan infections in aquariums,<ref name=":0">{{cite web |url=https://reefs.com/magazine/aquarium-fish-chloroquine-a-new-drug-for-treating-fish-diseases/ |title=Aquarium Fish: Chloroquine: A "New" Drug for Treating Fish Diseases | vauthors = Hemdal J |access-date=26 March 2020 |magazine=Advanced Aquarist |date=20 February 2013 |volume=XII |url-status=live |archive-url=https://web.archive.org/web/20130315115122/https://www.advancedaquarist.com/2013/2/fish |archive-date=15 March 2013}}</ref> e.g. the fish parasite ''[[Amyloodinium ocellatum]]''.<ref>{{cite web | vauthors = Francis-Floyd R, Floyd MR |title=Amyloodinium ocellatum, an Important Parasite of Cultured Marine Fish |url=http://agrilife.org/fisheries/files/2013/09/SRAC-Publication-No.-4705-Amyloodinium-ocellatum-an-Important-Parasite-of-Cultured-Marine-Fish.pdf |website=agrilife.org |access-date=24 March 2020 |archive-url=https://web.archive.org/web/20150601235926/http://agrilife.org/fisheries/files/2013/09/SRAC-Publication-No.-4705-Amyloodinium-ocellatum-an-Important-Parasite-of-Cultured-Marine-Fish.pdf |archive-date=1 June 2015 |url-status=dead }}</ref> It is also used in [[poultry malaria]].<ref name="McDougald-et-al-2019" />{{rp|1237}}

== Research ==

Chloroquine was proposed as a treatment for [[SARS]], with ''[[in vitro]]'' tests inhibiting the severe acute respiratory syndrome coronavirus ([[Severe acute respiratory syndrome coronavirus|SARS-CoV]]).<ref name="In vitro inhibition of severe acute">{{cite journal | vauthors = Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M | title = In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine | journal = Biochemical and Biophysical Research Communications | volume = 323 | issue = 1 | pages = 264–268 | date = October 2004 | pmid = 15351731 | pmc = 7092815 | doi = 10.1016/j.bbrc.2004.08.085 }}</ref><ref>{{cite journal | vauthors = Devaux CA, Rolain JM, Colson P, Raoult D | title = New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? | journal = International Journal of Antimicrobial Agents | volume = 55 | issue = 5 | pages = 105938 | date = May 2020 | pmid = 32171740 | pmc = 7118659 | doi = 10.1016/j.ijantimicag.2020.105938 }}</ref> In October 2004, a published report stated that chloroquine acts as an effective inhibitor of the replication of SARS-CoV in vitro.<ref name="In vitro inhibition of severe acute"/> In August 2005, a peer-reviewed study confirmed and expanded upon the results.<ref>{{cite journal | vauthors = Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, Seidah NG, Nichol ST | title = Chloroquine is a potent inhibitor of SARS coronavirus infection and spread | journal = Virology Journal | volume = 2 | pages = 69 | date = August 2005 | pmid = 16115318 | pmc = 1232869 | doi = 10.1186/1743-422X-2-69 | doi-access = free }}</ref>

Chloroquine was being considered in 2003, in pre-clinical models as a potential agent against [[chikungunya]] fever.<ref>{{cite journal | vauthors = Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R | title = Effects of chloroquine on viral infections: an old drug against today's diseases? | journal = The Lancet. Infectious Diseases | volume = 3 | issue = 11 | pages = 722–727 | date = November 2003 | pmid = 14592603 | pmc = 7128816 | doi = 10.1016/S1473-3099(03)00806-5 }}</ref>

=== COVID-19 ===

{{Excerpt|Chloroquine and hydroxychloroquine during the COVID-19 pandemic}}

=== Other ===

The [[radiosensitizing]] and [[chemosensitizing]] properties of chloroquine are being evaluated for anticancer strategies in humans.<ref>{{cite journal | vauthors = Savarino A, Lucia MB, Giordano F, Cauda R | title = Risks and benefits of chloroquine use in anticancer strategies | journal = The Lancet. Oncology | volume = 7 | issue = 10 | pages = 792–793 | date = October 2006 | pmid = 17012039 | doi = 10.1016/S1470-2045(06)70875-0 }}</ref><ref>{{cite journal | vauthors = Sotelo J, Briceño E, López-González MA | title = Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial | journal = Annals of Internal Medicine | volume = 144 | issue = 5 | pages = 337–343 | date = March 2006 | pmid = 16520474 | doi = 10.7326/0003-4819-144-5-200603070-00008 | s2cid = 24807955 }}<br />{{cite journal | vauthors = | title = Summaries for patients. Adding chloroquine to conventional chemotherapy and radiotherapy for glioblastoma multiforme | journal = Annals of Internal Medicine | volume = 144 | issue = 5 | pages = I31 | date = March 2006 | pmid = 16520470 | doi = 10.7326/0003-4819-144-5-200603070-00004 | doi-access = free }}</ref> In [[biomedicine|biomedicinal science]], chloroquine is used for ''[[in vitro]]'' experiments to inhibit [[lysosome|lysosomal]] degradation of protein products. Chloroquine and its modified forms have also been evaluated as treatment options for inflammatory conditions like rheumatoid arthritis and inflammatory bowel disease.<ref name="Goel_2020">{{cite book | vauthors = Goel P, Gerriets V | chapter = Chloroquine | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing LLC. | date = January 2020 | pmid = 31855356 | doi = | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK551512/ }}</ref>

== References ==

{{Reflist}}

== External links ==

{{Scholia|topic}}

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* {{cite web| url = https://www.cdc.gov/malaria/resources/pdf/fsp/drugs/Chloroquine.pdf | type = Fact sheet | publisher = U.S. [[Centers for Disease Control and Prevention]] (CDC) | title = Medicines for the Prevention of Malaria While Traveling – Chloroquine (Aralen) }}

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