Mepacrine

{{Drugbox | verifiedrevid = 464378394 | IUPAC_name = (''RS'')-''N''′-(6-Chloro-2-methoxy-acridin-9-yl)-''N'',''N''-diethylpentane-1,4-diamine | image = Quinacrine.svg | image_class = skin-invert-image | width = 215

| tradename = Atabrine, Atebrin | Drugs.com = {{drugs.com|CONS|quinacrine}}

| protein_bound = 80–90% | elimination_half-life = 5–14 days

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 83-89-6 | ATC_prefix = P01 | ATC_suffix = AX05 | ATC_supplemental = {{ATCvet|P51|AX04}} | PubChem = 237 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB01103 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 232 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = H0C805XYDE | KEGG = D08179 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 8711 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 7568 | PDB_ligand = QUN

| C=23 | H=30 | Cl=1 | N=3 | O=1 | smiles = CCN(CC)CCCC(C)Nc1c2ccc(cc2nc3c1cc(cc3)OC)Cl | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C23H30ClN3O/c1-5-27(6-2)13-7-8-16(3)25-23-19-11-9-17(24)14-22(19)26-21-12-10-18(28-4)15-20(21)23/h9-12,14-16H,5-8,13H2,1-4H3,(H,25,26) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = GPKJTRJOBQGKQK-UHFFFAOYSA-N }} '''Mepacrine''', also called '''quinacrine''' or by the trade names '''Atabrine''' or '''Atebrin''', is a medication with several uses. It is related to chloroquine and mefloquine. Although available from compounding pharmacies, as of August 2020 approved formulations are not available in the United States.<ref>{{Cite web|orig-year=8 February 2019 |date= 13 March 2019|title=Quinacrine Shortage & What the ACR Is Doing about It|url=https://www.the-rheumatologist.org/article/quinacrine-shortage-what-the-acr-is-doing-about-it/|access-date=24 August 2020}}</ref>

==Medical uses== [[File:Atabrine advertisement in Guinea during WW2.jpg|thumb|left|''These men didn't take their Atabrine''; this sign was posted at the 363rd Station Hospital on Papua New Guinea during World War II]] The main uses of mepacrine are as an antiprotozoal, antirheumatic, and an intrapleural sclerosing agent.<ref name=drugsdotcom>[https://www.drugs.com/mmx/quinacrine-hydrochloride.html Drugs.com: Quinacrine.] Retrieved on August 24, 2009.</ref>

Mepacrine finds off-label use as a primary antimicrobial agent for patients with metronidazole-resistant giardiasis and patients who should not receive or cannot tolerate metronidazole. Giardiasis with a high level of drug resistance may even require a combination of mepacrine and metronidazole to cure.<ref name=drugsdotcom/>

Mepacrine is also used off-label for the treatment of systemic lupus erythematosus,<ref name="pmid16623930">{{cite journal |vauthors=Toubi E, Kessel A, Rosner I, Rozenbaum M, Paran D, Shoenfeld Y |title=The reduction of serum B-lymphocyte activating factor levels following quinacrine add-on therapy in systemic lupus erythematosus |journal=Scand. J. Immunol. |volume=63 |issue=4 |pages=299–303 |year=2006 |pmid=16623930 |doi=10.1111/j.1365-3083.2006.01737.x|doi-access=free }}</ref> indicated in the treatment of discoid and subcutaneous lupus manifestations, particularly in patients who are unable to take hydroxychloroquine.<ref name=drugsdotcom/>

As an sclerosing agent, it is used as pneumothorax prophylaxis in patients at high risk of recurrence, e.g., in those with cystic fibrosis.<ref name=drugsdotcom/>

Mepacrine is not the drug of choice because side effects are common, including toxic psychosis, and may cause permanent damage. See mefloquine for more information.

In addition to medical applications, mepacrine is an effective in vitro research tool for the epifluorescent visualization of cells, especially platelets. Mepacrine is a green fluorescent dye taken up by most cells. Platelets store mepacrine in dense granules.<ref>{{cite journal |vauthors=Wall JE, Buijs-Wilts M, Arnold JT, etal | title = A flow cytometric assay using mepacrine for study of uptake and release of platelet dense granule contents. | journal = Br. J. Haematol. | volume = 89 | issue = 2 | pages = 380–385 | year = 1995 | doi = 10.1111/j.1365-2141.1995.tb03315.x| pmid = 7873389 | s2cid = 24132625 }}</ref>

==Mechanism== Its mechanism of action against protozoa is uncertain, but it is thought to act against the protozoan's cell membrane. It is known to act as a histamine ''N''-methyltransferase inhibitor. It also inhibits NF-κB and activates p53.

==History==

===Antiprotozoal=== left|thumb|Atabrine and mosquito poster Mepacrine was initially approved in the 1930s as an antimalarial drug. It was used extensively during the second World War by Allied forces fighting in North Africa and the Far East to prevent malaria.<ref>{{cite journal | author = Baird JK | title = Resistance to chloroquine unhinges vivax malaria therapeutics. | journal = Antimicrob. Agents Chemother. | year = 2011 | volume = 55 | issue = 5 | pages = 1827–1830 | doi=10.1128/aac.01296-10 | pmid=21383088 | pmc=3088196}}</ref>

This antiprotozoal is also approved{{where|date=December 2024}}{{by whom|date=December 2024}} for the treatment of giardiasis (an intestinal parasite),<ref name="pmid17072963">{{cite journal |vauthors=Canete R, Escobedo AA, Gonzalez ME, Almirall P |title=Randomized clinical study of five days apostrophe therapy with mebendazole compared to quinacrine in the treatment of symptomatic giardiasis in children |journal=World J. Gastroenterol. |volume=12 |issue=39 |pages=6366–70 |year=2006 |pmid=17072963 |doi=10.3748/wjg.v12.i39.6366|pmc=4088148 |doi-access=free }}</ref> and has been researched as an inhibitor of phospholipase A2.

Scientists at Bayer in Germany first synthesised mepacrine in 1931. The product was one of the first synthetic substitutes for quinine although later superseded by chloroquine.

===Anthelmintics=== In addition it has been used for treating tapeworm infections.<ref>{{DorlandsDict|nine/000956295|quinacrine}}</ref>

===Creutzfeldt–Jakob disease=== Mepacrine has been shown to bind to the prion protein and prevent the formation of prion aggregates ''in vitro'',<ref name="Doh-Ura">{{cite journal |vauthors=Doh-Ura K, Iwaki T, Caughey B | title = Lysosomotropic Agents and Cysteine Protease Inhibitors Inhibit Scrapie-Associated Prion Protein Accumulation | journal = J Virol | volume = 74 | issue = 10 | pages = 4894–7 |date=May 2000| pmid = 10775631 | doi = 10.1128/JVI.74.10.4894-4897.2000 | pmc = 112015}}</ref> and full clinical trials of its use as a treatment for Creutzfeldt–Jakob disease are under way in the United Kingdom and the United States. Small trials in Japan have reported improvement in the condition of patients with the disease,<ref name="Kobayashi">{{cite journal |vauthors=Kobayashi Y, Hirata K, Tanaka H, Yamada T | title = [Quinacrine administration to a patient with Creutzfeldt–Jakob disease who received a cadaveric dura mater graft--an EEG evaluation] | journal = Rinsho Shinkeigaku | volume = 43 | issue = 7 | pages = 403–8 |date=July 2003 | pmid = 14582366}}</ref> although other reports have shown no significant effect,<ref name="Haik">{{cite journal |vauthors=Haïk S, Brandel J, Salomon D, Sazdovitch V, Delasnerie-Lauprêtre N, Laplanche J, Faucheux B, Soubrié C, Boher E, Belorgey C, Hauw J, Alpérovitch A | title = Compassionate use of quinacrine in Creutzfeldt–Jakob disease fails to show significant effects | journal = Neurology | volume = 63 | issue = 12 | pages = 2413–5 |date=28 December 2004 | pmid = 15623716 | doi=10.1212/01.wnl.0000148596.15681.4d| s2cid = 37534686 }}</ref> and treatment of scrapie in mice and sheep has also shown no effect.<ref name="Barret">{{cite journal |vauthors=Barret A, Tagliavini F, Forloni G, Bate C, Salmona M, Colombo L, De Luigi A, Limido L, Suardi S, Rossi G, Auvré F, Adjou K, Salès N, Williams A, Lasmézas C, Deslys J | title = Evaluation of Quinacrine Treatment for Prion Diseases | journal = J. Virol. | volume = 77 | issue = 15 | pages = 8462–9 |date=August 2003 | pmid = 12857915 | doi = 10.1128/JVI.77.15.8462-8469.2003 | pmc = 165262}}</ref><ref name="Gayrard">{{cite journal |vauthors=Gayrard V, Picard-Hagen N, Viguié C, Laroute V, Andréoletti O, Toutain P | title = A possible pharmacological explanation for quinacrine failure to treat prion diseases: pharmacokinetic investigations in a ovine model of scrapie | journal = Br. J. Pharmacol. | volume = 144 | issue = 3 | pages = 386–93 |date=February 2005 | pmid = 15655516 | doi = 10.1038/sj.bjp.0706072 | pmc = 1576015}} - [http://www.nature.com/bjp/journal/v144/n3/abs/0706072a.html;jsessionid=26ACDAFB57BFF1222031D5379AE51252 Abstract]</ref> Possible reasons for the lack of an ''in vivo effect'' include inefficient penetration of the blood–brain barrier, as well as the existence of drug-resistant prion proteins that increase in number when selected for by treatment with mepacrine.<ref name="Ghaemmaghami">{{cite journal |vauthors=Ghaemmaghami S, Ahn M, Lessard P, Giles K, Legname G, etal | title = Continuous Quinacrine Treatment Results in the Formation of Drug-Resistant Prions | journal = PLOS Pathogens | volume = 5 | issue = 11 | pages = 2413–5 |date=November 2009 | doi = 10.1371/journal.ppat.1000673 | pmid = 19956709 | pmc = 2777304 | editor1-last = Mabbott | editor1-first = Neil | doi-access = free }}</ref>

===Non-surgical sterilization for women=== The use of mepacrine for non-surgical sterilization for women has also been studied. The first report of this method claimed a first year failure rate of 3.1%.<ref>{{cite journal |vauthors=Zipper J, Cole LP, Goldsmith A, Wheeler R, Rivera M | title=Quinacrine hydrochloride pellets: preliminary data on a nonsurgical method of female sterilisation | journal=International Journal of Gynecology & Obstetrics | year=1980 | volume=18 | pages=275–90 |pmid=6109672 | issue=4| doi=10.1002/j.1879-3479.1980.tb00496.x | s2cid=41946631 | url=https://repositorio.uchile.cl/handle/2250/161758 | doi-access=free }}</ref> However, despite a multitude of clinical studies on the use of mepacrine and female sterilization, no randomized, controlled trials have been reported to date and there is some controversy over its use.<ref name=drugsdotcom/>

Pellets of mepacrine are inserted through the cervix into a woman's uterine cavity using a preloaded inserter device, similar in manner to IUCD insertion. The procedure is undertaken twice, first in the proliferative phase, 6 to 12 days following the first day of the menstrual cycle and again one month later. The sclerosing effects of the drugs at the utero-tubal junctions (where the Fallopian tubes enter the uterus) results in scar tissue forming over a six-week interval to close off the tubes permanently.

In the United States, this method has undergone Phase I clinical testing. The FDA has waived the necessity for Phase II clinical trials because of the extensive data pertaining to other uses of mepacrine. The next step in the FDA approval process in the United States is a Phase III large multi-center clinical trial. The method is currently used off-label.

Many peer reviewed studies suggest that<ref>{{cite journal|title=Quinacrine sterilization: reports on 40,252 cases.|journal=International Journal of Gynaecology and Obstetrics |date=October 2003|volume=83 |issue=Suppl 2|pages=S1–159|pmid=14763179}}</ref> mepacrine sterilization (QS) is potentially safer than surgical sterilization.<ref>{{cite journal | author=Sokal, D.C., Kessel. E., Zipper. J., and King. T. | title=Quinacrine: Clinical experience | journal=Background Paper for the World Health Organization Consultation on the Development of New Technologies for Female Sterilization | year=1994 |pages=25–7}}</ref><ref>{{cite journal | author=Peterson, H.B., Lubell, L., DeStefano, F., and Ory, H.W.| title=The safety and efficacy of tubal sterilization: an international overview | journal=Int. J. Gynaecol. Obstet. | year=1983 | pages=139–44 |pmid=6136433| doi=10.1016/0020-7292(83)90051-6| volume=21 | issue=2| s2cid=15179539 }}</ref> Nevertheless, in 1998 the Supreme Court of India banned the import or use of the drug, allegedly based on reports that it could cause cancer or ectopic pregnancies.<ref>{{Cite journal|title=Govt drags feet on quinacrine threat|first=Nirmala|last=George|journal=Indian Express|date=July 25, 1998|url=http://www.indianexpress.com/res/web/pIe/ie/daily/19980725/20650684.html}}.</ref>

===Skin dye=== During World War II, Caucasian American operatives involved in Sino-American Cooperative Organization activities the Second Sino-Japanese War yellowed their skin using mepacrine tablets in order better blend in with the native Chinese population.<ref name="NavyTimes">{{Cite web | url=https://www.navytimes.com/news/your-navy/2018/12/30/how-naked-world-war-ii-sailors-ended-up-riding-mongolian-ponies-in-the-gobi-desert-to-shoot-bazookas-at-the-japanese/ | title=How naked World War II sailors ended up riding Mongolian ponies in the Gobi Desert to shoot bazookas at the Japanese| date=2019-01-26}}</ref>

==See also== * Chloroquine * Amodiaquine * Pamaquine * Mefloquine

==References== {{Reflist|2}}

==External links== * [http://www.clinicaltrials.gov/show/NCT00183092 National Institute on Aging (NIA) trial]

Category:Disulfiram-like drugs Category:Antiprotozoal agents Category:Antimalarial agents Category:Sterilization (medicine) Category:Experimental methods of birth control Category:Acridines Category:Chloroarenes Category:Phenol ethers Category:Aromatic amines Category:Diethylamino compounds