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{{Drugbox
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 464378394
| verifiedrevid = 443271804
| IUPAC_name = (''RS'')-''N′''-(6-Chloro-2-methoxy-acridin-9-yl)-''N'',''N''-diethylpentane-1,4-diamine
| IUPAC_name = 4,5-diacetyloxy-9,10-dioxo-anthracene-2-<br>carboxylic&nbsp;acid
| image = Quinacrine.png
| image = Diacerein.svg
| width = 200
| alt = Structural formula of diacerein
| imagename =  
| image2 = Diacerein 3D ball.png
| alt2 = Ball-and-stick model of the diacerein molecule


<!--Clinical data-->
<!--Clinical data-->
| tradename =
| tradename = Atabrine
| Drugs.com = {{drugs.com|international|diacerein}}
| Drugs.com = {{drugs.com|CONS|quinacrine}}
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B            / C / D / X -->
| pregnancy_category = Lacking information
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!--            / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL        / P      / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC                  / Rx-only  / Schedule I, II, III, IV, V -->
| legal_status = 
| routes_of_administration = Oral


<!--Pharmacokinetic data-->
<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = 80-90%
| protein_bound = 99%
| elimination_half-life = 5 to 14 days
| metabolism = [[Liver|Hepatic]]: [[acetylation|deacetylation]] to [[Rhein (molecule)|rhein]], later [[glucuronidation]] and [[sulfate]] conjugation
| elimination_half-life = 4 to 5 hours
| excretion = [[Kidney|Renal]] (30%)


<!--Identifiers-->
<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 13739-02-1
| CAS_number = 83-89-6
| ATC_prefix = M01
| ATC_prefix = P01
| ATC_suffix = AX21
| ATC_suffix = AX05
| PubChem = 26248
| ATC_supplemental =  {{ATCvet|P51|AX04}}
| PubChem = 237
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank =
| DrugBank = DB01103
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 24456
| ChemSpiderID = 232
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 4HU6J11EL5
| UNII = H0C805XYDE
| KEGG_Ref = {{keggcite|correct|kegg}}
| ChEBI_Ref = {{ebicite|correct|EBI}}
| KEGG = D07270
| ChEBI = 8711
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 41286
| ChEMBL = 7568
| PDB_ligand = QUN


<!--Chemical data-->
<!--Chemical data-->
| C=19 | H=12 | O=8
| C=23 | H=30 | Cl=1 | N=3 | O=1
| molecular_weight = 368.294 g/mol
| molecular_weight = 399.957 g/mol
| smiles = O=C(Oc3cccc2C(=O)c1cc(cc(OC(=O)C)c1C(=O)c23)C(=O)O)C
| smiles = CCN(CC)CCCC(C)Nc1c2ccc(cc2nc3c1cc(cc3)OC)Cl
| InChI = 1/C19H12O8/c1-8(20)26-13-5-3-4-11-15(13)18(23)16-12(17(11)22)6-10(19(24)25)7-14(16)27-9(2)21/h3-7H,1-2H3,(H,24,25)
| InChI = 1/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)
| InChIKey = TYNLGDBUJLVSMA-UHFFFAOYAJ
| InChIKey = GPKJTRJOBQGKQK-UHFFFAOYAJ
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C19H12O8/c1-8(20)26-13-5-3-4-11-15(13)18(23)16-12(17(11)22)6-10(19(24)25)7-14(16)27-9(2)21/h3-7H,1-2H3,(H,24,25)
| 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_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = TYNLGDBUJLVSMA-UHFFFAOYSA-N
| StdInChIKey = GPKJTRJOBQGKQK-UHFFFAOYSA-N
| synonyms = <small>Diacetylrhein; Diacerhein; 2-Anthracenecarboxylic acid, 4,5-bis(acetyloxy)-9,10-dihydro-9,10-dioxo-; 2-Anthroic acid, 9,10-dihydro-4,5-dihydroxy-9,10-dioxo-, diacetate; 9,10-Dihydro-4,5-dihydroxy-9,10-dioxo-2-anthroic acid, diacetate</small>
}}
}}


Line 63: Line 51:
==Overview==
==Overview==


'''Diacerein''' ([[International Nonproprietary Name|INN]]), also known as '''diacetylrhein''', is a slow-acting medicine of the class [[anthraquinone]] used to treat joint diseases such as osteoarthritis (swelling and pain in the joints).<ref>Harry Gouvas: Use of Sodium Hyaluronate in the treatment of Osteoarthritis, Greece, 2011</ref> It works by inhibiting [[interleukin-1 beta]]. A 2005 [[Cochrane Collaboration|Cochrane]] [[systematic review|review]] found diacerein to be slightly, but [[statistical significance|significantly]], more effective than placebo in improving pain and slowing the progress of osteoarthritis in the hip and knee.<ref name="Cochrane">{{cite journal |author=Fidelix TS, Soares BG, Trevisani VF |title=Diacerein for osteoarthritis |journal=[[Cochrane Library|Cochrane database of systematic reviews (Online)]] |volume= |issue=1 |pages=CD005117 |year=2006 |pmid=16437519 |doi=10.1002/14651858.CD005117.pub2 |editor1-last=Fidelix |editor1-first=Tania S.A.}} [http://www.cochrane.org/reviews/en/ab005117.html Free summary]</ref>
'''Mepacrine''' ([[International Nonproprietary Name|INN]]; also called '''quinacrine''' in the [[United States]] and '''Atabrine''' (trade name) is a [[medication|drug]] with several [[Medicine|medical]] applications. It is related to [[mefloquine]].


Diacerein-containing medicines are currently authorized in the following [[European Union]] (EU) Member States: [[Austria]], [[Czech Republic]], [[France]], [[Greece]], [[Italy]], [[Portugal]], [[Slovakia]] and [[Spain]].
==Medical uses==
[[File:Atabrine advertisement in Guinea during WW2.jpg|thumb|left|''These men didn't take their Atabrine'' (as anti-malaria drug) ; 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>[http://www.drugs.com/mmx/quinacrine-hydrochloride.html Drugs.com: Quinacrine.] Retrieved on August 24, 2009.</ref>


==Pharmacology==
Antiprotozoal use include targeting [[giardiasis]], where mepacrine is indicated as a primary agent for patients with [[metronidazole]]-resistant giardiasis and patients who should not receive or can not tolerate metronidazole. Giardiasis that is very resistant may even require a combination of mepacrine and metronidazole.<ref name=drugsdotcom/>
'''Diacerein''' works by blocking the actions of [[interleukin-1 beta]], a protein involved in the inflammation and destruction of [[cartilage]] that play a role in the development of symptoms of degenerative joint diseases such as [[osteoarthritis]]. Due to its specific mode of action, which does not involve the inhibition of [[prostaglandin]] synthesis, diacerein has been shown to have anti-osteoarthritis and cartilage stimulating properties in vitro and animal models. Due to its excellent gastro-intestinal tolerance, a combination therapy with an analgesic or a NSAID may be recommended during the first 2-4 weeks of treatment.


==Side effects==
Mepacrine is also used "off-label" for the treatment of [[systemic lupus erythematosus]],<ref name="pmid16623930">{{cite journal |author=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}}</ref> indicated in the treatment of discoid and subcutaneous lupus erythematosus, particularly in patients unable to take [[chloroquine]] derivatives.<ref name=drugsdotcom/>
The most common [[adverse drug reaction|side effects]] of diacerein treatment are [[gastrointestinal tract|gastrointestinal]], such as [[diarrhea]].<ref name="Cochrane"/>Due to the risks associated with severe diarrhoea it is advisable to start treatment with half the normal dose (i.e. 50 mg per day) for the first 2 to 4 weeks, after which the recommended dose is 50 mg twice a day.<ref>http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Diacerein/Position_provided_by_CMDh/WC500163532.pdf</ref> Discoloration of urine (yellow or pink) is another side effect of Diacerein. This effect is due to the elimination of rhein metabolites via the urine and no clinical significance has been found; it may also be dependent on general fluid intake. <ref>http://www.faran.gr/en/node/357</ref>


==Special warning==
As an intrapleural sclerosing agent, it is used as [[pneumothorax]] prophylaxis in patients at high risk of recurrence, e.g., cystic fibrosis patients.<ref name=drugsdotcom/>
Diacerein should not be administered during pregnancy and lactation. It is also should not be used in any patient with liver disease or a history of liver disease.<ref>http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Diacerein/Position_provided_by_CMDh/WC500163532.pdf</ref>


==Dosage and administration==
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.
Diacerein should not be taken below 15 years of old as no clinical studies have been undertaken in this age group. The usual dosage of diacerein is 50&nbsp;mg twice daily, after meals, for 3 years. <ref>http://arthritis-research.com/content/8/2/206</ref>


==Marketing==
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 | author = Wall JE, Buijs-Wilts M, Arnold JT, ''et al.'' | 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&ndash;385 | year = 1995 | doi = 10.1111/j.1365-2141.1995.tb03315.x}}</ref>
It is marketed in Egypt and the Middle East by Eva Pharma.<ref>http://www.evapharma.com/products/Diacerein-Cap/</ref> The Original product company was TRB Ltd Swiss.<ref>http://www.trbchemedica.com/</ref> In [[Pakistan]], [[Bangladesh]] and [[India]], Diacerein is marketed and sold as a single preparation or combination with [[Glucosamine]] Sulfate. In [[Greece]] it has been sold since 2001 by Faran Ltd under the trade name Verboril.<ref>Faran AE, Brochure of Diacerein (VERBORIL), 2001</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 of uses==
===Antiprotozoal===
Mepacrine was initially approved in the 1930s as an [[antimalarial drug]]. It was used extensively during the [[second World War]] by US forces fighting in 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&ndash;1830 | doi=10.1128/aac.01296-10}}</ref>
This [[antiprotozoal]] is also approved for the treatment of [[giardiasis]] (an [[intestinal parasite]]),<ref name="pmid17072963">{{cite journal |author=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=}}</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 | author = 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 | url=http://jvi.asm.org/cgi/content/full/74/10/4894?view=long&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 | author = 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 | author = 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}}</ref>
and treatment of [[scrapie]] in [[lab mouse|mice]] and [[sheep]] has also shown no effect.<ref name="Barret">{{cite journal | author = 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 | url=http://jvi.asm.org/cgi/content/full/77/15/8462?view=long&pmid=12857915 | doi = 10.1128/JVI.77.15.8462-8469.2003 | pmc = 165262}}</ref><ref name="Gayrard">{{cite journal | author = 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 | author = Ghaemmaghami S, Ahn M, Lessard P, Giles K, Legname G, et al. | 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 }}</ref>
===Non-surgical sterilization for women ===
The use of mepacrine for non-surgical [[Sterilization (medicine)|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 | author=Zipper J, Cole LP, Goldsmith A, Wheeler R, Rivera M. | title=Quinacrine hydrochloride pellets: preliminary data on a nonsurgical method of female sterilisation | journal=Asia Oceania J. Obstet. Gynaecol. | year=1980 | volume=18 | pages=275–90 |pmid=6109672 | issue=4}}</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/>
[[Pelletizing|Pellets]] of mepacrine are inserted through the cervix into a woman's [[uterus|uterine cavity]] using a preloaded inserter device, similar in manner to [[Intrauterine device|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|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 use|off-label]].
Many peer reviewed studies suggest that<ref>{{cite journal | author=International Journal of Gynecology and Obstetrics | title=Quinacrine Sterilization: Reports on 40,252 cases | journal=London: Elsevier. Vol 83 (Suppl. 2) | year=October 2003}}</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=A background paper for the WHO consultation on the development of new technologies for female sterilization. | year=1994}}</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}}</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 pregnancy|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|postscript=.}}.</ref>
==See also==
==See also==
* [[Rhein (molecule)|Rhein]]
*[[Chloroquine]]
*[[Amodiaquine]]
*[[Pamaquine]]
*[[Mefloquine]]


==References==
==References==
{{Reflist}}
{{Reflist|2}}
 
==External links==
* [http://www.clinicaltrials.gov/show/NCT00183092 National Institute on Aging (NIA) trial]


{{Anti-inflammatory and antirheumatic products}}
{{Antiprotozoal agent}}
{{Excavata antiparasitics}}
{{Anthelmintics}}
{{Histaminergics}}


[[Category:Anti-inflammatory agents]]
[[Category:Antiprotozoal agents]]
[[Category:Anthraquinones]]
[[Category:Antimalarial agents]]
[[Category:Carboxylic acids]]
[[Category:Sterilization]]
[[Category:Acetate esters]]
[[Category:Experimental methods of birth control]]
[[Category:Acridines]]
[[Category:Organochlorides]]
[[Category:Phenol ethers]]
[[Category:Aromatic amines]]

Latest revision as of 18:20, 7 April 2015

Mepacrine
Clinical data
Trade namesAtabrine
AHFS/Drugs.comMicromedex Detailed Consumer Information
ATC code
Pharmacokinetic data
Protein binding80-90%
Elimination half-life5 to 14 days
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
PDB ligand
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC23H30ClN3O
Molar mass399.957 g/mol
3D model (JSmol)
  (verify)


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Mepacrine (INN; also called quinacrine in the United States and Atabrine (trade name) is a drug with several medical applications. It is related to mefloquine.

Medical uses

These men didn't take their Atabrine (as anti-malaria drug) ; 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.[1]

Antiprotozoal use include targeting giardiasis, where mepacrine is indicated as a primary agent for patients with metronidazole-resistant giardiasis and patients who should not receive or can not tolerate metronidazole. Giardiasis that is very resistant may even require a combination of mepacrine and metronidazole.[1]

Mepacrine is also used "off-label" for the treatment of systemic lupus erythematosus,[2] indicated in the treatment of discoid and subcutaneous lupus erythematosus, particularly in patients unable to take chloroquine derivatives.[1]

As an intrapleural sclerosing agent, it is used as pneumothorax prophylaxis in patients at high risk of recurrence, e.g., cystic fibrosis patients.[1]

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.[3]

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 of uses

Antiprotozoal

Mepacrine was initially approved in the 1930s as an antimalarial drug. It was used extensively during the second World War by US forces fighting in the Far East to prevent malaria.[4]

This antiprotozoal is also approved for the treatment of giardiasis (an intestinal parasite),[5] 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.[6]

Creutzfeldt-Jakob disease

Mepacrine has been shown to bind to the prion protein and prevent the formation of prion aggregates in vitro,[7] 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,[8] although other reports have shown no significant effect,[9] and treatment of scrapie in mice and sheep has also shown no effect.[10][11] 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.[12]

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%.[13] 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.[1]

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[14] mepacrine sterilization (QS) is potentially safer than surgical sterilization.[15][16] 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.[17]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Drugs.com: Quinacrine. Retrieved on August 24, 2009.
  2. ↑ Toubi E, Kessel A, Rosner I, Rozenbaum M, Paran D, Shoenfeld Y (2006). "The reduction of serum B-lymphocyte activating factor levels following quinacrine add-on therapy in systemic lupus erythematosus". Scand. J. Immunol. 63 (4): 299–303. doi:10.1111/j.1365-3083.2006.01737.x. PMID 16623930.
  3. ↑ Wall JE, Buijs-Wilts M, Arnold JT; et al. (1995). "A flow cytometric assay using mepacrine for study of uptake and release of platelet dense granule contents". Br J Haematol. 89 (2): 380&ndash, 385. doi:10.1111/j.1365-2141.1995.tb03315.x.
  4. ↑ Baird JK (2011). "Resistance to chloroquine unhinges vivax malaria therapeutics". Antimicrob Agents Chemother. 55 (5): 1827&ndash, 1830. doi:10.1128/aac.01296-10.
  5. ↑ Canete R, Escobedo AA, Gonzalez ME, Almirall P (2006). "Randomized clinical study of five days apostrophe therapy with mebendazole compared to quinacrine in the treatment of symptomatic giardiasis in children". World J. Gastroenterol. 12 (39): 6366–70. PMID 17072963.
  6. ↑ Template:DorlandsDict
  7. ↑ Doh-Ura K, Iwaki T, Caughey B (May 2000). "Lysosomotropic Agents and Cysteine Protease Inhibitors Inhibit Scrapie-Associated Prion Protein Accumulation". J Virol. 74 (10): 4894–7. doi:10.1128/JVI.74.10.4894-4897.2000. PMC 112015. PMID 10775631.
  8. ↑ Kobayashi Y, Hirata K, Tanaka H, Yamada T (July 2003). "[Quinacrine administration to a patient with Creutzfeldt-Jakob disease who received a cadaveric dura mater graft--an EEG evaluation]". Rinsho Shinkeigaku. 43 (7): 403–8. PMID 14582366.
  9. ↑ 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 (28 December 2004). "Compassionate use of quinacrine in Creutzfeldt-Jakob disease fails to show significant effects". Neurology. 63 (12): 2413–5. doi:10.1212/01.wnl.0000148596.15681.4d. PMID 15623716.
  10. ↑ 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 (August 2003). "Evaluation of Quinacrine Treatment for Prion Diseases". J Virol. 77 (15): 8462–9. doi:10.1128/JVI.77.15.8462-8469.2003. PMC 165262. PMID 12857915.
  11. ↑ Gayrard V, Picard-Hagen N, Viguié C, Laroute V, Andréoletti O, Toutain P (February 2005). "A possible pharmacological explanation for quinacrine failure to treat prion diseases: pharmacokinetic investigations in a ovine model of scrapie". Br J Pharmacol. 144 (3): 386–93. doi:10.1038/sj.bjp.0706072. PMC 1576015. PMID 15655516. - Abstract
  12. ↑ Ghaemmaghami S, Ahn M, Lessard P, Giles K, Legname G; et al. (November 2009). Mabbott, Neil, ed. "Continuous Quinacrine Treatment Results in the Formation of Drug-Resistant Prions". PLoS Pathogens. 5 (11): 2413–5. doi:10.1371/journal.ppat.1000673. PMC 2777304. PMID 19956709.
  13. ↑ Zipper J, Cole LP, Goldsmith A, Wheeler R, Rivera M. (1980). "Quinacrine hydrochloride pellets: preliminary data on a nonsurgical method of female sterilisation". Asia Oceania J. Obstet. Gynaecol. 18 (4): 275–90. PMID 6109672.
  14. ↑ International Journal of Gynecology and Obstetrics (October 2003). "Quinacrine Sterilization: Reports on 40,252 cases". London: Elsevier. Vol 83 (Suppl. 2).
  15. ↑ Sokal, D.C., Kessel. E., Zipper. J., and King. T. (1994). "Quinacrine: Clinical experience". A background paper for the WHO consultation on the development of new technologies for female sterilization.
  16. ↑ Peterson, H.B., Lubell, L., DeStefano, F., and Ory, H.W. (1983). "The safety and efficacy of tubal sterilization: an international overview". Int J. Gynaecol. Obstet. 21 (2): 139–44. doi:10.1016/0020-7292(83)90051-6. PMID 6136433.
  17. ↑ George, Nirmala (July 25, 1998). "Govt drags feet on quinacrine threat". Indian Express..

External links

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