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Mepacrine (INN), also called quinacrine (USAN) or by the trade name Atabrine, 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 The product was one of the first synthetic substitutes for quinine although later superseded by chloroquine.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]

References

^ ^a ^b ^c ^d ^e Drugs.com: Quinacrine. Retrieved on August 24, 2009.
^ 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.
^ 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): 380–385. doi:10.1111/j.1365-2141.1995.tb03315.x.
^ Baird JK (2011). "Resistance to chloroquine unhinges vivax malaria therapeutics.". Antimicrob Agents Chemother 55 (5): 1827–1830. doi:10.1128/aac.01296-10.
^ 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.
^ "quinacrine" at Dorland's Medical Dictionary
^ 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.
^ 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.
^ 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.
^ 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.
^ 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
^ Ghaemmaghami S, Ahn M, Lessard P, Giles K, Legname G, et al. (November 2009). Mabbott N, 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.
^ 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.
^ International Journal of Gynecology and Obstetrics (October 2003). "Quinacrine Sterilization: Reports on 40,252 cases". London: Elsevier. Vol 83 (Suppl. 2).
^ 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.
^ 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.
^ George, Nirmala (July 25, 1998). "Govt drags feet on quinacrine threat". Indian Express. .

External links

National Institute on Aging (NIA) trial

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. リウマチ性疾患の治療における抗マラリア剤 antimalarial drugs in the treatment of rheumatic disease
2. 抗原虫治療 antiprotozoal therapies
3. 避妊の概要 overview of contraception
4. ジアルジア症の治療および予防 treatment and prevention of giardiasis
5. 全身性エリテマトーデスの皮膚粘膜症状 mucocutaneous manifestations of systemic lupus erythematosus

English Journal

Identification of Activators of ERK5 Transcriptional Activity by High-Throughput Screening and the Role of Endothelial ERK5 in Vasoprotective Effects Induced by Statins and Antimalarial Agents.

Le NT1, Takei Y1, Izawa-Ishizawa Y1, Heo KS1, Lee H1, Smrcka AV2, Miller BL3, Ko KA1, Ture S1, Morrell C1, Fujiwara K1, Akaike M4, Abe J5.
Journal of immunology (Baltimore, Md. : 1950).J Immunol.2014 Oct 1;193(7):3803-15. doi: 10.4049/jimmunol.1400571. Epub 2014 Sep 3.
Because ERK5 inhibits endothelial inflammation and dysfunction, activating ERK5 might be a novel approach to protecting vascular endothelial cells (ECs) against various pathological conditions of the blood vessel. We have identified small molecules that protect ECs via ERK5 activation and determined
PMID 25187658

Dexmedetomidine-induced contraction involves c-Jun NH2 -terminal kinase phosphorylation via activation of the 5-lipoxygenase pathway in the isolated endothelium-denuded rat aorta.

Ok SH1, Byon HJ, Jin H, Kim HJ, Kim W, Nam IK, Eun SY, Sohn JT.
Clinical and experimental pharmacology & physiology.Clin Exp Pharmacol Physiol.2014 Sep 15. doi: 10.1111/1440-1681.12307. [Epub ahead of print]
Vasoconstriction induced by dexmedetomidine, a highly selective alpha-2 adrenoceptor agonist, mainly involves c-Jun NH2 -terminal kinase (JNK) phosphorylation in the isolated endothelium-denuded aorta. We performed an in vitro study to determine the main arachidonic acid metabolic pathway that is in
PMID 25224579

Japanese Journal

Participation of the Arachidonic Acid Cascade Pathway in Macrophage Binding / Uptake of Oxidized Low Density Lipoprotein

Beppu Masatoshi,Watanabe Mitsuhiro,Sunohara Masaru [他],OHISHI Kenji,MISHIMA Eriko,KAWACHI Hirokazu,FUJII Motohiro,KIKUGAWA Kiyomi
Biological & pharmaceutical bulletin 25(6), 710-717, 2002-06-01
… Arachidonic acid cascade inhibitors, including phospholipase A_2 inhibitors, dexamethasone and quinacrine(mepacrine), cyclooxygenase inhibitors, indomethacin and aspirin, and lipoxygenase inhibitor AA861, prevented foam cell formation and cholesterol accumulation in the incubation of thioglycollate-induced mouse peritoneal macrophages with oxidized low density lipoprotein (LDL) at 37℃ for 24 h. …
NAID 110003638744

内耳一過性虚血障害における mepacrine の保護効果の検討

田渕経司,辻茂希,安積靖敏,高橋和彦,和田哲郎,伊東善哉,原晃,草刈潤
Otology Japan 10(4), 530, 2000-09-20
NAID 10013204202

Application of DLC Film to Biomaterials

平栗健二
炭素 1999(190), 313-319, 1999
… In case of DLC coated diaphragms such an enrichment could not beobserved.<BR>The Epifluorescent Video Microscopy (EVM) system measured the platelet adhesion onthe DLC film surface, using whole human blood containing Mepacrine-labeled platelets perfused at a wall shear rate of 100s<SUP>-1</SUP> …
NAID 130004358422

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リンク元

「メパクリン」

Mepacrine
Systematic (IUPAC) name
	(RS)-N′-(6-Chloro-2-methoxy-acridin-9-yl)-N,N-diethylpentane-1,4-diamine
Clinical data
Trade names	Atabrine
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pharmacokinetic data
Protein binding	80-90%
Biological half-life	5 to 14 days
Identifiers
CAS Number	83-89-6
ATC code	P01AX05 (WHO) QP51AX04 (WHO)
PubChem	CID 237
DrugBank	DB01103
ChemSpider	232
UNII	H0C805XYDE
ChEBI	CHEBI:8711
ChEMBL	CHEMBL7568
PDB ligand ID	QUN (PDBe, RCSB PDB)
Chemical data
Formula	C23H30ClN3O
Molar mass	399.957 g/mol
	SMILES CCN(CC)CCCC(C)Nc1c2ccc(cc2nc3c1cc(cc3)OC)Cl ;
	InChI InChI=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) ; Key:GPKJTRJOBQGKQK-UHFFFAOYSA-N ;
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　　[★]

英: mepacrine
関: キナクリン

[drugsdotcom-1] Drugs.com: Quinacrine. Retrieved on August 24, 2009.

[pmid16623930-2] 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): 380–385. 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): 1827–1830. doi:10.1128/aac.01296-10.

[pmid17072963-5] 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] "quinacrine" at Dorland's Medical Dictionary

[Doh-Ura-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.

[Kobayashi-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.

[Haik-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.

[Barret-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.

[Gayrard-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

[Ghaemmaghami-12] Ghaemmaghami S, Ahn M, Lessard P, Giles K, Legname G, et al. (November 2009). Mabbott N, 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. .

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mepacrine