Quinacrine

Quinacrine

Systematic (IUPAC) name
(RS)-N'-(6-chloro-2-methoxy-acridin-9-yl)- N, N-diethyl-pentane-1,4-diamine
Clinical data
Trade names	Atabrine
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy cat.	?
Legal status	?
Pharmacokinetic data
Protein binding	80-90%
Half-life	5 to 14 days
Identifiers
CAS number	83-89-6 Y
ATC code	P01AX05 QP51AX04
PubChem	CID 237
DrugBank	APRD00317
ChemSpider	232 Y
UNII	H0C805XYDE Y
ChEBI	CHEBI:8711 N
ChEMBL	CHEMBL7568 Y
Chemical data
Formula	C23H30ClN3O
Mol. mass	399.957 g/mol
SMILES	eMolecules & PubChem
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) Y Key:GPKJTRJOBQGKQK-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Quinacrine (trade name Atabrine) is a drug with a number of different medical applications. It is related to mefloquine.

Uses

Its main effects are as an antiprotozoal, antirheumatic and an intrapleural sclerosing agent.^[1]

Antiprotozoal use include targeting Giardiasis, where quinacrine 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 quinacrine and metronidazole.^[1]

Quinacrine 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]

Quinacrine is not the drug of choice because side effects are common, including toxic psychosis, and may cause permanent damage. View Mefloquine page for more information.

In addition to medical applications, quinacrine is an effective in vitro research tool for the epifluorescent visualization of cells, especially platelets. Quinacrine is a green fluorescent dye taken up by most cells. Platelet store quinacrine in dense granules.

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

Quinacrine was initially approved in the 1930s as an antimalarial drug. This antiprotozoal is also approved for the treatment of Giardiasis (an intestinal parasite),^[3] and has been researched as an inhibitor of phospholipase A2.

Scientists at Bayer in Germany first synthesised Quinacrine in 1931 and subsequently marketed as Mepacrine or Atebrine. 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.^[4]

Creutzfeldt-Jakob disease

Quinacrine has been shown to bind to the prion protein and prevent the formation of prion aggregates in vitro,^[5] 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,^[6] although other reports have shown no significant effect,^[7] and treatment of scrapie in mice and sheep has also shown no effect.^[8][9] 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 quinacrine.^[10]

Quinacrine non-surgical sterilization for women (QS)

The use of quinacrine for non-surgical sterilization for women has also been researched. This method,^[11] was developed by Zipper et al. who reported a first year failure rate of 3.1%.^[12] However, despite a multitude clinical studies on the use of quinacrine and female sterilization, no randomized, controlled trials have been reported to date and there is some controversy over its use.^[1]

Pellets of quinacrine 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 already undergone Phase I clinical testing for F.D.A. approval. The F.D.A. passed this method during a Phase I clinical trial as showing in a small sample that the method is safe and effective. This was the result of a study published by Dr. Lippes at the SUNY Buffalo (see link below). In addition, the F.D.A. has waived the necessity for Phase II clinical trials because of the extensive data of prior safe use of Quinacine. 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 legally used "off-label" in the US, until final FDA approval of the method is obtained.

Many peer reviewed studies suggest that^[13] quinacrine sterilization (QS) is potentially safer than surgical sterilization.^[14][15] Nevertheless, in 1998 the Supreme Court of India banned the import or use of the drug, based on reports that it could cause cancer or ectopic pregnancies.^[16]

References

1. ^ ^{a b c d e} 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. ^ 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. 
4. ^ "quinacrine" at Dorland's Medical Dictionary
5. ^ 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. http://jvi.asm.org/cgi/content/full/74/10/4894?view=long&pmid=10775631. 
6. ^ 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. 
7. ^ 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. PMID 15623716. 
8. ^ 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. http://jvi.asm.org/cgi/content/full/77/15/8462?view=long&pmid=12857915. 
9. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1576015.  - Abstract
10. ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2777304. 
11. ^ Pravin Kini. "Quinacrine Pellet Method of Female Sterilization". http://www.obgyn.net/medical.asp?page=/ENGLISH/PUBS/ARTICLES/kini_art. 
12. ^ 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. 
13. ^ International Journal of Gynecology and Obstetrics. (October 2003). "Quinacrine Sterilization: Reports on 40,252 cases". London: Elsevier. Vol 83 (Suppl. 2).. 
14. ^ 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.. 
15. ^ 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. 
16. ^ George, Nirmala (July 25, 1998). "Govt drags feet on quinacrine threat". Indian Express. http://www.indianexpress.com/res/web/pIe/ie/daily/19980725/20650684.html .

External links

• The most extensive online database about quinacrine sterilization.
• Clinical Trial Results -- FDA Phase I clinical trial of quinacrine sterilization
• National Institute on Aging (NIA) trial
• Medical Research Council PRION-1 trial