Quinacrine

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Quinacrine
File:Quinacrine.svg
Pharmacokinetic data
Protein binding80-90%
Elimination half-life5 to 14 days
Identifiers
CAS Number
PubChem CID
DrugBank
E number{{#property:P628}}
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Chemical and physical data
FormulaC23H30ClN3O
Molar mass399.957 g/mol

Quinacrine (trade name: Atabrine) is a drug with a number of different medical applications being initially used in the 1930s as an antimalarial drug. It has also been used as an antibiotic in the treatment of Giardiasis (an intestinal parasite)[1], and in research as an inhibitor of phospholipase A2. It has also been proposed for use in systemic lupus erythematosus.[2]

History and licensed uses

Scientists at Bayer in Germany first synthesised Quinacrine in 1931 and subsequently marketed as Mepacrine or Atebrin. The product was one of the first synthetic substitutes for quinine although later superseded by chloroquine.

Its mechanism of action against giardia is uncertain, but it is thought to act against the bacteria cell wall. In addition it has been used for treating cutaneous leishmaniasis.

Quinacrine Sterilization (QS)

Controversially, Quinacrine has been used as a method of non-surgical sterlisation. This method [3], was developed by Zipper et al who reported a first year failure rate of 3.1%.[4] Pellets of quinacrine and an anti-inflammatory drug ibuprofen are inserted through the cervix into a woman's uterine cavity using a preloaded inserter device, similar in manner to IUCD insertion. The proceedure is undertaken twice, first in the proliferative phase 6th to 14th 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 over a six week interval to close off the tubes permanently.

In over 30,000 cases of quinacrine pellet sterilizations in Vietnam, 10,000 cases in India and 5000 cases in other regions not a single death has been reported;[5] which compares to the fatality rates of surgical sterilizations of 21 per 100,000 in India,[6] and in the US & UK of respectively 10 & 2 per 100,000.[7]

Controversy About Quinacrine Sterilization

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Use of quinacrine for sterilization is highly controversial. The two leading promoters of quinacrine sterilization are Dr. Elton Kessel and Stephen Mumford, who both previously worked for the Family Health International (FHI), a non-profit agency that funded quinacrine research in Chile during the 1970s. Subsequent funding from the conservative Leland Fikes Foundation and the Scaife Family Foundation made it possible for Mumford and Kessel to provide quinacrine free of charge to researchers, clinicians, and government health agencies worldwide. Mumford and Kessel's gifts of quinacrine were made possible not only through family foundations, but also through the financial support of individuals such as Sarah G. Epstein and Donald Collins, both board members of the Federation for American Immigration Reform (FAIR), an organization advocating reduced immigration.

Risks of quinacrine sterilization include cancer, development of abnormal lesions in the uterus, severe pain, ectopic pregnancy and fetal exposure.[citation needed] The pellets have already been banned in India and Chile (Wall Street Journal, 10/19/98).

Quinacrine has never been approved by the FDA for sterilization. Despite this fact, Kessel and Mumford have solicited abortion providers in the United States to perform quinacrine sterilization. According to Kessel, official government approval through the FDA would have been "desirable but not necessary" because the FDA permits approved drugs to be used "off-label." The FDA, however, disagreed and in October 1998, it ordered Kessel and Mumford to destroy their existing supply of quinacrine tablets and to immediately stop all export and distribution of the drug. The FDA stated that quinacrine used for sterilizations was an "unapproved new drug and a misbranded drug in violation of the Federal Food, Drug, and Cosmetic Act." and was an "unsafe use of this drug product.", with the FDA being "very concerned about the safety risks associated with the use of this drug and its effects on women and the fetus if a woman is or becomes pregnant." In addition to forbidding the marketing of quinacrine in the United States for sterilization purposes, the Warning Letter forbade the import of the drug into the United States or its exporting to another country.

From September 1998 until December 1999, little was written about Mumford and Kessel's quinacrine plans. The future of quinacrine sterilizations laid in abeyance until Warren Buffett revived quinacrine research by donating two million dollars to FHI, who will resume animal testing and begin human testing of quinacrine sterilizations in preparation for FDA approval.[citation needed] Planned Parenthood Federation of America, the largest reproductive health-care organization in the United States, has defended quinacrine sterilizations, indicating that they are willing to test quinacrine on their patients. In the meantime, Jack Lippes, Population Council consultant and inventor of the discontinued Lippes Loop IUD, has received approval from the Children's Hospital of Buffalo to conduct quinacrine sterilization on ten women.[8][9]

Concerns about consent

Field tests carried out in India and Vietnam led to notable concern over the lack of disclosure to test subjects regarding the permanent effects of the procedure, or that they were given quinacrine at all. In Vietnam, more than a hundred women were given quinacrine during routine pelvic exams, without their knowledge or consent, as "testing." These acts, along with a lack of knowledge about the long-term effects of Quinacrine Sterilization has led to a ban by the World Health Organization on further human testing.[10]

Quinacrine and Creutzfeldt-Jakob disease

Quinacrine has been shown to bind to the prion protein and prevent the formation of prion aggregates in vitro,[11] 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,[12] although other reports have shown no significant effect,[13] and treatment of scrapie in mice and sheep has also shown no effect.[14][15]

References

  1. 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.
  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. Pravin Kini. "Quinacrine Pellet Method of Female Sterilization".
  4. 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: 275–90. PMID 6109672.
  5. 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.
  6. Bhatt RV (1991). "Camp laparoscopic sterilization deaths in Gujarat State, India, 1978-1980". Asia-Oceania journal of obstetrics and gynaecology / AOFOG. 17 (4): 297–301. PMID 1839351.
  7. 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.: 139–44. PMID 6136433.
  8. Jack Lippes (November 8, 1999). "Quinacrine Sterilization (QS) - Safety and Efficacy". Workshop presentation at the American Public Health Association Annual Meeting, Chicago, IL.
  9. Judith A.M. Scully. "Maternal Mortality, Population Control, And The War In Women's Wombs: A Bioethical Analysis Of Quinacrine Sterilizations". Wisconsin International Law Journal. 19: 103. - Reproduced copy by Women's Human Rights Resources Programme
  10. Rao, Mohan (1997). "Surreptitious Sterilization : A Endangering Process". Health for Millions. 23 (4): 26–28. Unknown parameter |month= ignored (help) - Reproduced by Global Reproductive Health Forum South Asia
  11. Doh-Ura K, Iwaki T, Caughey B (2000). "Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation". J Virol. 74 (10): 4894–7. PMID 10775631. Unknown parameter |month= ignored (help)
  12. Kobayashi Y, Hirata K, Tanaka H, Yamada T (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. Unknown parameter |month= ignored (help)
  13. 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 (2004). "Compassionate use of quinacrine in Creutzfeldt-Jakob disease fails to show significant effects". Neurology. 63 (12): 2413–5. PMID 15623716. Unknown parameter |month= ignored (help)
  14. 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 (2003). "Evaluation of quinacrine treatment for prion diseases". J Virol. 77 (15): 8462–9. PMID 12857915. Unknown parameter |month= ignored (help)
  15. Gayrard V, Picard-Hagen N, Viguié C, Laroute V, Andréoletti O, Toutain P (2005). "A possible pharmacological explanation for quinacrine failure to treat prion diseases: pharmacokinetic investigations in an ovine model of scrapie". Br J Pharmacol. 144 (3): 386–93. PMID 15655516. Unknown parameter |month= ignored (help) - Abstract

External links

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