Clioquinol

A 1964 report described the use of clioquinol in both the treatment and prevention of shigella infection and Entamoeba histolytica infection in institutionalized individuals at Sonoma State Hospital in California. The report indicates 4000 individuals were treated over a 4-year period with few side effects.{{cite journal | vauthors = Gholz LM, Arons WL | title = Prophylaxis and Therapy of Amebiasis and Shigellosis with Iodochlorhydroxyquin | journal = The American Journal of Tropical Medicine and Hygiene | volume = 13 | issue = 3 | pages = 396–401 | date = May 1964 | pmid = 14162901 | doi = 10.4269/ajtmh.1964.13.396 }}

Several recently reported journal articles describing its use as an antiprotozoal include:

• A 2005 reference to its use in treating a Dutch family for Entamoeba histolytica infection.{{cite journal | vauthors = Kager PA | title = [Outbreak of amoebiasis in a Dutch family; tropics unexpectedly nearby] | language = nl | journal = Nederlands Tijdschrift voor Geneeskunde | volume = 149 | issue = 1 | pages = 51–2; author reply 52–3 | date = January 2005 | pmid = 15651505 }}
• A 2004 reference to its use in the Netherlands in the treatment of Dientamoeba fragilis infection.{{cite journal | vauthors = Bosman DK, Benninga MA, van de Berg P, Kooijman GC, van Gool T | title = [Dientamoeba fragilis: possibly an important cause of persistent abdominal pain in children] | language = nl | journal = Nederlands Tijdschrift voor Geneeskunde | volume = 148 | issue = 12 | pages = 575–579 | date = March 2004 | pmid = 15074181 }}
• A 1979 reference to the use in Zaire in the treatment of Entamoeba histolytica infection.{{cite journal | vauthors = Masters DK, Hopkins AD | title = Therapeutic trial of four amoebicide regimes in rural Zaire | journal = The Journal of Tropical Medicine and Hygiene | volume = 82 | issue = 5 | pages = 99–101 | date = May 1979 | pmid = 226725 }}

Clioquinol's use as an antiprotozoal drug has been restricted or discontinued in some countries due to an event in Japan where over 10,000 people developed subacute myelo-optic neuropathy (SMON) between 1957 and 1970. The drug was used widely in many countries before and after the SMON event without similar reports.{{cite journal | vauthors = Wadia NH | title = SMON as seen from Bombay | journal = Acta Neurologica Scandinavica. Supplementum | volume = 100 | pages = 159–164 | year = 1984 | pmid = 6091394 }} As yet, no explanation exists as to why it produced this reaction, and some researchers have questioned whether clioquinol was the causative agent in the disease, noting that the drug had been used for 20 years prior to the epidemic without incident, and that the SMON cases began to reduce in number prior to the discontinuation of the drug.{{cite journal | vauthors = Meade TW | title = Subacute myelo-optic neuropathy and clioquinol. An epidemiological case-history for diagnosis | journal = British Journal of Preventive & Social Medicine | volume = 29 | issue = 3 | pages = 157–169 | date = September 1975 | pmid = 127638 | pmc = 478909 | doi = 10.1136/jech.29.3.157 }} Theories suggested have included improper dosing, the permitted use of the drug for extended periods of time,{{cite journal | vauthors = Takasu T | title = [SMON--a model of the iatrogenic disease] | language = ja | journal = Rinsho Shinkeigaku = Clinical Neurology | volume = 43 | issue = 11 | pages = 866–869 | date = November 2003 | pmid = 15152488 }} and dosing which did not consider the smaller average stature of Japanese; however a dose dependent relationship between SMON development and clioquinol use was never found, suggesting the interaction of another compound. Researchers have also suggested the SMON epidemic could have been due to a viral infection with an Inoue-Melnick virus.{{cite journal | vauthors = Ito M, Nishibe Y, Inoue YK | title = Isolation of Inoue-Melnick virus from cerebrospinal fluid of patients with epidemic neuropathy in Cuba | journal = Archives of Pathology & Laboratory Medicine | volume = 122 | issue = 6 | pages = 520–522 | date = June 1998 | pmid = 9625419 }}

Clioquinol is a constituent of the prescription medicine Vioform, which is a topical antifungal treatment. It is also used in the form of a cream (and in combination with betamethasone or fluocinolone) in the treatment of inflammatory skin disorders.{{cn|date=June 2022}}

It has long been recognized that normal prostate cells have high zinc content through ZIP1 mediated uptake, and have low respiration (OXPHOS ATP generation is diverted to citrate export for sperm energetics). Prostate cancer cells have downregulated ZIP1 transporters which leads to greater ATP generation which is diverted to cancer proliferation, an example of a normal-like metabolic phenotype instead being malignant. The zinc ionophore clioquinol was shown in mice to restore zinc levels and stop the growth of prostate tumors.{{cite journal | vauthors = Costello LC, Franklin RB | title = A comprehensive review of the role of zinc in normal prostate function and metabolism; and its implications in prostate cancer | journal = Archives of Biochemistry and Biophysics | volume = 611 | issue = 1 | pages = 100–112 | date = December 2016 | pmid = 27132038 | pmc = 5083243 | doi = 10.1016/j.abb.2016.04.014 }}

Research at UCSF indicates that clioquinol appears to block the genetic action of Huntington's disease in mice and in cell culture.{{cite journal | vauthors = Nguyen T, Hamby A, Massa SM | title = Clioquinol down-regulates mutant huntingtin expression in vitro and mitigates pathology in a Huntington's disease mouse model | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 33 | pages = 11840–11845 | date = August 2005 | pmid = 16087879 | pmc = 1187967 | doi = 10.1073/pnas.0502177102 | doi-access = free | bibcode = 2005PNAS..10211840N }}

Recent animal studies have shown that clioquinol can reverse the progression of Alzheimer's, Parkinson's and Huntington's diseases.{{cite journal | vauthors = Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, Volitakis I, Liu X, Smith JP, Perez K, Laughton K, Li QX, Charman SA, Nicolazzo JA, Wilkins S, Deleva K, Lynch T, Kok G, Ritchie CW, Tanzi RE, Cappai R, Masters CL, Barnham KJ, Bush AI | display-authors = 6 | title = Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta | journal = Neuron | volume = 59 | issue = 1 | pages = 43–55 | date = July 2008 | pmid = 18614028 | doi = 10.1016/j.neuron.2008.06.018 | s2cid = 17263833 | doi-access = free }} According to Siegfried Hekimi and colleagues at McGill's Department of Biology, clioquinol acts directly on a protein called Clk-1, often informally called “clock-1,” and might slow down the aging process. They theorize that this may explain the apparent ability of the drug to be effective in the above conditions, but warn against individuals experimenting with this drug.{{Cite web |url=https://www.mcgill.ca/newsroom/news/item/?item_id=103574 |title=News: Old gastrointestinal drug slows aging, McGill researchers say |access-date=2017-08-25 |archive-url=https://web.archive.org/web/20110210121513/http://www.mcgill.ca/newsroom/news/item/?item_id=103574 |archive-date=2011-02-10 |url-status=dead }}

In addition, a study performed in Drosophila demonstrates that clioquinol can slow the pathogenesis of tauopathy model by removing the excessive zinc in the cell.{{cite journal | vauthors = Huang Y, Wu Z, Cao Y, Lang M, Lu B, Zhou B | title = Zinc binding directly regulates tau toxicity independent of tau hyperphosphorylation | journal = Cell Reports | volume = 8 | issue = 3 | pages = 831–842 | date = August 2014 | pmid = 25066125 | pmc = 4306234 | doi = 10.1016/j.celrep.2014.06.047 }}

• PBT2, a related 8-hydroxyquinoline
• Ionophore, other ionophores

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{{Antiseptics and disinfectants}}

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{{Gynecological anti-infectives and antiseptics}}

{{Otologicals}}

{{Agents against amoebozoa}}

Category:Antiprotozoal agents

Category:Antifungals

Category:Quinolinols

Category:Drugs developed by Novartis

Category:Iodoarenes

Category:Chloroarenes

Category:Otologicals