Clioquinol Explained

Clioquinol (iodochlorhydroxyquin) tradename Entero-Vioform is an antifungal drug and antiprotozoal drug. It is neurotoxic in large doses. It is a member of a family of drugs called hydroxyquinolines which inhibit certain enzymes related to DNA replication. The drugs have been found to have activity against both viral and protozoal infections.[1]

Antiprotozoal use

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.[2]

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

Subacute myelo-optic neuropathy

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.[6] 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.[7] Theories suggested have included improper dosing, the permitted use of the drug for extended periods of time,[8] 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.[9]

Topical use

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.

Potential use as a preventive or treatment in prostate cancer

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.[10]

Use in neurodegenerative diseases

Research at UCSF indicates that clioquinol appears to block the genetic action of Huntington's disease in mice and in cell culture.[11]

Recent animal studies have shown that clioquinol can reverse the progression of Alzheimer's, Parkinson's and Huntington's diseases.[12] 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.[13]

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.[14]

Continued use and manufacture around the world

CountryComments
United StatesIn August 2004, Prana Biotechnology, an Australian company and P.N Gerolymatos S.A (PNG) agreed to recognize each other's rights to market clioquinol in their respective territories, with PNG holding right for European territories, and Prana holding rights for US and Japan.
CanadaIn 2001, the Canadian company Paladin Labs bought the rights to market Vioform from Novartis. Vioform is licensed for use in Canada as a topical anti-fungal.
Netherlands2004 and 2005 reports describe use in treatment of Dientamoeba fragilis and Entamoeba histolytica infection.
IndiaManufactured by Eskay Iodine Pvt. Ltd., Vishal Laboratories, DNS Fine Chemicals[15] and LASA Laboratory[16]
ColombiaManufactured by "Altea Farmacéutica C.A." for "Scandinavia Pharma"[17]

See also

Notes and References

  1. Rohde W, Mikelens P, Jackson J, Blackman J, Whitcher J, Levinson W . Hydroxyquinolines inhibit ribonucleic acid-dependent deoxyribonucleic acid polymerase and inactivate Rous sarcoma virus and herpes simplex virus . Antimicrobial Agents and Chemotherapy . 10 . 2 . 234–240 . August 1976 . 185949 . 429727 . 10.1128/aac.10.2.234 .
  2. Gholz LM, Arons WL . Prophylaxis and Therapy of Amebiasis and Shigellosis with Iodochlorhydroxyquin . The American Journal of Tropical Medicine and Hygiene . 13 . 3 . 396–401 . May 1964 . 14162901 . 10.4269/ajtmh.1964.13.396 .
  3. Kager PA . [Outbreak of amoebiasis in a Dutch family; tropics unexpectedly nearby] . nl . Nederlands Tijdschrift voor Geneeskunde . 149 . 1 . 51–2; author reply 52–3 . January 2005 . 15651505 .
  4. Bosman DK, Benninga MA, van de Berg P, Kooijman GC, van Gool T . [Dientamoeba fragilis: possibly an important cause of persistent abdominal pain in children] . nl . Nederlands Tijdschrift voor Geneeskunde . 148 . 12 . 575–579 . March 2004 . 15074181 .
  5. Masters DK, Hopkins AD . Therapeutic trial of four amoebicide regimes in rural Zaire . The Journal of Tropical Medicine and Hygiene . 82 . 5 . 99–101 . May 1979 . 226725 .
  6. Wadia NH . SMON as seen from Bombay . Acta Neurologica Scandinavica. Supplementum . 100 . 159–164 . 1984 . 6091394 .
  7. Meade TW . Subacute myelo-optic neuropathy and clioquinol. An epidemiological case-history for diagnosis . British Journal of Preventive & Social Medicine . 29 . 3 . 157–169 . September 1975 . 127638 . 478909 . 10.1136/jech.29.3.157 .
  8. Takasu T . [SMON--a model of the iatrogenic disease] . ja . Rinsho Shinkeigaku = Clinical Neurology . 43 . 11 . 866–869 . November 2003 . 15152488 .
  9. Ito M, Nishibe Y, Inoue YK . Isolation of Inoue-Melnick virus from cerebrospinal fluid of patients with epidemic neuropathy in Cuba . Archives of Pathology & Laboratory Medicine . 122 . 6 . 520–522 . June 1998 . 9625419 .
  10. Costello LC, Franklin RB . A comprehensive review of the role of zinc in normal prostate function and metabolism; and its implications in prostate cancer . Archives of Biochemistry and Biophysics . 611 . 1 . 100–112 . December 2016 . 27132038 . 5083243 . 10.1016/j.abb.2016.04.014 .
  11. Nguyen T, Hamby A, Massa SM . Clioquinol down-regulates mutant huntingtin expression in vitro and mitigates pathology in a Huntington's disease mouse model . Proceedings of the National Academy of Sciences of the United States of America . 102 . 33 . 11840–11845 . August 2005 . 16087879 . 1187967 . 10.1073/pnas.0502177102 . free . 2005PNAS..10211840N .
  12. 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 . 6 . Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta . Neuron . 59 . 1 . 43–55 . July 2008 . 18614028 . 10.1016/j.neuron.2008.06.018 . 17263833 . free .
  13. Web site: News: Old gastrointestinal drug slows aging, McGill researchers say . 2017-08-25 . https://web.archive.org/web/20110210121513/http://www.mcgill.ca/newsroom/news/item/?item_id=103574 . 2011-02-10 . dead .
  14. Huang Y, Wu Z, Cao Y, Lang M, Lu B, Zhou B . Zinc binding directly regulates tau toxicity independent of tau hyperphosphorylation . Cell Reports . 8 . 3 . 831–842 . August 2014 . 25066125 . 4306234 . 10.1016/j.celrep.2014.06.047 .
  15. Web site: Manufacturers of Clioquinol. DNS Fine Chemicals . 23 December 2017. 2016-01-06.
  16. Web site: Herlekar O . Clioquinol manufacturers India. Lasa labs. 12 March 2013. 29 June 2019. https://web.archive.org/web/20190629061431/http://www.lasalabs.com/clioquinol.html. dead.
  17. Web site: Dermosupril C 0,1% desonide + 3% clioquinol for topical use . Medihealth laboratories. 19 September 2016.

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