Chemistry:Clioquinol

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Short description: Medication
Clioquinol
Skeletal formula of clioquinol
Ball-and-stick model of the clioquinol molecule
Clinical data
Trade namesCortin
AHFS/Drugs.comMicromedex Detailed Consumer Information
MedlinePlusa682367
Pregnancy
category
  • US: C (Risk not ruled out)[1]
Routes of
administration		topical only
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC9H5ClINO
Molar mass305.50 g·mol−1
3D model (JSmol)
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Clioquinol (iodochlorhydroxyquin) 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.[2]

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.[3]

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.[4]
  • A 2004 reference to its use in the Netherlands in the treatment of Dientamoeba fragilis infection.[5]
  • A 1979 reference to the use in Zaire in the treatment of Entamoeba histolytica infection.[6]

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.[7] 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.[8] Theories suggested have included improper dosing, the permitted use of the drug for extended periods of time,[9] 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.[10]

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.[citation needed]

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.[11]

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.[12]

Recent animal studies have shown that clioquinol can reverse the progression of Alzheimer's, Parkinson's and Huntington's diseases.[13] 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.[14]

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.[15]

Continued use and manufacture around the world

Country Comments
United States In 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.
Canada In 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.
Netherlands 2004 and 2005 reports describe use in treatment of Dientamoeba fragilis and Entamoeba histolytica infection.[5]
India Manufactured by Eskay Iodine Pvt. Ltd., Vishal Laboratories, DNS Fine Chemicals[16] and LASA Laboratory[17]
Colombia Manufactured by "Altea Farmacéutica C.A." for "Scandinavia Pharma"[18]

See also

References

  1. ↑ "Clioquinol topical medical facts from Drugs.com". https://www.drugs.com/mtm/clioquinol-topical.html. 
  2. ↑ "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. doi:10.1128/aac.10.2.234. PMID 185949. 
  3. ↑ "Prophylaxis and Therapy of Amebiasis and Shigellosis with Iodochlorhydroxyquin". The American Journal of Tropical Medicine and Hygiene 13 (3): 396–401. May 1964. doi:10.4269/ajtmh.1964.13.396. PMID 14162901. 
  4. ↑ "[Outbreak of amoebiasis in a Dutch family; tropics unexpectedly nearby]" (in nl). Nederlands Tijdschrift voor Geneeskunde 149 (1): 51–2; author reply 52–3. January 2005. PMID 15651505. 
  5. ↑ 5.0 5.1 "[Dientamoeba fragilis: possibly an important cause of persistent abdominal pain in children]" (in nl). Nederlands Tijdschrift voor Geneeskunde 148 (12): 575–579. March 2004. PMID 15074181. 
  6. ↑ "Therapeutic trial of four amoebicide regimes in rural Zaire". The Journal of Tropical Medicine and Hygiene 82 (5): 99–101. May 1979. PMID 226725. 
  7. ↑ "SMON as seen from Bombay". Acta Neurologica Scandinavica. Supplementum 100: 159–164. 1984. PMID 6091394. 
  8. ↑ "Subacute myelo-optic neuropathy and clioquinol. An epidemiological case-history for diagnosis". British Journal of Preventive & Social Medicine 29 (3): 157–169. September 1975. doi:10.1136/jech.29.3.157. PMID 127638. 
  9. ↑ "[SMON--a model of the iatrogenic disease]" (in ja). Rinsho Shinkeigaku = Clinical Neurology 43 (11): 866–869. November 2003. PMID 15152488. 
  10. ↑ "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. PMID 9625419. 
  11. ↑ "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. doi:10.1016/j.abb.2016.04.014. PMID 27132038. 
  12. ↑ "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. doi:10.1073/pnas.0502177102. PMID 16087879. Bibcode: 2005PNAS..10211840N. 
  13. ↑ "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. doi:10.1016/j.neuron.2008.06.018. PMID 18614028. 
  14. ↑ "News: Old gastrointestinal drug slows aging, McGill researchers say". https://www.mcgill.ca/newsroom/news/item/?item_id=103574. 
  15. ↑ "Zinc binding directly regulates tau toxicity independent of tau hyperphosphorylation". Cell Reports 8 (3): 831–842. August 2014. doi:10.1016/j.celrep.2014.06.047. PMID 25066125. 
  16. ↑ "Manufacturers of Clioquinol". DNS Fine Chemicals. 2016-01-06. http://dnsfine.com/. 
  17. ↑ "Clioquinol manufacturers India". Lasa labs. http://www.lasalabs.com/clioquinol.html. 
  18. ↑ "Dermosupril C 0,1% desonide + 3% clioquinol for topical use". Medihealth laboratories. http://medihealth.net/prospectos/DermosuprilCCrema_1.pdf. 



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