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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.^[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:

A 2005 reference to its use in treating a Dutch family for Entamoeba histolytica infection.^[3]

A 2004 reference to its use in Denmark in the treatment of Dientamoeba fragilis infection.^[4]

A 1979 reference to the use in Zaire in the treatment of Entamoeba histolytica infection.^[5]

Clioquinol and SMON

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 SMON (subacute myelo-optic neuropathy) 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 dependant 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 a Inoue-Melnick virus.^[9]

Topical use

Clioquinol is used in the drug Vioform, which is a topical antifungal treatment.

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.^[10]

Evidence from phase 2 clinical trials suggested that clioquinol could halt cognitive decline in Alzheimer's disease, possibly owing to its ability to act as a chelator for copper and zinc ions. This led to development of analogs including PBT2 as potential therapeutic compounds for the treatment of Alzheimer's disease.^[11]

Recent animal studies have shown that clioquinol can reverse the progression of Alzheimer's, Parkinson's and Huntington's diseases. According to Dr. 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.[1]

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 others rights to market clioquinol in their respective territories, with PNG holding right for European territories, and Prana holding rights for US and Japan. Prana has performed research into the use of hydroxyquinolines drugs in the treatment of Alzheimers disease.
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. ^[4] ^[4]
India	Manufactured by Vishal Laboratories, INDIA^{[citation needed]}

References

^ Rohde W, Mikelens P, Jackson J, Blackman J, Whitcher J, Levinson W (1976). "Hydroxyquinolines inhibit ribonucleic acid-dependent deoxyribonucleic acid polymerase and inactivate Rous sarcoma virus and herpes simplex virus". Antimicrob. Agents Chemother. 10 (2): 234–40. PMC 429727. PMID 185949. //www.ncbi.nlm.nih.gov/pmc/articles/PMC429727/.
^ GHOLZ LM, ARONS WL (1964). "Prophylaxis And Therapy Of Amebiasis And Shigellosis With Iodochlorhydroxyquin". Am. J. Trop. Med. Hyg. 13: 396–401. PMID 14162901.
^ Kager PA (2005). "[Outbreak of amoebiasis in a Dutch family; tropics unexpectedly nearby]" (in Dutch; Flemish). Nederlands tijdschrift voor geneeskunde 149 (1): 51–2; author reply 52–3. PMID 15651505.
^ ^a ^b ^c Bosman DK, Benninga MA, van de Berg P, Kooijman GC, van Gool T (2004). "[Dientamoeba fragilis: possibly an important cause of persistent abdominal pain in children]" (in Dutch; Flemish). Nederlands tijdschrift voor geneeskunde 148 (12): 575–9. PMID 15074181.
^ Masters DK, Hopkins AD (1979). "Therapeutic trial of four amoebicide regimes in rural Zaire". The Journal of tropical medicine and hygiene 82 (5): 99–101. PMID 226725.
^ Wadia NH (1984). "SMON as seen from Bombay". Acta Neurol. Scand., Suppl. 100: 159–64. PMID 6091394.
^ Meade TW (1975). "Subacute myelo-optic neuropathy and clioquinol. An epidemiological case-history for diagnosis". British journal of preventive & social medicine 29 (3): 157–69. PMC 478909. PMID 127638. //www.ncbi.nlm.nih.gov/pmc/articles/PMC478909/.
^ Takasu T (2003). "[SMON--a model of the iatrogenic disease]" (in Japanese). Rinsho Shinkeigaku 43 (11): 866–9. PMID 15152488.
^ Ito M, Nishibe Y, Inoue YK (1998). "Isolation of Inoue-Melnick virus from cerebrospinal fluid of patients with epidemic neuropathy in Cuba". Arch. Pathol. Lab. Med. 122 (6): 520–2. PMID 9625419.
^ Nguyen T, Hamby A, Massa SM (2005). "Clioquinol down-regulates mutant huntingtin expression in vitro and mitigates pathology in a Huntington's disease mouse model". Proc. Natl. Acad. Sci. U.S.A. 102 (33): 11840–5. doi:10.1073/pnas.0502177102. PMC 1187967. PMID 16087879. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1187967/.
^ Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta.

UpToDate Contents

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1. 銅欠乏性脊髄神経障害 copper deficiency myeloneuropathy
2. うっ滞性皮膚炎 stasis dermatitis
3. 食物中の微量ミネラルの概要 overview of dietary trace minerals

English Journal

The antineurodegenerative agent clioquinol regulates the transcription factor FOXO1a.

Cameron AR, Wallace K, Logie L, Prescott AR, Unterman TG, Harthill J, Rena G.AbstractMany diseases of ageing including Alzheimer's Disease (AD) and type 2 diabetes (T2D) are strongly associated with common risk factors, such as hypertension, hyperglycaemia and hyperinsulinaemia, suggesting that there may be shared ageing mechanisms underlying these diseases, with scope to identify common cellular targets for therapy. Here we have studied insulin-like signalling properties of an experimental AD 8-hydroxyquinoline drug known as clioquinol. The insulin/IGF-1 signal transduction (IIS) kinase Akt/PKB inhibits the transcription factor FOXO1a by phosphorylating it on residues that trigger its exit from the nucleus and in 293 cells we found that clioquinol treatment induces similar effects. A key transcriptional response to IIS is inhibition of hepatic gluconeogenic gene expression and in rat liver cells, clioquinol represses expression of the key gluconeogenic regulatory enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). The effects on FOXO1a and gluconeogenic gene expression require the presence of zinc ions, reminiscent of much earlier literature examining diabetogenic properties of 8-hydroxyquinolines. Comparative investigation of the signalling properties of a panel of these compounds demonstrates that CQ alone exhibits FOXO1a regulation without diabetogenicity. Our results suggest that zinc-dependent regulation of FOXOs and gluconeogenesis may contribute to the therapeutic properties of this drug. Further investigation of this signalling response might illuminate novel pharmacological strategies for the treatment of age-related diseases.
The Biochemical journal.Biochem J.2012 Jan 16. [Epub ahead of print]
Many diseases of ageing including Alzheimer's Disease (AD) and type 2 diabetes (T2D) are strongly associated with common risk factors, such as hypertension, hyperglycaemia and hyperinsulinaemia, suggesting that there may be shared ageing mechanisms underlying these diseases, with scope to identify c
PMID 22248233

Significance of serum glucocorticoid and chelatable zinc in depression and cognition in zinc deficiency.

Takeda A, Tamano H, Ogawa T, Takada S, Ando M, Oku N, Watanabe M.SourceDepartment of Medical Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Global COE, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. takedaa@u-shizuoka-ken.ac.jp
Behavioural brain research.Behav Brain Res.2012 Jan 1;226(1):259-64. Epub 2011 Sep 19.
Dietary zinc deficiency elicits neuropsychological symptoms and cognitive dysfunction. To pursue the mechanisms of these symptoms, in the present study, the relationship among serum glucocorticoid, chelatable zinc in the synaptic cleft and brain function based on behavior was examined in young rats
PMID 21946308

New applications of old metal-binding drugs in the treatment of human cancer.

Schmitt SM, Frezza M, Dou QP.SourceThe Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, and Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, USA.
Frontiers in bioscience (Scholar edition).Front Biosci (Schol Ed).2012 Jan 1;4:375-91.
Significant advances in the use of metal complexes, precipitated by platinum, have fostered a renewed interest in harnessing their rich potential in the treatment of cancer. In addition to platinum-based complexes, the anticancer properties of other metals such as ruthenium have been realized, and r
PMID 22202066

Japanese Journal

Effects of Clioquinol Analogues on the Hypoxia-Inducible Factor Pathway and Intracelullar Mobilization of Metal Ions

Kim So Yeon,Lee Myong Jin,Kim Jeong Won [他],Na Yu-Ran,Lee Ho-Youl,Cho Hyunju,Lee Keun Byeol,Lee You Mie,Lee Cheolju,Park Hyunsung,Yang Eun Gyeong
Biological and Pharmaceutical Bulletin 35(12), 2160-2169, 2012
… We previously found that clioquinol (CQ) increases functional hypoxia-inducible factor-1α (HIF-1α) with enhanced transcription of its target genes. …
NAID 130002480505

Neuropharmacokinetic Heterogeneity of Mefloquine in the Treatment of Progressive Multifocal Leukoencephalopathy

Lee Nevin Remington
Internal Medicine 51(16), 2257-2257, 2012
NAID 130002062300

Clinical studies on rising and re-rising neurological diseases in Japan - A personal contribution -:– A personal contribution –

Igata Akihiro
Proceedings of the Japan Academy, Series B 86(4), 366-377, 2010
… Through the chemical analysis of the green urine, characteristic of this disease, it was found that this disease was caused by intoxication of the administered clioquinol, an anti-diarrheal drug. …
NAID 130000258734

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★リンクテーブル★

リンク元	「キノホルム」「クリオキノール」「Chinoform」

「キノホルム」

Clioquinol
Systematic (IUPAC) name
	5-chloro-7-iodo-quinolin-8-ol
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
MedlinePlus	a682367
Pregnancy cat.	?
Legal status	PoM (UK); Rx (US)
Routes	topical only
Identifiers
CAS number	130-26-7
ATC code	D08AH30; D09AA10 (dressing) G01AC02 P01AA02 S02AA05
PubChem	CID 2788
DrugBank	DB04815
ChemSpider	2686
UNII	7BHQ856EJ5
KEGG	D03538
ChEMBL	CHEMBL497
Chemical data
Formula	C9H5ClINO
Mol. mass	305.499 g/mol
	SMILES Ic1c(O)c2ncccc2c(Cl)c1;
	InChI InChI=1S/C9H5ClINO/c10-6-4-7(11)9(13)8-5(6)2-1-3-12-8/h1-4,13H ; Key:QCDFBFJGMNKBDO-UHFFFAOYSA-N ;
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