Name:	Clioquinol
Other Names:	iodochlorhydroxyquin, PBT-1
Therapy Types:	pharmacological
Mechanisms:	metal-protein-attenuation
Development Status:	investigational in U.S.
FDA Phase:	Discontinued
Primary Medical Role:	Clioquinol, iodochlorhydroxyquin, is a metal-protein- attenuating compound (MPAC). It is an anti-bacterial and anti-fungal agent. Clioquinol topical preparations are used to treat skin infections.
Role in Alzheimer's Disease:	Clioquinol inhibits zinc and copper ions from binding to Aβ, thus promoting the solubilization and clearance of Aβ. A pilot phase II clinical trial suggests that clioquinol improves cognition and lowers plasma levels of Aβ42 in some patients.
Pharmacological Role:	Clioquinol promotes the removal of zinc-copper compounds, and also makes Aβ soluble allowing it to be eliminated.
Side Effects:	Oral use of clioquinol was found to be associated with subacute myelo-optic neuropathy, possibly caused by vitamin B12 deficiency.
Evidence pro its efficacy:	A small phase II trial reports that patients on the drug had a slower cognitive decline than patients on placebo.
Notes:	Related news stories: Jan 2004; Jul 2001. Related live discussion.

References

Treiber C, Simons A, Strauss M, Hafner M, Cappai R, Bayer TA, Multhaup G. Clioquinol Mediates Copper Uptake and Counteracts Copper Efflux Activities of the Amyloid Precursor Protein of Alzheimer's Disease. J Biol Chem. 2004 Dec 10; 279(50):51958-51964. Abstract

Ritchie CW, Bush AI, Masters CL. Metal-protein attenuating compounds and Alzheimer's disease. Expert Opin Investig Drugs. 2004 Dec ;13(12):1585-92. Abstract

Atamna H, Frey WH. A role for heme in Alzheimer's disease: Heme binds amyloid {beta} and has altered metabolism. Proc Natl Acad Sci U S A. 2004 Jul 27; 101(30):11153-8. Abstract

Di Vaira M, Bazzicalupi C, Orioli P, Messori L, Bruni B, Zatta P. Clioquinol, a drug for Alzheimer's disease specifically interfering with brain metal metabolism: structural characterization of its zinc(II) and copper(II) complexes. Inorg Chem. 2004 Jun 28 ; 43(13):3795-7. Abstract

Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny RA, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003 Dec;60(12):1685-91. Abstract

Rosenberg RN. Metal chelation therapy for Alzheimer disease. Arch Neurol. 2003 Dec;60(12):1678-9. Abstract

Regland B, Lehmann W, Abedini I, Blennow K, Jonsson M, Karlsson I, Sjogren M, Wallin A, Xilinas M, Gottfries CG. Treatment of Alzheimer's disease with clioquinol. Dement Geriatr Cogn Disord. 2001 Nov-Dec;12(6):408-14. Abstract

Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta- amyloid accumulation in Alzheimer's disease transgenic mice. Neuron. 2001 Jun ; 30(3):665-76. Abstract

Multhaup G, Schlicksupp A, Hesse L, Beher D, Ruppert T, Masters CL, Beyreuther K. The amyloid precursor protein of Alzheimer's disease in the reduction of copper(II) to copper(I). Science. 1996 Mar 8;271(5254):1406-9. Abstract

Bush AI, Pettingell WH, Multhaup G, Paradis Md, Vonsattel JP, Gusella JF, Beyreuther K, Masters CL, Tanzi RE. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science. 1994 Sep 2;265(5177):1464-7. Abstract

Bush AI, Multhaup G, Moir RD, Williamson TG, Small DH, Rumble B, Pollwein P, Beyreuther K, Masters CL. A novel zinc(II) binding site modulates the function of the beta A4 amyloid protein precursor of Alzheimer's disease. J Biol Chem. 1993 Aug 5;268(22):16109-12. Abstract