Therapeutics

Clioquinol

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Overview

Name: Clioquinol
Synonyms: iodochlorhydroxyquin, PBT-1
Chemical Name: 5-chloro-7-iodo-quinolin-8-ol
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Metals
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Prana Biotechnology Limited

Background

Clioquinol is an old drug that was used to treat fungal and protozoal infections but was found to be neurotoxic when used chronically at high doses. A one-time epidemic of subacute-myelo-optico-neuropathy in Japan prompted its removal or restrictions on its use in many countries. Topical clioquinol remains in clinical use for certain fungal and other skin disorders. Clioquinol is a hydroxyquinoline ionophore that acts as a zinc and copper chelator (Bareggi and Cornelli, 2012). 

Clioquinol has been explored as a treatment for Alzheimer's disease because it is a metal protein-attenuating compound.  MPACs have been reported to disrupt the interaction between metals and the Aβ peptide in the brain. According to scientists at Prana, increasing bioactive metal levels in the aging brain accelerate formation of amyloid plaques as well as neurotoxic oxidative processes. The rationale of evaluating clioquinol was that it would prevent Aβ accumulation while restoring copper and zinc ion homoeostasis in cells. For example, clioquinol was reported to cut brain amyloid deposition in half in a mouse model of Alzheimer's amyloidosis (Cherny et al., 2001).

Findings

In December 2003, Prana scientists formally reported a beneficial cognitive and plasma biomarker effect from a pilot Phase 2 trial in 36 patients with moderate to severe Alzheimer's disease (Jan 2004 news story). In October 2004 the company stated that an extension study supported a cognitive benefit and tolerability for clioquinol taken for 18 months (see 2004 press release). An independent meta-analysis according to the Cochrane Handbook for Systematic Reviews of Interventions later reported an absence of evidence that PBT1 was safe or effective in this trial (see Sampson et al., 2014).

While preparing for a Phase 2/3 trial, Prana announced that it was terminating development of clioquinol because the drug's manufacturing process generated a toxic contaminant (Apr 2005 story). The second-generation compound in this line of investigation is PBT-2. 

Last Updated: 16 Oct 2014

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References

News Citations

  1. Pilot Study Suggests Clioquinol Benefits AD Patients
  2. Side-Reactions Sideswipe Clioquinol—Prevent Clinical Trial

Therapeutics Citations

  1. PBT2

Paper Citations

  1. Sampson EL, Jenagaratnam L, McShane R. Metal protein attenuating compounds for the treatment of Alzheimer's dementia. Cochrane Database Syst Rev. 2014 Feb 21;2:CD005380. PubMed.
  2. Bareggi SR, Cornelli U. Clioquinol: Review of its Mechanisms of Action and Clinical Uses in Neurodegenerative Disorders. CNS Neurosci Ther. 2010 Dec 27; PubMed.
  3. 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. PubMed.

External Citations

  1. 2004 press release

Further Reading

Papers

  1. Sampson EL, Jenagaratnam L, McShane R. Metal protein attenuating compounds for the treatment of Alzheimer's dementia. Cochrane Database Syst Rev. 2014 Feb 21;2:CD005380. PubMed.
  2. Schimmer AD. Clioquinol - a novel copper-dependent and independent proteasome inhibitor. Curr Cancer Drug Targets. 2011 Mar;11(3):325-31. PubMed.
  3. Kenche VB, Barnham KJ. Alzheimer's disease & metals: therapeutic opportunities. Br J Pharmacol. 2011 May;163(2):211-9. PubMed.
  4. Bandyopadhyay S, Huang X, Lahiri DK, Rogers JT. Novel drug targets based on metallobiology of Alzheimer's disease. Expert Opin Ther Targets. 2010 Nov;14(11):1177-97. PubMed.
  5. Igata A. Clinical studies on rising and re-rising neurological diseases in Japan--a personal contribution. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(4):366-77. PubMed.