Compound May Be Effective In Reducing Alzheimer’s Plaques
Clioquinol appeared to decrease levels of plasma beta amyloid, the protein whose toxic accumulation in the brain is believed to be centrally linked to Alzheimer’s disease, and led to improvement on the Alzheimer’s Disease Assessment Scale (ADAS) score in those with the most severe disease.
The compound, which had been withdrawn for oral use in 1970 because of its association with subacute myelo-optic neuropathy, was well tolerated. Authors of the small study, appearing in the December 2003 Archives of Neurology, said that the results argue for reconsideration of the drug’s use and for larger clinical trials.
Clioquinol is a compound that inhibits zinc and copper ions from binding to beta amyloid, thereby promoting the dissolution of that protein and diminishing its toxic properties.
In the study, 36 patients were randomized to receive treatment with clioquinol or placebo. The oral dosage of clioquinol was 125 mg twice daily from weeks 0 to 12, 250 mg twice daily from weeks 13 to 24, and 375 mg twice daily from weeks 25 to 36.
Patients who had a baseline ADAS score of 25 or more and were in the treatment arm showed a trend toward significant improvement on the score at weeks 4 and 24, compared with patients who were in the placebo arm and also had baseline scores of 25 or more. Plasma beta-amyloid levels declined in the clioquinol group and increased in the placebo group.
“The findings support a proof of concept in humans that a drug targeting metal beta-amyloid interactions can have a significant effect on beta-amyloid metabolism and, through this, a beneficial modification on the progression of Alzheimer’s,” wrote Craig B. Ritchie, M.B.Ch.B., and colleagues at the Mental Health Research Institute of Victoria at the University of Melbourne, Australia.
“The significant benefit seen in the more severely affected treatment group at four weeks [on the ADAS scores]. . .may represent the short-term effect of clioquinol neutralizing the neurotoxicity of the soluble pool of beta amyloid.”
The authors acknowledged that safety is of concern in a study involving the chronic administration of a drug with a history of adverse events. Clioquinol-associated optic neuropathy was suspected in one patient with a history of eye disease. But they said a direct causal link to clioquinol remains uncertain, given that “disturbances of color vision and other ophthalmologic changes occur during the natural history of Alzheimer’s disease.”
They added that 27 patients have agreed to participate in an open-label extension study of clioquinol, and that 10 of those have been receiving the drug at a dosage of 500 mg/d to 750 mg/d for more than 18 months. No clioquinol-attributable adverse events have developed in any of these patients, they reported.
In an accompanying editorial, Roger N. Rosenberg, M.D., editor of the Archives of Neurology, said zinc-copper chelation offers promise as a new therapeutic strategy. “Clearly, it is an innovative therapeutic approach to Alzheimer’s disease and merits a closer and more comprehensive assessment in larger clinical trials.”
An abstract of the study, “Metal-Protein Attenuation With Iodochlorhydroxyquin (Clioquinol) Targeting A Amyloid Deposition and Toxicity in Alzheimer Disease: A Pilot Phase 2 Clinical Trial,” is posted online at http://archneur.ama-assn.org/cgi/content/abstract/60/12/1685. ▪
Arch Neurol 2003 60 1685
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Published online: 6 February 2004
Published in print: February 6, 2004
Notes
Ten patients have been receiving clioquinol at a dosage of 500 mg/d to 750 mg/d for more than 18 months in an open-label extension study. No adverse events attributable to clioquinol have been detected.
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