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Novel 'metal-chelation' therapy may be helpful in patients with Alzheimer disease

The JAMA Network Journals

CHICAGO - A preliminary study suggests that a novel therapy may help improve cognitive functioning in patients with Alzheimer disease by lowering levels of a protein that is involved in the development of the disease, according to an article in the December issue of The Archives of Neurology, one of the JAMA/Archives journals.

According to the article, Alzheimer disease (AD) is thought to be caused by a buildup of "plaque" in the brain which includes the protein beta-amyloid. Scientists believe that blocking the production or accumulation of beta-amyloid in the brain could prevent or slow AD.

Colin L. Masters, M.D., of the University of Melbourne, Parkville, Victoria, Australia, and colleagues developed a study to determine whether clioquinol, a metal-protein - attenuating compound (MPAC), might help to reduce beta-amyloid levels and slow the rate of cognitive decline in patients with AD. The compound is thought to work by inhibiting zinc and copper ions from binding to beta-amyloid, thereby helping to dissolve the protein and preventing it from accumulating. Therapies that block metal ions from interacting with other molecules in the body are known as "chelation" therapies.

The researchers conducted a pilot phase 2 clinical trial of their compound in 36 patients with moderately severe AD. Eighteen patients received 125 milligrams of clioquinol twice per day for 12 weeks, then 250 milligrams twice per day for weeks 13 to 24, and 375 milligrams twice per day from weeks 25 to 36. Eighteen patients received similar doses of placebo over 36 weeks.

The patients were given tests to measure cognition at the beginning of the study and again at weeks 4, 12, 24, and 36. Levels of beta-amyloid in the blood were measured every four weeks.

The researchers found that "plasma beta-amyloid levels declined in the clioquinol group and increased in the placebo group." Patients taking clioquinol also had better scores on tests of cognitive ability.

"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 AD," write the authors.

"The safety profile and the biochemical efficacy of clioquinol in this population are sufficiently encouraging to allow for future trials to take this investigation of a novel therapeutic intervention (clioquinol itself or a pharmacologically improved backup) targeting beta-amyloid to the next phase. This class of MPAC may also be considered for related conditions such as Parkinson disease... ," the researchers write.

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(Arch Neurol. 2003;60:1685. Available post-embargo at archneurol.com)

Editorial: Metal Chelation Therapy for Alzheimer Disease

In an accompanying editorial, Roger N. Rosenberg, M.D., editor of The Archives of Neurology and at the University of Texas Southwestern Medical Center, Dallas, writes, "Ritchie et al report that clioquinol therapy significantly slowed the rate of cognitive decline in a subset of patients with AD, as compared with that in control subjects. The slowing of cognitive decline in patients treated with clioquinol was seen only in those who were more severely affected."

Dr. Rosenberg writes: "Zinc-copper chelation offers promise as a new therapeutic strategy. Clearly, it is an innovative therapeutic approach to AD and merits a closer and more comprehensive assessment in larger clinical trials."

(Arch Neurol. 2003;60:1678-1679. Available post-embargo at archneurol.com)

For more information, contact JAMA/Archives Media Relations at 312-464-JAMA (5262) or e-mail mediarelations@jama-archives.org.

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