Researchers identify a drug candidate for treating, preventing Alzheimer's

Thursday, August 07, 2003

JACKSONVILLE, Fla., Aug. 7, 2003 — Researchers at Mayo Clinic, the University of California at San Diego (UCSD) and Myriad Pharmaceuticals, Inc. tested 20 commonly used non-steroidal anti-inflammatory drugs (NSAIDs) and found eight of them reduced the formation of a protein implicated in the development of Alzheimer's disease (AD). They report their results in this month's issue of The Journal of Clinical Investigation.

Investigators found that flurbiprofen and its two composite forms significantly reduced the formation of the protein amyloid beta 42 (Aß42) in cultures of human brain cells and in mice more than the other NSAIDs tested. These drugs act by selectively targeting the mechanism by which cells make Aß42 from a larger protein.

Senile plaques, found in the brains of people with AD, are made primarily of accumulations of Aß42. A substantial body of AD research now supports the hypothesis that accumulation of Aß42 leads to the development of AD.

Todd Golde, M.D., Ph. D., a neuroscientist, led Mayo Clinic's work on this study. He says epidemiologic studies suggest that long-term use of NSAIDs reduces the risk of developing AD. However, gastrointestinal bleeding and kidney damage are associated with long-term use of these drugs, which inhibit enzymes called cyclooxygenases (COX) from initiating inflammation in the body. "If you give large doses of these to the elderly for long periods of time, you'll have significant morbidity and mortality," he says. "So even if one was effective for treating AD, a lot of people wouldn't end up taking it. They wouldn't be able to tolerate it because of the side-effects."

Golde and his collaborators looked for NSAID-like compounds that would not inhibit COX activity but still lower Aß42. Flurbiprofen, a Food and Drug Administration approved NSAID, is composed of two forms, R-flurbiprofen and S-flurbiprofen. These forms are identical in composition but are mirror images of each other, much like one's right and left hand.

Previous research showed S-flurbiprofen was active against COX while R-flurbiprofen wasn't. Investigators included both in this study, and both lowered Aß42. But since R-flurbiprofen has much less action against the body's inflammatory response mechanism, Golde believes that of the NSAIDs tested, it is the most promising for further study in AD. "This is the best thing we have in our hands today," he says. "We know that it's going to be reasonably safe. We don't know how safe, but we know it's going to be reasonably safe, because people have been taking this as a 50 –50 mixture with the S form for years."

Coincidently, R-flurbiprofen is in a clinical trial evaluating its potential role in treating prostate cancer. According to Golde, that will make evaluating R-flurbiprofen as a potential AD therapy faster than evaluating a drug never before tested in humans. "This really speeds up the process of bench to bedside," he says. "It doesn't mean it's going to work; we just have the chance to get there quicker."

R-flurbiprofen is in fact already part of an AD clinical trial at Mayo Clinic and UCSD designed primarily to get safety data of promising NSAIDs at different doses. However, Golde says the trial will also provide data about R-flurbiprofen's ability to lower Aß42 in normal persons — it is not yet being tested in people with Alzheimer's. It will also shed light on whether it's the anti-inflammatory properties of certain NSAIDs or their Aß42 lowering property that may reduce the risk of developing AD.

Those interested in volunteering for this trial may call (904) 953-2677 for more information.

Jason Eriksen at Mayo Clinic is lead author on The Journal of Clinical Investigation paper. Co-authors are: Tawnya Smith, Pritam Das, D.C. McLendon, Victor Ozols and Todd Golde, Mayo Clinic; Sarah Sagi, Sascha Weggen and Edward Koo, UCSD; Kevin Jessing and Kenton Zavitz, Myriad Pharmaceuticals, Inc.

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