Magazine article Clinical Psychiatry News

Dimebon's Action May Challenge Amyloid Theory

Magazine article Clinical Psychiatry News

Dimebon's Action May Challenge Amyloid Theory

Article excerpt

VIENNA -- Dimebon-the abandoned Russian antihistamine that burst onto the Alzheimer's study scene with the only positive clinical data of 2008--may throw yet another curve ball into a research world that for years has focused almost entirely on the amyloid hypothesis.

Rather than lowering amyloid beta (Abeta) levels, as two failed investigational drugs--tramiprosate and taren-flurbil--have attempted, dimebon appears to almost immediately increase them, raising Abeta by as much as 200% in three mouse models of Alzheimer's disease (AD), Dr. Samuel Gandy reported at the International Conference on Alzheimer's Disease.

While preliminary, the findings--combined with the nearly unprecedented cognitive benefit dimebon conferred in its phase II trial--could be enough to dethrone the long-reigning amyloid hypothesis, according to Mark A. Smith, Ph.D., an Alzheimer's researcher. "This drug is clearly not targeting amyloid, but increasing it acutely," said Dr. Smith of Case Western Reserve University, Cleveland. "If you believe the dogma, therefore, you should believe that this increase will cause Alzheimer's. These results question that dogma. If this holds up, it could be enough to wound the amyloid theory, potentially mortally."

Dimebon's 2008 phase II study found that patients with mild to moderate AD who took the drug for 12 months gained about 2 points on the Alzheimer's Disease Assessment Scale-Cognition (ADAS-cog), while those taking placebo declined almost 6 points from baseline (Lancet 2008;372:207-15). A 6-month open-label extension trial found similarly positive results. Patients who completed a full 18 months of dimebon continued to show benefit on ADAS-cog. Former placebo patients who crossed over to dimebon stabilized their cognitive decline.

Dr. Gandy of the Mount Sinai School of Medicine, New York, investigated the drug's effect on amyloid in three models of the disease: cultured nerve cells, isolated synaptic terminals, and brains from mice that overexpress human amyloid. "In every single system dimebon stimulated amyloid secretion," Dr. Gandy said in an interview. "The levels of the amyloid peptides in the interstitial brain fluid roughly doubled whenever the drug was given. If we think about the increased risk of Alzheimer's in Down syndrome patients who have a 50% increase in amyloid, this acute increase with dimebon could be significant over a period of many years of prescribed use."

Dr. Gandy noted that similar results were obtained by John Cirrito, Ph.D., and Dr. David Holtzman of Washington University, St. Louis, who collaborated with him in studying the brains of freely moving transgenic mice that overexpress human Abeta. …

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