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Ohio State University, Columbus, Ohio; From the Division of Cognitive Neurology, Department of Neurology, Ohio State University, Columbus, Ohio.
Address for reprints: Douglas W. Scharre, MD, Division of Cognitive Neurology, Department of Neurology, Ohio State University, 1654 Upham Drive, Columbus, OH 43210; e-mail: scharre.1{at}osu.edu.
The growing prevalence of Alzheimer's disease (AD) due to the aging of the US population is well recognized: By the year 2050, more than 13.2 million people in the United States are expected to have AD.1 Although this number represents a 3-fold increase in the overall AD population, the greatest increase will be in the segment of patients who are older than 85 years, which will quadruple in size from 1.8 million to 8 million. The 75- to 84-year-old group will double in size from 2.4 million to 4.8 million. Unfortunately, approximately a quarter of these AD elders will have severe disease, creating a great burden for their families and increased costs to the health care system. Given that the estimated direct and total costs of AD were $20.6 billion and $67.3 billion, respectively, in 1991, the long-term cost to the US economy is expected to reach into the trillions.2 Clearly, one of the challenges facing us is the need for more effective treatments across all stages of the disease.
This special issue of The Journal of Clinical Pharmacology is devoted to a discussion of the feasibility of combination therapy with galantamine and memantine. Galantamine is an acetylcholinesterase inhibitor (AChEI) with an additional mechanism of action as an allosteric modulator of nicotinic cholinergic receptors approved in the United States for the treatment of mild to moderate AD since 2000. Memantine is an uncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist that was approved in 2003 in the United States for the treatment of moderate to severe AD. Combination therapy makes sense because both cholinergic deficiency and glutamate excitotoxicity are postulated to be involved in AD pathophysiology. Given that there are 3 commonly used AChEIs, until appropriate head-to-head clinical trials can be performed, it would be important to examine the potential benefits or disadvantages of one AChEI plus memantine combination pairing to another.
In the first article, Hugo Geerts and George T. Grossberg discuss the pharmacology of galantamine and memantine and examine the rationale for combination therapy in AD. The authors begin with a brief overview of the pathophysiology of AD and the roles of the cholinergic and glutamatergic systems in memory, information processing, and learning. They then describe the typical AD alterations in these 2 neurotransmitter systems and how galantamine and memantine may work together to provide a more normal neurophysiologic response in patients with AD.
In the second article, George T. Grossberg, Keith R. Edwards, and Qinying Zhao review the effectiveness of galantamine and memantine as monotherapy in AD. Treatment with galantamine has resulted in improvements in cognition, functionality, and behavior in patients with mild to moderate AD.3-5 Memantine has been effective in maintaining activities of daily living in patients with moderate to severe AD.6 The authors also describe pharmacokinetic and pharmacodynamic studies that support the feasibility of combination therapy with galantamine and memantine and discuss the safety and tolerability of both agents as monotherapy and as combination therapy.
We believe this special issue of The Journal of Clinical Pharmacology will provide clinicians with thought-provoking ideas on new ways to use combination therapy to manage patients throughout the progressive stages of AD.
Douglas W. Scharre, MD, has served as a consultant or speaker for Abbott, Eisai, Forest, Ortho-McNeil, and Pfizer. He has received research grants from Astellas, Eisai, Forest, Janssen, Myriad, Ono, Pfizer, Sanofi-Aventis, Voyager, and Wyeth.
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