Pharmacotherapeutic approaches to the treatment of Alzheimer's disease.
BACKGROUND
Alzheimer's disease (AD), a progressive degenerative disorder of the brain, is the most common cause of cognitive impairment in the elderly. The pharmacotherapy of AD is evolving rapidly. Cholinergic stabilization with cholinesterase-inhibitor (ChEI) therapy implies neuroprotection and a resultant slowing of disability and disease progression. The moderate-affinity N-methyl-d-aspartate (NMDA)-receptor antagonist memantine may block neural excitotoxicity.


OBJECTIVE
The purpose of this review was to examine the evidence for the responsiveness to pharmacotherapy of established AD; specifically, the extent to which the benefits of therapy have been proved, the extent to which currently available ChEIs support cholinergic neurotransmission, and the extent to which currently available ChEIs and memantine provide neuroprotection.


METHODS
Relevant studies were identified through a comprehensive search of MEDLINE for articles published between January 1999 and February 2004 using the terms Alzheimer's pharmacotherapy, cholinesterase inhibitor therapy, Alzheimer's disease, donepezil, rivastigmine, galantamine, glutamatergic system modifiers, and memantine; a search of the reference lists of identified articles; and a manual search of pertinent journals. Articles were selected that contained higher-level evidence, based on explicit validated criteria.


RESULTS
ChEI therapy was associated with quality-of-life improvements that included enhanced performance of activities of daily living, reduced behavioral disturbances, stabilized cognitive impairment, decreased caregiver stress, and delay in the first dementia-related nursing home placement. In large clinical trials in moderate to severe AD (a stage that is associated with distress for patients and caregiver burden, and for which other treatments are not available), memantine showed an ability to delay cognitive and functional deterioration. The combination of memantine and ChEI therapy was significantly more efficacious than ChEI therapy alone (P < 0.001) and was well tolerated.


CONCLUSIONS
The idea that AD is pharmacologically unresponsive appears to be changing. With the use of ChEI and NMDA-receptor antagonist therapy, the symptoms and outcomes of this devastating neurodegenerative disease can be improved and its course altered.
Standridge
John B
JB
Department of Family Medicine, University of Tennessee Health Science Center College of Medicine, Chattanooga Unit, 1100 E. 3rd Street, Chattanooga, TN 37403, USA. StandrJB@erlanger.org
D000203:Activities of Daily Living; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D017028:Caregivers; D002800:Cholinesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003071:Cognition / Q000187:drug effects; D006801:Humans; D008559:Memantine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011788:Quality of Life; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D008559:Memantine