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Alzheimer’s Disease
Combination Therapies for Treating Alzheimer’s Disease
a report by
Roy Yaari, MD, MAS
1
and Pierre N Tariot, MD
1,2
1. Banner Alzheimer’s Institute; 2. Department of Psychiatry, University of Arizona College of Medicine
The pathobiology of Alzheimer’s disease (AD) is extremely complex and Each of the four studies was separated by a minimum of 56 hours. While
not yet fully understood. AD is characterized by the clinical syndrome of highly topical for its time, the study was essentially negative.
a slowly progressive dementia and the classic neuropathological findings
of amyloid plaques, neurofibrillary tangles, and neuronal death.
1
These In a double-blind, cross-over study with two sequential randomized
histological features develop in heterogeneous patterns and in people periods of treatment lasting for eight weeks each, Gauthier et al.
with varying genetic predisposition, nutritional histories, and exposure to evaluated the combination of the maximal tolerated dose of THA (up to
either potentially harmful or helpful environmental agents.
1
100mg/day) plus lecithin 4.7g/day in 52 AD patients.
3
This study showed
no clinical benefit to combination use of THA and lecithin as measured
The precise chain of events leading to the characteristic pathology is by global ratings, a functional scale, and a behavioral scale. A double-
not known, but it is likely to involve a cascade of events, including blind cross-over study with four-month follow-up by Chatellier and
oxidative stress, excitotoxic damage, altered cell-cycle regulation, Lacomblez randomized 67 AD patients to tacrine (dose ranging from 50
pathological inflammation, oxidative and excitotoxic damage, failure of to 125mg/day) and tacrine (1,200mg/day) versus placebo.
4
There was no
trophic responses, demyelination, apoptosis, and the failure of significant improvement on the Mini Mental State Examination (MMSE)
neurotransmitter function, among others. In this context, it makes sense or the Stockton geriatric rating scale. A fourth, small, double-blind study
to consider the therapeutic potential of combining agents with different in 10 patients showed no therapeutic effect.
5
mechanisms of action in the hope that impinging on multiple aspects of
the illness process may afford a greater benefit than that seen with a Acetylcholinesterase Inhibitors and Acetyl-L-Carnitine
single agent. Acetyl-L-carnitine (ALC), an intracellular carrier of acetyl groups that are
necessary for acetylcholine synthesis (which was thought to have the
What follows is a somewhat selective overview of the available clinical potential to enhance the effect of acetylcholinesterase inhibitors
evidence as we see it. The reality is that relatively few studies combine [AChEIs]), was tested in combination with an AChEI (either donepezil or
what we now might consider to be the most promising strategies: most rivastigmine).
6
After a three-month period on an AChEI only, 38% of
data come from earlier studies addressing putative neurotransmitter patients were classified as ‘responders’ and 48% as ‘non-responders’ as
dysfunction. It is important to note that some studies were true determined by changes in the MMSE and Alzheimer’s Disease
‘combination’ studies, in which multiple agents were co-administered
simultaneously, and others were ‘add-on’ designs, in which case a
Roy Yaari, MD, MAS, is Associate Director of the Memory
second agent was administered some time after a prior therapy was
Disorders Clinic at the Banner Alzheimer’s Institute in Phoenix,
initiated. This distinction is methodologically important.
Arizona. He is actively engaged in multiple clinical trials testing
new drugs for the treatment of Alzheimer’s disease. He is a
member of the American Academy of Neurology (AAN) and the
Cholinergics
Arizona Neurological Society. Dr Yaari earned his medical degree
The earliest and most obvious efforts addressed what might happen if
in 2000 from the University of Southern California, Keck School
different cholinergic therapies were combined. There is compelling
of Medicine in Los Angeles. He completed a residency in
neurology at the University of California, San Diego School of
evidence for structural and functional cholinergic impairment in AD, and
Medicine and is board-certified in neurology.
emerging evidence that cholinergic therapeutics might confer clinically
E:
Roy.Yaari@bannerhealth.com
discernible benefit.
Pierre N Tariot, MD, is Director of the Banner Alzheimer’s
Tacrine and Lecithin
Institute Memory Disorders Center and a Research Professor of
Psychiatry at the University of Arizona College of Medicine. Prior
What may have been the first combination study in AD addressed the
to this, he was a member of the faculty of the University of
effects of tetrahydroaminoacridine (THA) combined with lecithin.
2
Ten Rochester Medical Center, achieving the rank of Professor of
patients diagnosed with ‘primary progressive dementia’ were studied in
Psychiatry, Medicine, Neurology, and Aging and Developmental
Biology. He has published over 240 papers, and received the
four trials of random order: placebo, lecithin alone, THA alone, or a
American Geriatrics Society New Investigator Award for
combination of lecithin and THA. Medications were administered in divided Neuroscience and the 2005 University of California Los
doses of THA 90mg and/or lecithin 180mg at three intervals over a 14-hour
Angeles Turken Award.
period. Cognitive testing was performed two hours after the final dose.
© TOUCH BRIEFINGS 2008
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