Ezio Giacobini
Department of Geriatrics, University Hospitals of Geneva, University
of Geneva, Medical School, CH-1226 Thonex, Geneva, Switzerland
Abstract: Clinical trials in the USA, Japan and Europe have confirmed
the hypothesis that a steady state increase of acetylcholine resulting from
cholinesterase inhibition in the brain results in an improvement of cognitive
function in mild to moderate Alzheimer disease (AD) patients. During the
last decade, a systematic effort to develop a pharmacological treatment
for AD has resulted in two drugs being registered for the first time in
the USA and Europe for this specific indication. Both are cholinesterase
inhibitors (ChEI). Based on these first positive results, several second
generation ChEI are being developed. An additional effect of certain ChEI
is to maintain cognitive function at a constant level during a 6 months
to one year period of treatment as compared to placebo. It is possible that
the drug effect is one of slowing down cognitive deterioration. Comparison
of clinical effects of 5 ChEI demonstrates a rather similar magnitude of
improvement. For some drugs, this may represent a limit, while for others
it may be possible to increase the benefit further. To maximize and prolong
positive drug effects, it is important to start early and adjust the dosage
during the treatment. Other strategies may involve combinations with other
cholinergic drugs such as muscarinic or nicotinic agonists. A second important
class of drugs which is being developed is that of muscarinic m1 agonists.
However, their clinical use is still limited by side effects. The increased
knowledge and recognition of the beta-amyloid molecule as a central focus
of AD pathology has strongly stimulated research with the hope of finding
ways of influencing its processing and deposition. At this point, no product
in this line of development has reached clinical trial level. Other pharmacological
approaches are related to preventive and neuroprotective interventions (estrogens,
anti-oxidants and anti-inflammatories). In conclusion, given the relatively
short time of research in this field, results are encouraging.
Keywords: Alzheimer disease, Cholinesterase inhibitor, Beta-amyloid