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Alzheimer's - and the Pharmaceutical
industry
Medicines For Alzheimer's In The Development
Pipeline
Medicines acting on acetylcholine
Several other AChE inhibitors are in clinical trial and one in
preclinical development. The most advanced is TAK-147 (Takeda), which is one
of a related group of molecules designed to bind to the enzyme acetylcholine
esterase and block its action. TAK-147 appears to survive for long periods
in the brain. It also has a beneficial effect on some other brain pathways
and stimulates brain energy metabolism which is depressed in Alzheimer's.
Finally and unexpectedly, it was found to stimulate the growth of neurons
that use ACh and in that respect behaves like a naturally-occurring nerve
growth factor (NGF). Takeda speculates that TAK-147 will not only improve
the symptoms of Alzheimer's, but also prevent or slow its progression. With
this interesting range of properties, the outcome of early clinical trials
that have now started will be keenly awaited.
Another AChE inhibitor at an earlier stage of development is huberzine A,
originally derived from a Chinese herb called Huperzia serrata. Improvements
in cognitive performance have been reported in several small trials in
China. Herbal remedies are currently available containing this compound,
even though adequate toxicity studies have not yet been done. Recent reports
of tacrine-huberzine hybrid molecules which bind very tightly to AChE have
also appeared and may be developed further in the future.
Still at the preclinical stage is CHF2819 (Chiesi Farma), an orally
active AChE inhibitor. Model studies show that it significantly increases
ACh levels in ageing animals. A role in the treatment of Alzheimer's is
possible, but it is unclear whether it will have advantages over currently
available medicines.
As explained above, the ACh esterase inhibitors donepezil, galantamine,
rivastigmine and tacrine all block the breakdown of acetylcholine. An
alternative approach would be to boost its levels.
One simple strategy to achieve this has been to give dietary supplements
of the starting materials from which ACh is made, such as lecithin, which is
rich in choline, or choline itself. The benefits were at best marginal,
though a small placebo-controlled clinical trial of a molecule that gives
rise to choline, called citicholine, did give some improvements in word and
object recall memory tests. Despite this modest outcome, it is clear that
alternative approaches are needed.
Medicines acting on M and N acetylcholine receptors
Several companies have investigated the role in Alzheimer's of muscarinic
or M receptors. If M receptors are stimulated, extra ACh is released from
internal stores inside neurons, thus providing short-term improvement. Their
stimulation also causes the cells to produce more of the harmless beta-amyloid,
rather than the toxic BAP42 found in plaques. It is just feasible,therefore,
that medicines of this type will slow progression as well as treat some of
the symptoms. Five types of M receptor have been discovered, numbered M1 to
M5. They are found in various parts of the body outside the brain and their
stimulation gives rise to symptoms such as sweating, salivation, nausea and
vomiting, which would be unwanted in a medicine. The key is to find
molecules that act only on M receptors in the brain.
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