Lou Pagnucco (lpagnucco at delphi.com) wrote:
>Until more negative results are published, it seems
>reasonable to use Alcar as a speculative therapy.
I agree.
>You may also want to do a Medline search on NSAIDs and Nimodipine
>effects on the progression of Alzheimers. These certainly look promising
>at this point.
I was aware of the epidemiological data on NSAIDs and I agree with
you about it. However, I would not advocate chronic therapy with
NSAIDs for healthy elderly individuals as a way to prevent AD, like
some people do. Contrary to popular belief, long term use of these
drugs is not without risks. Patients with rheumatoid arthritis (RA) have
a substantially reduced life expentancy, which is thought to be caused
in part by NSAIDs. Estimates of loss of life expectancy vary from 3 to
18 years. While young people tolerate long term NSAID therapy well,
the risk of serious complications like renal disease increases
exponentially with age (Br J Rheumatol 1988;27 Suppl 1:44-54). Other
complications in elderly patients include sudden death due to ulcer
perforation. An ulcer in an old person doesn't always give any
symptoms before it gets perforated.
I think I'm going to discuss Nimodipine in another post later.
James L. Rice wrote:
>Dr. Hatanpaa is incorrect. The eye test group of 58 individuals
>included 14 probable Alzheimer's Disease patients, and 4
>patients with one of the following non-Alzheimer's type
Seems like I should have read the original paper and not just the
abstract in this case. Thanks for pointing this out. Anyway, I don't
think a diagnostic test like this can be based on just one study with
such small numbers of subjects. More patients, especially with
other types of dementia need to be studied.
What makes me suspicious is that the idea of an eye test for AD
was first presented as early as in the 70's. Then Drs. Sacks and
Smith published a short paper in 1989 where they compared pupil
reactions in Down's syndrome patients and controls. They used
0.01 % tropicamide eyedrops and found a three times higher
response in Down's syndrome group. They mentioned the
possibility that this might be a diagnostic tool for AD.
Then finally in 1994 came out this paper by Scinto et al., where
they also used 0.01 % tropicamide, and presented this as a
potential diagnostic test for AD.
There is a huge demand for a simple test for AD. Why did it take 5
years to test AD patients with this test that already had been
developed and published? Maybe Scinto et al. just were lucky and
got publishable results after, say, 34 other groups had tried the
same thing and failed. This phenomenon is called "publication
bias". It means that positive results get published more often than
negative results.
>I disagree strongly that the problem with Tacrine is not efficacy.
>A quote from "Development of pharmacologic treatments for
>Alzheimer-type dementia, J. Royal Soc. Med. 87:Supp 23, as
>included in my paper: "(With Tacrine), the magnitude of the
>changes (in patients recieving tacrine) was small, even in
>responsive patients, and many patients responded only partially
>or not at all. Furthermore, it appears that treatment response
>is obtained only at higher doses on the margin of patient
>tolerability."
I tried to say that if tacrine had no adverse effects it would probably
be much more effective than it is now, because it could then be
given at higher doses. Higher doses would inhibit AchE more than
lower doses. That is what I meant when I said that the problem with
tacrine is not efficacy but side effects. Isn't your quote implying
exactly the same thing?
I agree with the quote. The effects are small and some patients do
not respond at all. But I disagree with the conclusion you base on it,
the conclusion that therefore nobody should be getting tacrine. Even
a small change can make a big difference when we are talking about
AD patients. For example, for a responding patient tacrine may
mean that she can live a few months longer at home, taking care of
herself.
>The problem I have with this approach is that it is symptomatic
>only: it does nothing to halt the increased lipofuscin deposition
>found in AD patients (B-amyloidosis), nor does it affect in any
>way the low-grade inflammation response resulting in neuronal
>cell death which may be the cause of AD.
Well, lipofuscin (also called "age pigment", intracellular material that
accumulates with aging) deposition is not the same thing as beta-
amyloidosis (the accumulation of extracellular beta-protein, which
occurs in AD and to a lesser extent in normal aging). But let's not get
into side issues here.
We don't know what the primary defect in AD is. It might be the loss
of Ach at the synapse which could start the whole cascade of
degeneration. The inflammation response might be secondary to this
(the body responds by inflammation to all kinds of damage in the
tissues). If this is true, then the better AchE inhibitors now being
developed could really alter the course of AD. Some researchers
believe that even tacrine can do that if you focus only on responders
to the therapy, and if the therapy is initiated early in the course of
the disease (Neurobiol Aging 15(suppl 1):S81, 1994).
What causes the depletion of Ach at the synapse? It has been
shown by Dr. Galdzicki's group that beta-amyloid causes choline
(the precursor of Ach) to leak out from the nerve terminal. The
neurons try to compensate for this by working harder to make Ach,
but they finally get exhausted, degenerate, and die. I'm not saying
that this is what is happening in AD, but I am saying it is possible. If
you inhibit AchE, then more Ach will remain at the synapse and the
neurons don't have to work so hard. A similar mechanism may be
the explanation to the fact that Deprenyl, a MAO inhibitor, makes
Parkinson's disease patients live longer and therefore seems to alter
the course of the disease.
Kimmo Hatanpaa, M.D.
