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Date: Sat, 24 Sep 94 16:22:00 MST
From: [log in to unmask] (HICNet Medical News)
Subject: Deprenyl - A Parkinson's Drug - 1994 Update
 
                   Deprenyl - A 1994 Update
            The American Parkinson Disease Association
                     Summer 1994 Newsletter
            Copyright 1994, Reproduced with Permission
 
 
EDITOR'S NOTE: In 1989 APDA published "Deprenyl Update" an
educational supplement authored by A. Lieberman, M.D.,
Chairman of the APDA Medical Advisory Board. At that time
Deprenyl had just been approved by the FDA for use in this
country.
 
A short time ago an article on Selegiline (Eldepryl-Deprenyl)
authored by E. Brunt, M.D., appeared in Parkinson Magazine
highlighting the presentations made at a June 1993 neurologists
meeting in Budapest, the city where Prof. Knoll developed this drug
30 years earlier.
 
APDA is grateful to both Dr. Brunt and to Parkinson Magazine
for sharing this article with our readers.
 
Originally developed as a "psychic energizer" selegiline,
also known as I-deprenyl or Eldepryl, appeared to be an irreversible
inhibitor of the MAO-B enzyme. The MAO-B enzyme constitutes
the main degrading pathway for dopamine, the transmitter which
is deficient in the brain in Parkinson's disease (PD). An
important advantage of selegiline compared with other MAO
inhibitors was its lack of the "cheese effect". This effect is caused
by the uptake of a food constituent, tyramine, which is present
in high concentrations in cheese and Chianti wine, and causes
the sudden, marked elevation of blood pressure in patients
treated with other, previously used MAO inhibitors.
 
In the seventies, Prof. Birkmayer, Prof. Csanda and Dr. Lees
were among the first to apply, in the medical treatment of PD
patients, the concept of slowing down the dopamine degradation
by selegiline. The addition of selegiline to levodopa therapy
appeared to be successful, as patients with motor fluctuations
showed improvement and levodopa dosage could be reduced.
 
In 1985 Birkmayer reported a nine year retrospective study
from which appeared that addition of selegiline to levodopa
therapy in PD patients also lengthened their lifetime. Thus,
selegiline not only improved the response to levodopa, but
also appeared to have a protective action against deterioration
in PD. Support for a possible protective role of selegiline came
from studies on two animal models of PD. In the "MPTP model"
and the "6- hydroxy-dopa model", simultaneous administration of
selegiline appeared to prevent the development of parkinsonism.
The MPTP animal model of PD originates from the discovery
that this substance, methylphenytetrahydropyridine was
responsible for the development of a PD-like disease in
users of a synthetic heroine-like drug in California in the early
eighties. MPTP was found to be oxidized in the brain by the
MAO-B enzyme into MPP+, which could destroy dopamine
producing cells after being taken up into these cells, causing
a PD-like syndrome. In this model, blocking of MAO-B enzyme
prevents death of dopaminergic cells by MPTP.
 
In the 6-hydroxy-dopa model of PD, this substance is injected
into the brain of rodents in the tract formed by the dopamine
nerve cell fibers running from the brainstem to their target in
the basal ganglia. After being taken up into the nerve endings,
6-hydroxy-dopa also causes death of these cells, again producing
a PD-like syndrome. Also in this model, selegiline prevents the
damage, by blocking the uptake of the substance into the nerve
cells.
 
Thus in the second half of the previous decade, both human
and animal studies suggested a possible neuroprotective action
of selegiline in PD.
 
To evaluate the results of previous open studies and to
investigate the supposed neuroprotective effect of selegiline,
several controlled studies have been performed by the groups
of Dr. Langston, the Parkinson Study Group in the United States,
and by the groups of Dr. Myllyla in Finland and Dr. Allain in
France.
 
The largest and most important of these studies was a
multicenter study called "DATATOP" (deprenyl and tocopherol
antioxidant therapy of Parkinson). Over 800 newly diagnosed
PD patients from 40 centers in the US and Canada
were included in this study and randomized to treatment with
selegiline, vitamin E (tocopherol) or placebo. This study showed
a strongly significant delay of the need to add levodopa therapy
in the selegiline treated group. However, the interpretation as to
whether this effect was due to a symptomatic or protective effect
remained controversial. In other words it could not be ascertained
whether the delay was due to improvement of PD symptoms, or to
slowing down of the progression of the disease. Critics argued
that the one-month "wash-out" period following the withdrawal
of selegiline, after which the groups of patients had been
compared, was too short. Indeed, early this year, it was reported
that the difference in favor of the selegiline treated group was no
longer obvious after a prolonged wash-out period of 3 months.
 
As the time needed for the restoration of MAO-B in humans is
now estimated to be about 40 days, the current interpretation of
the DATATOP study is that selegiline does have a symptomatic
effect, and possibly a protective effect.
 
A comparable conclusion on the action of selegiline was drawn
by Dr. Myllyla in Finland from the interim analysis of a recently
concluded study on the effect of selegiline in newly treated
PD patients. Also in this study, the group treated with selegiline
required introduction of levodopa at a later date. In addition, in the
following years patients in the selegiline treated group needed
less levodopa than those in the placebo treated group. In a recent
report on the French selegiline multicenter trial, Dr. Allain also
reported both an improvement of symptoms and a delay in
progression in the selegiline treated group.
 
As mentioned before, selegiline not only is being used in many
countries in the treatment of PD, but also has had a major impact
upon the research on PD and other neurodegenerative diseases.
The exciting story of selegiline includes study on the possible
role of MAO-B enzyme in the pathogenesis of PD and evidence
for protective or even rescue effect of the drug upon endangered
and damaged nerve cells.
 
Investigations on the MAO enzymes have made clear that the
two different types, A and B. have their own distribution both
outside and inside the human brain, - and act upon different
substances. The wide differences found between individuals
on the amounts of MAO-A and MAO-B present in skin and blood
may be important in the study of diseases such as PD.
 
Although preferably metabolized by MAO-B, dopamine is
also degraded by MAO-A and auto-oxidation. In the brain about
60% of MAO is of B type and the amount of MAO-B increases
after age 60.
 
After its production and excretion from the nerve cell to act upon
the receptors of other nerve cells, dopamine is re-uptaken and
subsequently degraded. This degradation takes place mainly
outside the nerve cells, possibly in the nearby support glial cells,
which are known to contain the highest concentration of
MAO-B enzyme.
 
It appears that in the normal process of dopamine degradation
by MAO enzymes, toxic compounds such as hydrogen peroxide
are formed, which may react to form "free radicals". These "free
radicals" are aggressive oxidative substances which can impair
the energy production or damage the membrane of nerve cells,
causing their death. At the Budapest meeting, Profs. Olanow,
Jenner and Youdim presented data suggesting that in dopamine
cells of PD patients the production of the oxidizing substances is
increased, while at the same time the defense mechanisms
against this "oxidative stress' is reduced. As selegiline reduces
the turnover of dopamine by impeding its degradation and
increases one of the defending enzymes, reduction of  "oxidative
stress" may be one way in which it may protect nerve cells.
 
Evidence to support a protective role of selegiline was also
provided by Prof. Knoll. He has found a reduction of age related
changes in the dopamine nerve cells of the substantia nigra
and increased longevity in rats treated with selegiline.
 
Maybe the most exciting findings on the action of selegiline
were discussed at this meeting by Prof. Tatton.
 
Several experiments suggest an action of selegiline which
differs from MAO-inhibition or protection from oxidative free
radicals.
 
The first example is the MPTP-mouse model in which low
dose selegiline given following MPTP administration at a time
when lethal damage to neurons has been completed, triples
the number of surviving nerve cells. At this dosage selegiline
causes less than 50% inhibition of the MAO-B enzyme, so this
cannot explain the rescue. Another example is an experiment
in which one facial nerve is cut in rats of two weeks of age.
At this age the cells of the facial nerve are dependent on
nurturing substances ('trophic" or "growth" factors) from the
muscles with which they are connected. These trophic factors
are transported via the nerve and cutting of the nerve
normally results in death for most of the nerve cells.
Selegiline given to these rats both in high and in low dosage,
more than doubled the number of surviving cells, apparently
providing a substitute for the trophic factors. The suggestion
that selegiline provides a substitute for trophic factors is
also supported by the observation that in cultures of brain
cells, selegiline promotes the growth of these cells and
increases the production of growth factors.
 
These examples suggest that selegiline, used in low dosage,
may have a "rescue" effect, comparable to the effect of trophic
factors. Several of these neurotrophic factors have been identified
and they play an important role both in the growth and in
maintenance of nerve cells, and they have also been shown to
be important in fetal cell transplantation.
 
It can be concluded that selegiline has proven to be a
fascinating drug for its use in the treatment of PD and for its
inspiration of a vast area of research on neurodegeneration.
Actions of selegiline at different dosages include; MAO-B
inhibition, dopamine re-uptake inhibition, reinforcement of
defense against "oxidative stress", and substitution for
trophic factors.
 
A symptomatic and levodopa sparing effect of selegiline
in the treatment of PD patients has become evident, supporting
its use in patients already treated with levodopa. A protective
action in PD patients, by diminishing the rate of progression
of the disease, awaits further clinical proof. Therefore, the
decision to use selegiline as monotherapy in early stage PD
and during its further course is currently based upon the
suggestion of possible benefit rather than evidence. Its
suggested rescue effect and substitution of trophic factors for
nerve cells opens most exciting perspectives.
 
Selegiline has now taken a place in the treatment of PD and
experimental work has opened exciting perspectives. Whether
these promises will become a reality for the patients depends
on clinical results. In the end only these count. Much work
needs to be done, but the hope for a better treatment of this
disease is a good reason for doing it.
 
 
 
 
 
--
     J. Philip Miller, Professor, Division of Biostatistics, Box 8067
         Washington University Medical School, St. Louis MO 63110
          [log in to unmask] - (314) 362-3617 [362-2693(FAX)]