Although our ideas are changing, the prevailing opinion today is that
if you have symptoms of PD and can live with the symptoms it's best
not to be treated. However, data is accumulating about drugs that
slow the rate of progression of PD. Such drugs include the dopamine
agonists Mirapex and Requip and Co-enzyme Q-10. At present there is
disagreement as to whether the benefits in slowing the rate of
progression of PD are so clear-cut that all newly diagnosed PD
patients should be started on Mirapex and Requip or Co-enzyme Q-10 in
high doses (1200 mg per day).

There's agreement that when symptoms interfere with daily life
treatment should be started. The disagreement centers on when
symptoms are severe enough to interfere with daily life. The tremor
that does not bother you may be a major embarrassment to your friend.
The common reasons people with PD seek treatment are:

(1) Increasing tremor. Your tremor may interfere with your daily
activities or may be a major embarrassment to you socially or at
work.

(2.) Slowness of movement. You may become so slow in your activities
that this imperils your work or makes it impossible for you to go
without help.

(3). Difficulty walking. Not being able to keep up with your partner.
Or an increased tendency to fall.

(4) Painful stiffness or rigidity of a major joint: the shoulder or
hip. Cramping of your arms or legs.

Dopamine Agonists as First Treatment

For people 60 years and younger who are diagnosed with PD and who
need treatment the first line drugs are the dopamine agonists,
Mirapex and Requip and Permax PD results from a loss of cells deep in
the brain in a region called the substantia nigra.

The cells in the substantia nigra are darkly pigmented and contain
dopamine. Indeed their dark pigment represents condensed molecules of
dopamine

The cells in the substantia nigra project to a region of the brain
called the striatum (so named because the region is striated or
striped)

L-dopa or levodopa, a naturally occurring amino acid, similar to the
amino acid tyrosine, is changed inside the cells of the substantia
nigra to dopamine which is then transported upward through long
processes of the cells called axons


In the striatum dopamine is released and taken up by cells in the
striatum. The dopamine is released onto dopamine specialized
receptors. There are 2 kinds of receptors: the DA-1 and DA-2. The
agonists stimulate DA-2. Dopamine stimulates DA-1 and DA-2. This may
make dopamine more powerful but it also may result in dyskinesia.
Drugs such as Requip, Mirapex and Permax, like dopamine, can attach
themselves to the receptors and thus mimic the actions of dopamine.
They are called dopamine mimetic or dopamine agonists. A dopamine
antagonist is a drug that blocks the dopamine receptor (or
antagonizes) it while an agonist is the opposite, hence the name.


There is evidence that Mirapex and Requip, in addition to improving
the symptoms of PD, may slow the progression of PD. As PD progresses,
the cells in the substantia nigra drop-out and the remaining cells,
like factories, must work harder, to "pump" dopamine to the striatum.
The agonists mimic the actions of dopamine in the striatum: they do
not need the remaining dopamine cells to "pump" dopamine to the
striatum. In order for you and your doctor to make a logical decision
as to whether this information warrants a change in your treatment
requires an understanding of how the studies were done. Several
questions will jump to mind.

Question 1. I was recently diagnosed with PD. I and my doctor do not
feel my symptoms are sufficiently troubling to warrant treatment. In
light of the new studies should I be placed on Mirapex or Requip even
though my symptoms are not sufficiently troubling to warrant
treatment?

In the first study patients whose symptoms were sufficiently
troubling to require treatment were randomly and blindly assigned to
either Mirapex or Sinemet. The measure of PD progression used an
imaging technique called SPECT or single photon emission computed
tomography. The SPECT study uses an isotope abbreviated CIT that
labels dopamine transporters. The dopamine transporters are located
on axons of dopamine cells. The axons of these cells project to the
striatum. SPECT measures the radio-activity of the striatum by
lighting up the dopamine transporters. The fewer cells in the
substantia nigra the less the distribution and intensity of radio-
activity.

In the second study patients whose symptoms were sufficiently
troubling to require treatment were randomly and blindly assigned to
either Requip or Sinemet. The measure of PD progression used an
imaging technique called PET or positron emission tomography. PET
uses an isotope called fluro-dopa. Fluro-dopa is transported up the
substantia nigra axons into the striatum. Here, fluro-dopa is taken
up by the dopamine receptors on nerve cells of the striatum. PET,
like SPECT, measures the radio-activity of the striatum. The fewer
substantia nigra cells the less the distribution and intensity of
radio-activity. As, at present, there are no direct comparisons
between SPECT and PET, it cannot be said which is a more accurate
marker of the remaining substantia nigra cells. Both studies compared
the rate of progression of PD in a group of newly diagnosed PD
patients whose symptoms were sufficiently troubling to require
treatment. Although it's reasonable to believe newly diagnosed PD
whose symptoms are NOT sufficiently troubling to warrant treatment
will also benefit, the potential benefit in slowing the disease
progression must be weighed against the side effects of Mirapex or
Requip. This issue must be discussed with your doctor.

Question 2. I have PD and my symptoms were sufficiently troubling to
start me on Sinemet. In light of the new data should I be changed to,
or should I add Mirapex or Requip to Sinemet?

In addition to the two recent studies, in which there was 9 – 15%
less progression of PD per year with Mirapex or Requip than with
Sinemet other studies were done comparing Mirapex, Requip and
Sinemet. In a 4 year study comparing Mirapex and Sinemet, one
separate from the SPECT study, 301 newly diagnosed PD patients whose
symptoms required treatment were randomly and blindly assigned to
treatment with either Mirapex or Sinemet. After 3 months
investigators were, if needed, allowed to add Sinemet to all
patients. After 4 years 25% of patients initially assigned to Mirapex
had dyskinesia (but only after supplemental Sinemet was added) versus
54% of patients assigned to Sinemet. 54% of patients assigned to
Mirapex had "wearing off" versus 71% of patients assigned to Sinemet.
Mirapex alone, or Mirapex combined with Sinemet, results in FEWER
DYSKINESIA than Sinemet alone.


In a 5 year randomized trial of Requip versus Sinemet in 268 recently
diagnosed PD patients reported in the New England Journal of Medicine
2000 (volume 343, page 1484) whose symptoms required treatment and
were randomly and blindly assigned to treatment with either Requip
and Sinemet. After several months investigators were, if needed,
allowed to add Sinemet to all patients. After 5 years 20% of patients
initially assigned to Requip had dyskinesia (but only after Sinemet
was added to Requip) versus 45% of patients initially assigned to
Sinemet. The improvement of symptoms was comparable in patients
initially assigned to Sinemet or Requip. The dose of Requip was 16.5
mg per day. The dose of Sinemet was 427 mg per day. Requip, alone, or
Requip combined with Sinemet, results in FEWER DYSKINESIA than
Sinemet alone.


Because of differences in the way patients were assigned to treatment
in the studies on Mirapex and Requip the results of the two studies
cannot be compared. Of the patients completing both studies and not
dropping out because of side effects or failure to comply with the
terms of the study, approximately 30% remained on Requip without
Sinemet for 4 - 5 years.

Question 3 repeated. I have PD and my symptoms were sufficiently
troubling to start me on Sinemet. In light of the new data should I
be changed to, or should I add Mirapex or Requip to Sinemet?

What will be done will be determined, in part, by your age. If you're
60 years or less, most neurologists, before the new studies, started
you on an agonist because of the decreased likelihood of an agonist
precipitating "wearing-off", "on-off", or dyskinesia. With the new
studies, this trend will be accelerated.

If you're 70 years or older, most neurologists will start you on
Sinemet. This is because in 30% of PD patients 70 years or older, PD
becomes associated with a dementia. The dementia evolves slowly.
Although the symptoms of dementia are obvious when they appear,
before they appear the underlying dementia is "silent" and difficult
to recognize. Often the first symptom of such a "silent" dementia is
the appearance of a psychosis: hallucinations, delusions, agitation.
The psychosis is often precipitated by drugs and the agonists are
more likely than Sinemet to do this. Because of this the treatment of
patients 70 years or older may not change because the desire to slow
disease progression may be less critical at age 70 years than the
fear of precipitating a psychosis, unmasking, temporarily, an
underlying dementia.

If you're 60 - 69 years in light of the new studies, many
neurologists will start you on Mirapex or Requip. Many will start you
on Sinemet. In addition, if you're on Sinemet and having increased
symptoms of PD, most neurologists will now add Mirapex or Requip
rather than increase Sinemet. Mirapex and Requip will be added as
much for their effect on the symptoms of PD as for their effect on
slowing disease progression. Although the possibility of
precipitating a psychosis, unmasking, temporarily, an underlying
dementia is less at age 60 - 69 than at age 70 years or older, this
possibility remains. In these patients the judgment of the
neurologist as to which drug to use will be critical.