Sinemet, a combination of two drugs: carbidopa plus levodopa, remains
the most potent drug for the treatment of PD. As people with PD live
longer (because treatment delays their becoming bed-bound) the side-
effects of treatment seem to over-shadow the benefits. When your
doctor suggests you start Sinemet, your first thought may be: "Isn't
Sinemet dangerous? Isn't it toxic?" Sinemet like any drug may be
toxic in that it may have side-effects. However, it is not toxic in
the sense that it destroys or poisons cells and makes PD worse. PD
progresses, gets worse, because of the underlying disease process,
not because of L-dopa or Sinemet.

Next ask yourself whether you think Sinemet is toxic or dangerous or
whether you're afraid to accept the fact that your PD has progressed
and you need additional treatment? It's helpful and revealing but
painful to remind people with PD about the impact Sinemet has had on
the main symptoms of PD: tremor, rigidity, slowness of movement, and
difficulty walking. Before Sinemet more people with PD became totally
bed-bound (Stage 4 or 5 PD) in a shorter period of time than now.

Parkinson Disease Before Sinemet

In 1967, before L-dopa, before Sinemet, people diagnosed with PD
lived on average, 5 - 15 years from diagnosis to death. Death came as
follows:

(1) People with PD, 5-15 years after being diagnosed became bed-
bound. Some developed difficulty swallowing and aspirated or
swallowed food into the lungs. This resulted in an aspiration
pneumonia. The pneumonia challenged the defenses in the lungs while
the rigidity of PD restricted the movement of the chest wall muscles,
the muscles necessary to overcome the pneumonia. As the pneumonia
spread, it overwhelmed the body's defenses. Or the infection spread
from the lungs to the blood and people died of sepsis (blood
poisoning).

(2) People with PD, 5-15 years after being diagnosed became bed-
bound. Unless they were turned in bed every hour, their skin broke
down, they developed pressure sores, the sores became infected, and
the infection spread. The person debilitated from PD lacked the will
and the ability to fight the infection and died.

The introduction first of L-dopa, then Sinemet changed everything.
People diagnosed with PD now live longer. Sinemet doesn't "cure" PD,
but it postpones the day when people become bed-bound, and this in
turn postpones the complications of being bed-bound. Would any of us
trade these extra years for the side-effects of Sinemet?

As PD advances, as more cells are lost, the production and delivery
of dopamine from the cell "factories" in the nigra becomes more
erratic, less continuous, sporadic. This is related to continued loss
of cell "factories" in the nigra and to levodopa's short duration of
action. Together they may be responsible for the "wearing-
off", "fading-out", or "turning-off" of an individual dose of
Sinemet. To make-up for the more erratic, less continuous delivery of
dopamine from the cell "factories" in the nigra, the receptors for
dopamine on the cells in the striatum become super-sensitive.
Initially, the dose of Sinemet required to relieve symptoms is less
than that required to cause dyskinesia. As PD progresses, as the
delivery of levodopa becomes more erratic, less continuous, as
striatal cells become super-sensitive, the dose of Sinemet required
to relieve symptoms approaches that required to cause dyskinesia.


Making Sinemet Last Longer

When Sinemet's short duration of action was recognized and related,
in part, to "wearing-off", "fading-out" or "turning-off" of
individual doses of Sinemet, attempts were made to prolong it's
action and make it's delivery to the brain less erratic, more
continuous. By providing the over-worked cell "factories" in the
nigra with a more continuous delivery of levodopa, the "factories",
although fewer in number, are able to produce dopamine more
continuously, similar to the way they produced dopamine early in PD,
during the Sinemet "honeymoon."

Sinemet Controlled Release (Sinemet CR)

To overcome Sinemet's short duration of action, Sinemet was embedded
in a specific matrix that delayed it's absorption in the stomach and
resulted in a more prolonged delivery of an individual dose of
Sinemet to the brain. This form of Sinemet, Sinemet is called Sinemet
controlled release (Sinemet-CR). Sinemet-CR is available in two
ratios: Sinemet-CR 50/200 which contains 50 mg of carbidopa and 200
mg of levodopa, and Sinemet-CR 25/100 which contains 25 mg of
carbidopa and 100 mg of levodopa. Sinemet-CR had a modest effect
on "wearing-off", "fading out", and "turning-off" of an individual
dose of Sinemet. Although the matrix in which Sinemet was embedded
delayed and prolonged the delivery of levodopa from the stomach, the
delivery remained erratic and was not continuous. More-over, people
who were on regular Sinemet complained upon being changed to Sinemet-
CR, that Sinemet-CR didn't kick-in, and often, when they were "off",
Sinemet-CR, unlike regular Sinemet, didn't turn them-on. This was
related to the fact that regular Sinemet results in a high pulse or
peak of levodopa 30 - 60 minutes after taking an individual dose. It
is this high pulse or peak that results in the feeling of Sinemet
kicking-in and turning people on. The absence of a high pulse or peak
limited Sinemet-CR's usefulness. In some people, the benefits of
Sinemet-CR could be realized, in part, by taking regular Sinemet
together with Sinemet-CR. The limitation in this approach were that
two separate tablets, regular Sinemet and Sinemet-CR, although
swallowed together were not absorbed together from the stomach, while
the high dose of levodopa that resulted from taking Sinemet and
Sinemet-CR together resulted in dyskinesia.

Selegiline or Eldepryl

Levodopa, the active part of Sinemet, is "broken-down" metabolized by
3 separate enzymes: dopa decarboxylase, COMT, and MAO-B. Carbidopa by
blocking dopa decarboxylase in the stomach and liver allows more
levodopa to leave the stomach and enter the brain. However, although
more levodopa leaves the stomach, it's delivery to the brain remains
erratic and not continuous. Carbidopa decreased the nausea associated
with having too much dopamine produced in the stomach, carbdiopa
allowed more people to take less levodopa, but carbidopa did not
result in less "wearing off" and it did not result in less
dyskinesia. MAO-B is an enzyme present inside dopamine cells in the
brain. By blocking or inhibiting MAO-B, the dopamine formed from
levodopa remains in place longer. Eldepryl blocks or inhibits MAO-B.

Eldepryl, 5 mg twice a day, when added to Sinemet has a modest effect
on prolonging Sinemet `s duration of action and this in turn, has a
mild to modest effect on decreasing the "wearing off" of an
individual dose of Sinemet. In the late 1980s and early 1990s there
was great interest in Eldepryl because it was believed, incorrectly,
that Eldepryl slowed the progression of PD.

COMT is the most potent of the enzymes that break-down levodopa, and
blocking (inhibiting) COMT has the greatest effect on Sinemet:
prolonging it's duration of action and resulting is a less erratic
and more continuous delivery of levodopa to the brain. COMT is
present in the stomach, liver, kidney, and brain. COMT also
circulates in the blood. Comtan which blocks or inhibits COMT has
emerged as a safe and widely used drug..


When Sinemet is given without Comtan most of the levodopa is changed
by stomach, liver, and circulating COMT to 3 methoxy-dopa (or 3-OMD).
3-OMD has no effect on PD, it acts as a reservoir or "sink" for
levodopa. Such a "sink" delays the action of Sinemet and results in a
more erratic and less continuous delivery of levodopa to the brain.
Comtan by inhibiting COMT outside the brain results in a more
sustained level of levodopa in the blood. Unlike Sinemet-CR, the peak
effect of levodopa is unchanged, so people who take Comtan with
regular Sinemet feel themselves "turning-on" as Sinemet "kicks-in."


The more sustained, continuous, level of levodopa in the blood
results and in the brain results in a decrease in symptoms such
as "wearing-off." This in turn results in the person experiencing
more "on" time, more time when his symptoms of PD are reduced or
absent. For the most benefit Comtan should be started early, when
symptoms of "wearing-off" begin. This could be when: (1) You're
thinking of switching from regular Sinemet 3 times a day to regular
Sinemet 4 times a day. (2) You're thinking of switching from Sinemet-
CR 2 or 3 times a day to Sinemet-CR 3 or 4 times a day. (3)You wake-
up in the morning and you immediately need Sinemet (4) Your dose of
Sinemet does not "kick-in." (5) You need an extra dose of Sinemet
before you go out at night.

Comtan (200 mg) should be given with each dose of Sinemet up to 8
times per day. Comtan can be used with regular Sinemet or Sinemet-CR.
The dose of Comtan (200 mg) does not change regardless of the number
of Sinemet tablets in each dose. Comtan when added to Sinemet when
increase the side effects of Sinemet such as dyskinesia, confusion,
delusions and hallucinations. If side-effects occur the simplest way
to treat them is to eliminate one or more of doses of Sinemet.