Slaves Of The Clock: Living With Levodopa  16 Apr 2k  Page 1 of 3

Parkinson's disease is a progressive, neurodegenerative disease
of the extrapyramidal nervous system, affecting the mobility and
control of the skeletal muscular system. Its main features are
resting tremor, rigidity, and bradykinesia. Symptomatic treatment
such as levodopa medication may usually improve mobility.

Symptoms of PD are related to depletion of dopamine in the corpus
striatum. Administration of dopamine is ineffective because it
doesn't cross the blood-brain barrier. However, dopamine's
metabolic precursor levodopa does cross that barrier into the
brain, where presumably it is converted to dopamine.

Levodopa alone, taken orally, is rapidly decarboxylated outside
the central nervous system to dopamine, so that only a very
small proportion of a given dose survives to enter the brain.
Hence, adequate control of motor symptoms requires large doses,
and the corresponding amount of dopamine formed outside the CNS
very often causes nausea and vomiting. Moreover, levodopa
competes with other amino acids for the limited transport
pathways through the gut wall, so a high-protein intake may
further impair absorption.

The enzyme decarboxylase is inhibited by carbidopa, which doesn't
cross the blood-brain barrier, and therefore doesn't affect
metabolism of levodopa to dopamine within the brain. Thus, more
levodopa enters the brain if it is taken combined with carbidopa.
The addition reduces levodopa required for a given therapeutic
response by about 75%, and increases its plasma half-life from
about 50 minutes to about 90 minutes. And as a bonus, nausea
from superfluous peripheral dopamine is avoided. "Sinemet" is a
Latin neologism for "no vomit".

The optimum effective amount of carbidopa, to suppress completely
the action of decarboxylase, is 75 to 100mg/day. Sinemet is a
combination of carbidopa/levodopa, supplied as tablets in several
formulations, of which the most commonly used is Sinemet 25/100.
The recommended starting dose for new patients is 3 of these per
day, increasing gradually if needed, up to 8 per day.

After several years of dopaminergic therapy, PD patients notice
that the effect of each medication dose is perceptible, not only
in relief of motor symptoms but also in elevation of mood and
energy. Conversely, at the end of each dose interval the patient
may notice the return of PD tremor, fatigue, depression, and
rigidity or painful muscle cramps from dystonia,. The rapidity of
these changes has led to the term "On-Off" for the phases.

Another effect that appears after several years of levodopa use
is dyskinesia, involuntary writhing or oscillatory motion that
seems due to temporary excess of dopamine from the most recent
dose of medication. In comparison with the symptoms above being
called  "end-of-dose" effect, this is called the "peak-dose"
effect.

Slaves Of The Clock: Living With Levodopa             Page 2 of 3

No doubt, dopamine may not be the only factor in PD, but it's
probably the most important and easiest to deal with. In my view,
the level of available dopamine has two components: a baseline
level that declines gradually as neurons of the substantia nigra
are lost with the progression of PD (clinical motor symptoms of
PD appear when about 4/5 of the SN dopamine neurons are lost),
and the transient added amount from medication which, as
mentioned above, has a half-life measured in minutes.

The aim of each succeeding dose of Sinemet is to add
temporarily enough dopamine in the brain to relieve the PD
symptoms; but there is also a kind of storage effect, where
the successive intermittent doses tend to restore the normal
baseline level, that may take several days or weeks to be
felt. And a more rational goal of medication is somehow to
raise the baseline of dopamine availability to a level above
the threshold where PD motor symptoms appear. But replenishing
the long-term supply of dopamine usually is done by the same
intermittent dosing of Sinemet. The individual dose amount is
limited by the appearance of dyskinesia as a "peak-dose"
effect, so the net result is a kind of sawtooth pattern where
dopamine concentration goes up and down with each dose. Ideally,
one would like the baseline to be as smooth in time as it is
in the absence of PD.

While trying to maintain a condition between too much and too
little, the excursion of dopamine level can be reduced by taking
smaller doses of Sinemet at more frequent intervals, but here
a "quality of life" factor enters, namely the resulting frequent
interruptions of sleep at night and activities of waking hours.
The dose interval may at first be 8 hours, but as the natural
baseline declines with disease progression, the upper limit or
dyskinesia threshold declines even faster, leaving the "window"
of tolerable dose amount smaller and smaller. So PD patients
respond by dosing more frequently; every 6 hours, then 4, 3, 2
and so on, until some reach the point where continuous infusion
by means of a shunt and pump is the best remaining choice.

When a scheduled dose is omitted because the patient forgets
or oversleeps, the lost baseline level cannot be restored by
increasing the next following dose amount, because of the
dyskinesia limit. Instead therefore the alternative is cautiously
to shorten the next few dose intervals until the assigned
schedule is regained.

Slaves Of The Clock: Living With Levodopa             Page 3 of 3

All this sounds complicated enough, but there is more: First,
in absence of PD the natural dopamine level and production rate
probably varies during each day, I suspect it is less during
sleep, and greater during any demanding activity, either mental
or physical. So it would seem that the patient should not only
follow a set dose schedule, but also learn to anticipate and
prevent "off" periods by judicious temporary adjustments of
the schedule. Second, growing evidence suggests that the onset
of dyskinesia is accelerated by separation of medication into
intermittent doses, so that the constant variation in dopamine
level causes lasting changes in the way that dopamine receptors
respond. Ideally, there should be a simple means for the patient
to know if and how much medication is needed at any given time,
to mimic the non-PD state.

As a final note of caution, Sinemet is one of several drugs
whose abrupt reduction or withdrawal after prolonged chronic use
has (very rarely) caused a life-threatening syndrome first
associated with neuroleptic drugs, therefore named Neuroleptic
Malignant Syndrome. NMS features may include sudden onset, high
fever, altered mental state, autonomic dysfunction, and signs of
rhabdomyolysis. Therefore any reduction or withdrawal of Sinemet
should be gradual if possible, carefully monitored otherwise.

Because of dyskinesia, and possibly other suspicions that
chronic levodopa medication may be harmful, some neurologists
prefer to start their patients on other medication, such as one
of the dopamine agonists, until the greater effectiveness of
levodopa is needed. But the pulsed stimulation of dopamine
receptors by an agonist for several years may also cause the
onset of dyskinesia, and other neurologists feel it is better
to start with levodopa. Several long-term studies seem to show
that the eventual outcomes are similar, and have failed
so far to resolve the dispute to everyone's satisfaction.

Until the day that a cure for PD is found, dopaminergic drugs
will continue as the mainstay of treatment. Generally, for the
first 5 to 10 years after diagnosis, on-off fluctuations are
not noticeable and peak-dose dyskinesia may appear as no more
than a slight tremor. That period is known as the "levodopa
honeymoon". From then on, though, the patient will be constantly
aware of symptoms that change during each interval between
doses, and should learn to adjust the dose schedule to achieve
the best quality of life under the circumstances, without
risking a future penalty such as faster progression of the
disease. And, always keeping track of the time.

Cheers,
Joe
--
J. R. Bruman   (818) 789-3694
3527 Cody Road
Sherman Oaks, CA 91403-5013