Ernie and others:

Question from Ernie:  ... I was on 1 tablet CR (50/200) twice daily, ... my
neurologist thought I was under medicated so suggested I add an extra half
tablet at lunchtime. I was only filling in the gap not INCREASING the dose.
 Have I put this clear enough?  I don’t think there is a Sinemet CR 25/100 in
the UK.

Comment:

I do not know what is available in the UK.  In the US there is 50/200 and
25/100 in the CR formula.  It sometimes gets confusing talking about 25/100
as it is available in both regular and sustained release.  There is also the
10/100 and 25/250 regular Sinemet.  Every patient should have some 10/100
Sinemet tablets available.  I will not go into the reason in this message.

You are correct about the release of medication in the CR formulation.  The
release is a function of the surface area.  For this reason a CR (50/200)
broken in two increases the surface area and actually erodes quicker.  In
studies this shortens the time to peak plasma level and actually increases
the peak plasma level.  The duration of benefit is slightly shorter.

Newly diagnosed

I want to make a comment on the newly diagnosed use of Sinemet CR  which is
Ernie’s case.   One of the emerging strategies is to start a recently
diagnosed patient with one or two CR daily.  It is not important that a gap
may result between doses.  Recently diagnosed patients have the ability to
store and regulate release of excess levodopa.  This function slowly
decreases as the disease progresses (or so it is assumed).  The regulation of
release smoothes the delivery and the smoother delivery rate of CR to the
blood seems to be the best of both worlds.  It is hoped this will delay the
time when the progression of the disease reduces this storage and regulation.
 One way of experiencing the storage is to evaluate one's status first thing
in the morning.  During the night, a reduced level of levodopa seems to be
needed.  As such, it is assumed that excess production is thus stored for the
waking hours.  Often patients say they are awaking feeling better and "not
needing medication" for a few hours.  This does not mean you should not take
the morning CR.  It is important to always take medication consistently and
on time.

Your strategy of two CR daily with a half CR boaster around noon is perfectly
justifiable approach.  This follows the circadian rhythm which has a second
low point in the 1 -3 PM time frame.  This valley has nothing to do with what
you've eaten for lunch. It is a natural low that is 12 hours after the night
time low.  Believe it or not, the hours from 3 PM - 8 PM are expected to be
the best hours for us.  (They are not my best hours.  I might add my previous
post was written from midnight to about 2 AM which is the low-low point in
the circadian graph.)

My own experience of taking Sinemet for 12 years might shed some light on
what I am trying to say.  When first diagnosed in 1984, I was told to take
Sinemet 25/250 tablets, 3 to 5 or 6 a day and I would feel better.  I did and
I did.  As I look back these tablets were providing  high peaks, a real BANG
- BANG to the brain.  In December of 1985 I returned from Thanksgiving
Holiday only to be told the whole division was being axed.  My job was
terminated as of Dec 31, 1985.  By acting quickly I networked employment with
a startup company.  I was expected to fly to the home office in Dallas and do
7 one-hour interviews with the vice presidents and president of the company.
 I flew into Dallas the night before but got little sleep.  There was a two
hour time difference from the West Coast.  This meant I started my interviews
around 6:00 AM my time.  I was nervous, the medications were not working
properly.  I started with a 25/250 about 7:00 AM Dallas time.  I had a short
break in the first interview so took another 25/250 about 8:30 AM.  Still
nothing.  I took a third 25/250 at 9:00 AM.  Still nothing during this hour
interview.  I began to lose my faith in medicine so I took a fourth 25/250 at
10:00 AM.  It was around 10:15 that all four of the tablets must have decided
to work.  I had to keep my left arm in a pocket or it was waving down people
I didn’t know.  I actually sat on my left leg or it would have done a walking
tour of Dallas.  Through all this I was expected to ask intelligent questions
and impress the management that I was the right person for the job.    The
only question I wanted to ask was, “Can I go now?”  I made it through the day
and got the job.  I will never forget that experience.  I could have damaged
the brain due to the overload.  I started to have regulation problems in 1987
only three years after diagnosis.  At that time, the sustained formulation
was not available.

In May of 1991 I participated in a research study where liquid Sinemet was
pumped directly into my small intestine.  The pump would deliver LS every 30
seconds.  This was a very controlled release method of medication.  I was not
dependent on erosion of a tablet.  The study concluded that  (1) if blood
plasma levels of levodopa varied, patient response could be unpredictable and
(2) if blood plasma levels of levodopa were constant, patient response would
also be constant and predictable.  These results and earlier results showing
similar findings were the target of the marketing of Sinemet CR.  A tablet
that depends on erosion factors of the gut will never be as good as the
infusion system.  My system is mechanical and these things do not last
forever.  I have dropped the pump in the toilet and dried it with a
hairdryer.  I use a single IV bag for about 6 months.  The hospital uses them
once.  It has been 5 years since I started infusion.  One finding that is
very important, is that after five years, those still using infusion have not
varied their medication level by more than 5 - 10%.  The disease has
progressed in the five years, but the medication levels still stayed the
same.

This goes to show that a smooth delivery is beneficial in long term levodopa
therapy.  I am not convinced the CR formulation meets this requirement.  I
will not go into the use of agonists, but this is where this drug class can
be beneficial.

I hope this gives a better picture of benefits and pitfalls of levodopa
therapy.

Regards,
Alan Bonander