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PARKINSN  May 1997, Week 3

PARKINSN May 1997, Week 3

Subject:

Re: A Sinemet question

From:

Brian Collins <[log in to unmask]>

Reply-To:

Parkinson's Information Exchange <[log in to unmask]>

Date:

Fri, 16 May 1997 06:29:50 -0400

Content-Type:

text/plain

Parts/Attachments:

Parts/Attachments

text/plain (1048 lines)

This message is in MIME format. If you are reading this text, then your mail
package doesn't fully support MIME - there may be a newer release available
from your supplier.

Created using the !Marcel mail package from ANT Ltd <[log in to unmask]>

--80-2107693160-863782190:#-1543471909
Content-Type: TEXT/PLAIN; CHARSET=ISO-8859-1


Hello Jim,  Thanks for taking the time to read my posting - I welcome comments
from someone like yourself, as you obviously know what you are talking about.
As a retired Engineer, I am acutely aware of my lack of knowledge about the
body's internal plumbing.

> >  If you know your ED, which is one of the outputs of my notorious
> analysis
> >  program (Don't worry, you won't need it for a few years yet),
>
> Would you send me a copy, please Brian?  I receive MIME, and can also
> handle any graphic format, spreadsheet, etc.

Can't be done, I'm afraid: My computer is a rare breed, made by a British
company called Acorn. The Acorn RiscPC is a fast, very user-friendly
computer. However, the price which I pay for such excellence is that the
Operating System is totally incompatible with DOS, Windows, or MAC operating
systems.  The way that I get round this is to get anyone who is interested
to record a few day's data on their condition, and send it to me to carry
out the analysis. This would be necessary anyway, because the analysis
requires the guidance of a human operator to get round the limitations of
the data. The key to the success or failure of the analysis, is the quality
of the record produced by the patient: I had to define my own way of
assessing my condition, because none of the available methods (finger
tapping, etc ) were sufficiently sensitive for my needs. However, you can
find out as much as you wish to know by accessing a web site run by Simon
Cole in the UK. The URL is :

    http://james.parkinsons.org.uk/

If you look for my name, you will find a straight-forward 'User Guide'
which gives instruction on how to produce data for analysis, and a much more
comprehensive description of how the program works.


> >  is take Madopar 62.5 dispersible tablets as my basic unit. They are
> better
>
> I tried Madopar, but they appeared to provoke a dry coughing reaction.  Any
> ideas why?

The Madopar Dispersible which I take contains citric acid,  on top of the
rather acidic taste of the ingredients, to enhance the taste when dissolved
in water. I take them dry, and find it to be like sucking an acid drop-
quite pleasant. However, if the slightest bit gets into your wind-pipe it
can be very irritating. Maybe this is what happened to you ?  Of course, you
can always do it properly and dissolve them in water. It is just difficult
to find water every 2 hours if you are not at home.

> > is because I have had PD for 18 years (Actually 24 years since first
> >  symptoms).
>
> You must be doing *something* right!  :-)
>
> >  Well! that's quite a lot of words, and I haven't answered your question
> >  yet. You should know that you are asking about a subject which is far
> > from
> >  settled even among neurologists.
>
> General opinion seems to be that any delay in increasing levodopa dosage
> will lengthen the number of years it is effective.  Speaking for myself, I
> would rather go out like a  Roman Candle sooner, than sputter out like a
> penny candle latter.

I disagree: What you quote as 'General opinion' is certainly one side of the
argument, but I have found, by  questioning a number of neurologists, that
about half of them agree with me that what you do in the early days has no
effect whatever on later events. I have never seen a convincing reason to
support what I will call 'your' view - the reasoning seems to be that as one
gets older, it gets more and more difficult to find an effective dose that
does not induce dyskinesia, and this must be because the brain is somehow
building up a resistance to the levodopa (or dopamine).
    I agree that it gets more and more difficult, but the obvious thing
which is changing and will continue to change is the continued decline of
the substantia nigra. As this decline continues, there are fewer and fewer
dopamine-producing cells in the Substantia Nigra, and as you will see in
chart A, there is a direct relationship between the number of active cells
and the 'size of the window' which we are trying to get through with our
choice of tablets.
   Charts A & B are merely models, I know, but I have yet to find a subject
that they cannot explain. I would like to hear your views on this
interesting and very important issue.  I have in mind particularly the fact
that when I was initially diagnosed I was put on Artane for the first year,
during which my condition declined so much that I was barely able to do my
job, and I almost took voluntary retirement. I then began to think for
myself, instead of accepting what the neuro said, and I moved to Sinemet.
I carried on working for a further 14 years !!  Those early years are
critical for many people who love their work, and do not want to retire so
early. (Once you retire, you can't go back and ask to be let back in
'because I've got some better tablets now.')

> >  No doubt you will have gathered that I prefe the latter approach, and
> > yet I  don't know of any factual evidence which proves that the
> > block-buster approach causes any harm to the patient. My choice is based
> > on instinct as

> One thing to watch is that an overdose of available
>dopamine within the lower digestive tract can produce moderate to severe
>nausea.
>
> >  By the way, my charts A and B are illustrations of the same
> > subject. If you

> > Copy of these too, please Brian?
>  > >  > Jim
                   copies of chart A & B attached NOTE NOTE NOTE

Due to my funny computer, I can't use the same names for files as the PC
uses. You will find in the attachment; Two ordinary text files called TextA
and TextB, and  two files with the charts.  These are named as CHTA/ZIP and
CHTB/ZIP - BEFORE YOU DO ANYTHING ELSE you must rename the files, putting
the correct format in. For instance: CHTA.ZIP, TextA.TXT  the zipped files
should unpack to BMP format, which I understand to be readable if you have
Windows 3.1 or 95   (We call it Windoze)
Regards
--
Brian Collins  <[log in to unmask]>

--80-2107693160-863782190:#-1543471909
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--80-2107693160-863782190:#-1543471909
Content-Type: TEXT/Plain; NAME=TextA
Content-Transfer-Encoding: QUOTED-PRINTABLE

THE INTERACTION OF LEVODOPA AND PARKINSON'S DISEASE

1) The system for producing the neuro transmitter Dopamine can be=20
   considered as a manufacturing unit. It is geared up to sypply the system
   which carries the messages from the brain to the muscles, and must at all
   times supply precisely AS MUCH as is needed, WHERE it is needed, WHEN it
   is needed. The actual production takes place in the Substantia Nigra.
  =20
2) Studies carried out at the University of Nottingham and elsewhere have
   established that people who do not have Parkinson's Disease do not=20
   suffer a loss of Dopamine production capacity with increasing age: The
   commonly-held picture of the entire population losing Dopamine production=20
   capacity, with the unlucky ones whose capacity drops below the 10% to 20%
   level developing PD is wrong. The picture is one where the majority of
   the population live their lives without significant loss of capacity,
   while the PWP (perhaps from birth) go steadily downhill.
  =20
3) An interesting side-issue stemming from this picture is that there are
   about twice the number of identified PWPs i.e. (240,000 people in the UK,
   1 million to 3 million in the USA - depending whose stastics you use)
   walking around in blissful ignorance that their personal clock has=20
   started ticking, and one day they will become a PWP.
  =20
4) It is established that the onset of tremor, which is the usual but not
   invariable first symptom of PD, occurs when 80% to 90% of the Dopamine-
   producng cells have ceased to function. In the chart, I have used 90%
   loss: It does not affect the argument.
  =20
5) When a person develops PD symptoms, we assume that his remaining 10% of
   Substantia Nigra (SN) cells are working flat out and just failing to=20
   meet the demand. The addition of a little levodopa puts everything right
   for the time being.=20
  =20
6) The PWP at this point can tolerate quite large doses of levodopa, because
   his control system can shut down the full 10% of flow to counteract the
   invading tablet's contents.
  =20
7) Note that for convenience I will refer to "10% of flow" when I should=20
   really say "The Dopamine flow corresponding to 10% of SN cells".
  =20
8) When the first symptom makes itself known, we know the critical 10% of
   flow number. It would seem reasonable to assume that this 'magic=20
   number' was the target for stable operation before the onset of symptoms,
   and will continue to be in the future. So the problem facing the PWP=20
   is:  How to maintain a steady 10%of flow.
 =20
9) Counting years from onset of symptoms, the SN production capacity=20
   continues to deteriorate, and the PWP must balance this with Dopamine
   from tablets. With such a crude tool to do the job it is no wonder that
   we have problems.

10) Consider what happens after 5 years (Remember this is a hypothetical
   model, not someone's actual experience. Since I have already seen 17
   years since diagnosis, and 23 years since first symptoms I can=20
   guarantee that it is not based on me!) At 5 years, the SN can only=20
   make 3% of flow. Starting from the zero flow line, suppose we gradually=20
   raise the tablet-supplied dopamine flow: nothing happens until the tablet
   flow ( Y ) reaches 7% Together with the SN-supplied 3% : stability is=20
   achieved.
  =20
11) If we continue to increase the tablet flow, the system will start to=20
   back off its 3% of flow, to keep the total=A0at 10%. However, when its=20
   output reaches zero, and the tablet contribution exceeds 10% of flow.
   the overdose symptoms then set in.=20
  =20
12) Thus a window of X% of flow exists for us to aim at. If we miss, the
   over-dosed symptoms or the underdosed symptoms will result, and as X=20
   grows smaller, the difficulty becomes greater.
  =20
13) Note that this apparent rejection of the levodopa with the diminishing
   window size ocurrs purely because of the progress of PD, and requires
   no other malfunction of the brain's system.
  =20
14)As the SN degrades further with time, so the value of X decreases, and
   Y increases, until one day the lines converge.
  =20
It must be remembered that this case grossly simplifies the situation, and
all the values quoted are simply for the sake of the argument.

Brian Collins, 15 Oct 1996


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Content-Type: TEXT/Plain; NAME=TextB
Content-Transfer-Encoding: QUOTED-PRINTABLE

HOW PARKINSON'S DISEASE AFFECTS THE DURATION OF EFFECTIVENESS OF TABLETS.

I was thinking recently about the bits of information which I had gathered
along the way, which seemed to indicate that newly-diagnosed PWPs seemed to
get a significantly longer duration of effectiveness out of each levadopa-
based tablet, compared with old hands like myself. I ruled out a theory
involving different rates of digestion affecting the concentration of=20
levodopa in the bloodstream a) because the effect would be measurable and=20
there are no reports correlating years since onset with levels of levodopa
in the blood stream, and b) because I did not see why age should cause the
speed of digestion to vary so progressively.

   I now realise that the answer was already available from my chart which
I produced to show how our sensitivity to levodopa increases with time as
a result of our continuing loss of SN (Substantia Nigra) cells and not to
do with any 'burn-out' due to excessive use of levodopa. The story is thus:

Referring to chart A

1) If we consider two PWPs, PWP1 at 1 year from onset of symptoms, and PWP2
   at 10 years from onset of symptoms, Chart A shows the remaining effective
   SN cells to be 8% and 1% respectively.

2) As described in the text accompanying Chart A, this means that PWP1 can
   tolerate variations in flow (from tablets) ranging from 2% to 10% flow
   without showing symptoms of overdose or underdose, whereas PWP2 can only
   tolerate variations between 9% and 10%.

3) Chart B shows the hypothetical effect of a tablet (or what's left of it)
   arriving at the SN, and the resultant Dopamine level in th SN. All sorts
   of shape for this envelope can be played with, but essentially it boils
   down to a fairly flat bit in the middle, with a build-up at the start,
   and a decay at the end. (It doesn't have to be symmetrical).

4) It is now easy to see that PWP1 will 'switch on' as soon as the tablet-
   induced flow exceeds 2%, and as this supposed tablet peaks-out at just
   about 10%, PWP1 will not show overdose symptoms, and will feel fine for
   a total of 5 hours. until the flow again drops below the 2% level.

5) PWP2, taking the same tablet, will a) appear to wait ages before any-
   thing happens, and then will only see an effective relief of symptoms
   for a total of 2 hours. Thus the same tablet can appear to be effective=20
   for periods ranging from 2hrs to 5hrs, depending on the level of PD in
   the patient.
--80-2107693160-863782190:#-1543471909--

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February 1996, Week 1
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December 1995, Week 5
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