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The accompanying attachmentmay be of interest if you have an
enquiring mind.........
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Brian Collins  <[log in to unmask]>

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 For Bernard Joly.
=20
 Hello Bernard,  here is my (Very late) response to your request for comments
on your most impressive MEG07.  I have not yet reviewed the spread sheet=20
calcs, but there is one point that I feel I must mention, if only because I
can raise a question and then provide the answer. Your graphs (in which I see
evidence from Ron Vetter and Alan Bonander) have a distictive saw-tooth shape
which is in direct contradiction with (I believe) most people's experience.   This op=
ens a bit of a credibility gap right at the start.=20
=20
  However, I aso have an explanation, which I believe to be a correct one. It
involves my 'CHART A' which I find so useful for explaining quite a lot of=20
Parkinson's-related questions.=20
=20
 The problem is that the traces are readings of Dopamine concentration in the blood s=
tream, before it crosses the blood/brain barrier, and gets to the=20
Substantia Nigra. The BBB will smooth out the jagged line a bit, but the=20
really powerful effect is shown in Chart A
=20
 To cater for those who cannot receive charts and pictures, I have produced a crude c=
opy of Chart A:  If your text browser uses a Proportionally spaced=20
font this chart will be rubbish: If you can substitute a non-proportional=20
font it should work.

The rather straggly line running from top left to bottom right is supposed to represe=
nt an exponential decay, and represents what I think is the most=20
likely shape to explain my and other people's experience of the way that our
normal Dopamine-producing capability is subject to a continual decay, due to=20
completely unknown sources.
 We know that we only begin to show the PD symptoms when about 80% of the=20
Dopamine-producing cells have been lost. This is the starting point for Chart A .  We=
 know that the '20%' line
represents the dopamine concentration or flow rate required to stop the PD=20
symptoms . I see no reason why it should not remain as the definition of=20
required flow for that person.(The actual quantity required will be specific
to each person
  If a person who does not have PD is given a big shot of levodopa, it has a=20
quite remarkable effect - nothing happens, and it keeps on happening: No=20
tremor, No Dyskinesia : Nothing.  The reason is that the brain's  'Control=20
System' which is part of a very sophisticated production process detects the=20
presence of the excess levodopa and responds by shutting down the equivalent
amount of naturally produced dopamine, so the flow to the axons is unaffected.

I believe that the brain, with a fully-functioning Dopamine system is so=20
clever, and so well designed that the term OVERDOSE simply does not exist:
and that is why, when we go into an overdose condition, we get dyskinesias,=20
etc =20
  Consider the case of a recently- diagnosed PWP:
  When a newly=3Ddiagnosed person is given Levodopa, he or she still has=20
control of 20% of the normal Dopamine production capacity and can use it to=20
respond to and smooth out any highs and lows experienced during the day.
This is why the newly-diagnosed PWP can tolerate a dose of say a 250/50=20
Sinemet tablet - a dose which would have me running around in little circles=20
on the ceiling! Interestingly, we can also see that although the system can
tolerate a lot of dopamine, it only NEEDS a small quantity. Referring to
chart A we see that the mimimum flow rate required to stabilise the system=20
and stop the PD symptoms is Y1: say 5%. However, the system  can accept and=20
absorb Y2-Y1 flow rate: another 10% of flow. To put it another way, the PWP
must aim for a nominal rate of 5% of capacity, with a tolerance of +/- 5% of flow -  =
It's like shooting at a Barn door!.This excess capabiity worries
me considerably. - If it is used regularly (and it is) does it do any harm=20
for the future ?=20
  =20
   Now consider the person at 8 years from diagnosis. He has constantly to=20
supply enough dopamine to make-up a shortfall of Y3 (say 15%). Not only that, there i=
s only 5% of naturally-provided Dopamine, which means that the=20
overdose correction capability is only 5%-worth of flow. This means that the
old PWP  must take tablets to make -up for the missing dopamine of at least=20
15%, BUT he can only over shoot that target by 5%. He must therefore shoot=20
for a target of 17.5% +/- 2.5%
=20
=20
=20
  ____________________________________________________________________________
 |
 | percentage of Dopamine
 | Producing cells remaining              CHART A  All values Are for          |     =
                                  explanation only
 |
 |30%
 |
 |=20
 | =20
 |p   =20
 | b   =20
 |  p      =20
 |    p   =20
 |.....b.............  .....Minimum .Dopamime requirement.for..no..Tremor....
 |20%    p           |                                    |
 |          b        |Y1                                  |                    |     =
              |                                    |
 |              b    |                                    |
 |                b  |                                    |
 |                  P|                                    | =20
 |                   | o                                  | =20
 |                   |   B                                |
 |                   |                                    | Y3
 |                   |        b                           |=20
 |10%                |           p                        |
 |                   |                                    |=20
 |                   I                 n                  |              =20
 |                   |Y2                  p               |                    |     =
              |                                    |
 |                   |                         *          |                 =20
 |                   |                               o    |                    |     =
              |                                    |o                  |             =
       |                                    |           o        |      0            =
2          4            6            8
 |      |            |                                    |  Y4                |0____=
_|____________|__________|____________|____________|_______I_________
=20
                    Years from Onset of Tremor  =20
                   =20
___________________________________________________________________________

  I'm sorry that took so long, but I hope you see now that the dopamine=20
control system will smooth out the peaks and valleys shown on your charts so=20
that they will simply not be observable to the PWP.

Incidentally, I have also given you my case for why levodopa becomes more=20
difficult to handle as time goes on. It has nothing to do with
"de-sensitization". "fluctuating response" etc. It is simply that armed as we are wit=
h a very coarse blunderbus. when you are shooting at a target of=20
17.5 +/-2.5, you are going to have more misses than when you were aiming at=20
5.0 +/- 5.0.   If you accept this argument, you will begin to see why I get
so annoyed by the 'Save the levodopa for as long as you can, so that it will=20
be more effectve' school of thought.  (I have yet to see a logical=20
explanation of their case.)















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