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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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