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]>

--80-1904222667-887102022:#-1543471909
Content-Type: TEXT/PLAIN; CHARSET=US-ASCII

I apologise for the messy graph on my last effort: this one should be
better

Regards,
--
Brian Collins  <[log in to unmask]>

--80-1904222667-887102022:#-1543471909
Content-Type: TEXT/Plain; CHARSET=ISO-8859-1; NAME=mara2f608
Content-Transfer-Encoding: QUOTED-PRINTABLE

 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.=20
This opens 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 stream, 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 copy 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. Set your column width to 78 characters.

The rather straggly line running from top left to bottom right is supposed to
represent 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 is 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
  __________________________________________________________________________
 |                                                                         |
 |                                                                         |
 | percentage of Dopamine                                                  |
 | Producing cells remaining              CHART A  All values Are for      |
 |                                                    explanation only     |
 |                                                                         |
 |30%                                                                      |
 |                                                                         |
 |                                                                         |
 |                                                                         |
 |p                                                                        |
 | b                                                                       |
 |  p                                                                      |
 |    p                                                                    |
 |.....b....................Minimum .Dopamime requirement.for..no..Tremor..|
 |20%    p           |                                    |                |
 |          b        |Y1                                  |                |
 |                   |                                    |                |
 |              b    |                                    |                |
 |                b  |                                    |                |
 |                  P|                                    |                |
 |                   | o                                  |                |
 |                   |   B                                |                |
 |                   |                                    | Y3             |
 |                   |        b                           |                |
 |10%                |           p                        |                |
 |                   |                                    |                |
 |                   I                n                   |                |
 |                   |Y2                 p                |                |
 |                   |                        *           |                |
 |                   |                              *    o|                |
 |                   |                                    |                |
 |     0             |2           4           6          8| Y4         10  |
 |______|____________|__________  |___________|___________|_____________|__|
                                                                           |
                    Years from Onset of Tremor                             |
                                                                           |
___________________________________________________________________________|

  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=20
we are with 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.)


















--80-1904222667-887102022:#-1543471909--