Effective Duration of Tablets

[Brian Collins <bjc@xxxxxxxxxxxxxxx>]

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Hello All,  The attached charts and text need to be read together. If I have
overloaded anyone's system, please accept my apologies. (You also need to be
able to handle picture files in GIF format). The charts provide a plausible
(and I hope reasonable) explanation of why it becomes progressively more
difficult to manage  our PD using levodopa tablets, and also explain how the
effective duration of each tablet can be affected by the severity of PD.

For Jon Meyer: You may like to know that it was trying to explain your
unusual results that led me to this theory, so you never know when that last
piece of the jigsaw will click into place.

I would welcome any comment on the charts; the way I see it, if I can
convince you sceptics, I can convince anyone!
--
Brian Collins  <bjc@xxxxxxxxxxxxxxx>

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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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.
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