Brian Collins wrote:
Dear Brian:
You did an excellent job with your presentation below. I and probably
many members appreciated the fact that you shared it with us. The theory
you put forth is as possible as any theories i have heard to date.
Thanks for sharing.
Henry Guttentag ([log in to unmask])






> 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  <[log in to unmask]>
>
>     ---------------------------------------------------------------
>     ---------------------------------------------------------------
>     ---------------------------------------------------------------
>
> THE INTERACTION OF LEVODOPA AND PARKINSON'S DISEASE
>
> 1) The system for producing the neuro transmitter Dopamine can be
>    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.
>
> 2) Studies carried out at the University of Nottingham and elsewhere have
>    established that people who do not have Parkinson's Disease do not
>    suffer a loss of Dopamine production capacity with increasing age: The
>    commonly-held picture of the entire population losing Dopamine production
>    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.
>
> 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
>    started ticking, and one day they will become a PWP.
>
> 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.
>
> 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
>    meet the demand. The addition of a little levodopa puts everything right
>    for the time being.
>
> 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.
>
> 7) Note that for convenience I will refer to "10% of flow" when I should
>    really say "The Dopamine flow corresponding to 10% of SN cells".
>
> 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
>    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
>    is:  How to maintain a steady 10%of flow.
>
> 9) Counting years from onset of symptoms, the SN production capacity
>    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
>    guarantee that it is not based on me!) At 5 years, the SN can only
>    make 3% of flow. Starting from the zero flow line, suppose we gradually
>    raise the tablet-supplied dopamine flow: nothing happens until the tablet
>    flow ( Y ) reaches 7% Together with the SN-supplied 3% : stability is
>    achieved.
>
> 11) If we continue to increase the tablet flow, the system will start to
>    back off its 3% of flow, to keep the total at 10%. However, when its
>    output reaches zero, and the tablet contribution exceeds 10% of flow.
>    the overdose symptoms then set in.
>
> 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
>    grows smaller, the difficulty becomes greater.
>
> 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.
>
> 14)As the SN degrades further with time, so the value of X decreases, and
>    Y increases, until one day the lines converge.
>
> 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
>
>     ---------------------------------------------------------------
>
> 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
> levodopa in the bloodstream a) because the effect would be measurable and
> 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
>    for periods ranging from 2hrs to 5hrs, depending on the level of PD in
>    the patient.