Brian Collins <[log in to unmask]> wrote:
<<<<<Hello everyone
The main body of this post is a repeat of an exchange of views which I
had with Bob & Joy Graham a couple of days ago. Looking back on it, I
thought that the range of subjects, and the interesting points which
were raised by them warranted a larger audience. I hope you agree.
Regards,  Brian Collins
On Thu 02 Jan, Bob & Joy Graham wrote:
> Hello from stinking hot Australia where we are in our second day of the new
> year and it is looking like being 42C again.
> I enjoyed reading your recent post about taking levodopa, and the option to
> take it in small quantities.  Of course, this is one recognised theory and
> that is why many advocate the slow release forms such as Sinemet CR and
> Madopar HBS
The sort of Controlled Release tablet which I am talking about for a
newly-diagnosed PWP would release about 10 mg/hour over a period which
could be anything you like, depending more on the ability of the tablet
manufacturer to turn out a regular release rate. In fact there should be
a range of such tablets, all lasting the same time, but each one having
a pre-set release rate,ranging from 10mg/hour up to about 100 mg/hour.
My ideal tablets would cover the range 10 mg/hr to 100 mg/hr in
increments of 10  and     1 mg/hr  to  9  mg/hr  in increments of 1. You
could then match anyone's requirement precisely. If you take my case as
it is right now, I take 1 and a half Madopar dispersibles every 2 hours
: That is 37.5 mg/hour. If my intake falls below about 32 mg/hr I switch
off, and if it goes above 42 mg/hr I get dyskinesias (These figures were
obtained with the help of my analysis program). There was a time when
the rate of release which I could tolerate was high enough to allow me
to use the standard controlled release tablets, which was great, but I
can't take them now. ( Note that I said 'tolerate' not 'need': that has
for a long time been 37.5 mg/hr).
>- but sadly, I understand that one has to take more of the
> levodopa to get the same response, and this is problematic.
I assume that you are referring to the 'Bio-availability' of the CR
tablet.I am far from convinced that such a thing exists: my program
matches the perceived output with the milligram content of the CR tablet
without the need of a factor on the effective size of the tablet. As I
understand the argument,less levodopa arrives at the brain because ,
since the tablet contents have been 'in transit' for a longer period of
time, the chemicals trying to attack the levodopa are more likely to
succeed. On the other hand, I suspect that a much more significant
feature is the amount of protective carbidopa available to shield the
levodopa from this attack. Either way, I don't see why it should be
'problematic': you just take a bit more levodopa to compensate.
> Bob and I were curious that whilst you recommend breaking the tablets up,
> and taking small amounts more frequently, you didn't recommend making
> liquid Sinemet.  Have you done this yourself?  Have you found that it
> doesn't work for you?  I certainly think it is useful for those having
> dyskinesias and a small "therapeutic window" after many years of treatment.
Theoretically I would agree with you: you can in principle tailor your
drink to any value of concentration you like. in fact, if you read my
program description on Ron Vetter's web site, you will see that I
suggest doing just that. But (and it is a big but), since I wrote that,
I have seen the effect of liquid Sinemet in data sent to me for my
program from a man who uses it. The effective characteristic is one
where the speed of uptake (i.e. the time from drinking the mixture to
the time for the effect to be felt) is amazingly short. The bad news is
that having dumped all its levodopa in record time, the output rate
fades back to zero at equal speed, which is the last thing that we want.
This man was having to cope with effectively a sine wave, alternating
from full on to full off at a rate of 2 cycles per hour! That is the
last thing I want
> Another point:
> We here in Aust are able to use Motilium/Domperidone which is the only anti
> nausea drug which does not (ultimately) produce drug-induced PD symptoms.
> Is it available in the UK?
> We noted in the APDA mag. recently that whilst it was not available in the
> USA, a neurologist was telling patients to contact him for an address of a
> pharmacy in Canada which would supply it.  The same doctor said that he had
> noticed more nausea with the Sinemet CR.  Is this your experience?
This is interesting - are you saying that Motilium can be used to enable
PWPs who suffer nausea when taking levodopa, to overcome the problem? If
this is known over here, I am not aware of it. I will make some
enquiries. I am not aware of any evidence that suggests that CR tablets
provoke more nausea.
> Do you know anyone who has tried the levodopa patch?  It seems to me that
> this could be a great solution, since one can simply remove it when one is
> getting overdosed, i.e. dyskinetic.  (It wouldn't work for those with
> sensitive skins, I know).
I think that if you read the small print you will find that the
statements do not actually state that the patches contain levodopa. I
suspect that they will contain one of the new dopamine agonists, and
thus will still require levodopa to be taken as well.
> i am curious that in your general advise, you don't comment on the action
> of Deprenyl which elevates dopamine concentrations by blocking its
> breakdown, and therefore enabling a person to take less l-dopa.  Are people
> in the UK still anti-deprenyl?   There are two articles in the recent NPF
> magazine (do you get these -- if you don't I thoroughly recommend them)
> which seem to refute the "infamous" UK study which slammed deprenyl, and
> prove it was ill advised, or at least too hasty.
You are making a lot of claims in the above paragraph. This is how I see
it: Deprenyl (We usually call it selegiline) works by blocking the
action of MAO -B, which normally attacks and breaks down dopamine. So
the hope is that a bit more dopamine will be left to prolong the
effective duration of a tablet. Why bother? I can get the same effect
either by taking a bigger tablet, or bringing forward the next tablet.
And what are you getting for your stretched time scale? - your MAO-B
ratios are all mixed up, you have got a compound in your brain which
produces Amphetamine as it breaks down ( That's why you have to avoid
taking the deprenyl near bedtime - The dreams are unforgettable. Yes,
I've been there, and I took myself off selegiline. My rule is basically
: The neuros can play with my brain, but my mind is mine and hands off!
These are dangerous chemicals which we are playing with- Selegiline +
Demerol can Kill you. My attitude to anti-cholinergic drugs is the same-
acetylcholine is there in your brain for a reason, and screwing about
with the proportions, in the hope that it will allow a bit more dopamine
to be produced seems crazy to me.
By the way, I have never accepted the story which came out of the UK
about Deprenyl, just as I never accepted the results of the tests which
said it was a good thing in the first place.  --
Brian Collins  <[log in to unmask]> >>>>>>>>>>>

Brian,
Your medication "design" is a designer drug delivery (= controller)
system
that is effectively a rate limiter.

Unfortunately, it is not easy to build such a pill. The multi-coatings
micro-encapsulated particles that are then packaged in the capsule - is
the way the 12-hour and 24-hour capsules are made. Somehow, these must
remain in the intestinal segments that can absorb the medication. I
doubt that the latter is reality for most chemicals/drugs. It might be
that the preparation of a liquid with sipping a titration/aliquot is the
better approach.  This makes the compounding easier, but requires the
dispensing person to be cognitive of the role of drug-dispenser that he
or she must play.  This would be possible in the onset phase, but not
easy to accept such focused cognitive attention for many of us - and,
the older we feel, the less likely we are to learn that learning to care
actively all the while we are awake is the kernel of critical activity
to "feed our drug habit".

In other words, your dispensing rate is accepted by your self - and,
thereby, you are paying attention to medicating your self optimumly.
THAT HABIT IS YOUR "SALVATION".

But, to "sell' that cognition-awareness-need to a newbie Parkinsonian is
an
enormous chore.

Similarly, it is very expensive to process-control pill batches.  Having
to make two versions of a medication doubles the cost essentially. There
may be the liquid (take a teaspoonful every hour) approach, but this is
not significantly different than taking a 10/100 every hour (or 70
minutes or 90 minutes ..) which is already available. (Neither of these
will bypass the stomach non-absorbtion-delay-by-food-digestion
difficulty.)  Transdermal patches will bypass the intestinal, but they
are maximal transfer when applied and decay in dosage with time. A new
patch added every hour could be done, but the things are rather
expensive. And, it may be that levodopa is not transdermally potent
enough - ie est, we need to take a lot rather than just a little.

This has become too long, but I think it is a "thread" that is quite
central to the issue of medicating optimization - which deserves much of
our attention.  "Our" includes the pharmacology and clinical
professionals as well as the researchers who read this listserv (I hope)
- as well as those of us who are seeking to help self and the others
confronting this neurodegeneration.

thank you for reading a long message. If you have thoughts about it,
pass them along - participation is good in this new year.  As always,
ron
--
ron      1936, dz PD 1984  Ridgecrest, California
Ronald F. Vetter <[log in to unmask]>
http://www.ridgecrest.ca.us/~rfvetter