Question for advanced PWP
 

Do you suffer a bad "off" immediately after a sinemet tablet wears off?
Does it gradually improve with no further sinemet over the next few hours?
After nearly18 years of PD, my off's in the mornings before I have taken any sinemet, are not too bad. I can get around. However, when a tablet wears off, I am infinitely worse, and cannot walk at all. The "relapse" gradually fades over the next 1 to 2 hours.
A very strange thing is I occassionally switch on without any sinemet. It lasts for up to an hour. However, I suffer the same relapse when the on wears off. I can't help feeling there is a big clue here. The relapse can't be blamed on toxic compounds from the levodops, I haven't had any!!!!
If any of this sounds famililiar, or any ideas, please respond.
Ron

A very interesting question
 

For myself, my absolute worst times are at night as bedtime approaches and the last meds fade away. One would think that there would be some buildup at that time. By the next morning functioning has improved by a factor of three or more with no further meds.

RON;

I think that as we rest our brains manufacture and store whatever dopamine that they are capable of manufacturing. I noted this when my left IPG's battery died. my right side was akinetic til i got up and moved around a bit. (Possibly stimulating the receptors?), Then I could move around for an hour or two. Then I got akinetic on my right side again. Unfortunately Sinemet didn't help me at all.

Charlie

Ditto
 

That's pretty much what happens to me, Ron. When the Sinemet wears off, I'm much worse than before I took it and it takes roughly 2 hours to get back to the pre-Sinemet level of function. I don't know why either, but suspect it has to do w/ CNS burnout from overstimulation. Like a hangover? :eek:

Ibby

fluctuations....... me too......
 

Everything that I have read/felt lead me to believe that this is caused by fluctuation which gets more as the effective response to dose becomes shorter etc, I believe better management would help reduce this. (This is where patient led information could really start to make a difference.) And I do too believe that it is peak dose that gives the toxic feeling and then the later feeling of being 'better' which then gives way to a return of symptoms. We would get an easier ride and less side effects if this aspect of levodopa therapy was really tackled i.e. we didnt have to search for this information ourselves but were taught how to manage our drugs in the same way that diabetics are taught to manage insulin. Here is an abstract that seems to confirm this:

http://content.nejm.org/cgi/content/...ract/310/8/483

Abstract

To determine whether the oscillating clinical response to levodopa in Parkinson's disease (the "on-off" phenomenon) reflects fluctuations in absorption and transport of the drug, we investigated this phenomenon in nine patients with an oscillating motor state. We studied the response to continuous infusion of levodopa and the effects of meals on the plasma levodopa concentrations and on the clinical response during oral and intravenous administration of the drug. Meals reduced peak plasma levodopa concentrations by 29 per cent and delayed absorption by 34 minutes. Bypassing absorption by constant infusion of the drug produced a stable clinical state lasting for 12 hours in all of six patients and for up to 36 hours in some. High-protein meals or oral phenylalanine, leucine, or isoleucine (100 mg per kilogram of body weight) reversed the therapeutic effect of infused levodopa without reducing plasma levodopa concentrations. Glycine and lysine at identical doses had no effect. We conclude that interference with absorption of levodopa by food and by competition between large neutral amino acids and levodopa for transport from plasma to the brain may be partly responsible for the fluctuating clinical response in patients with Parkinson's disease.

So, I think what is happening,
 

when both dopa and other amino acids are infused IV, is that the presence of elevated levels of phenylalanine and the large aliphatic amino acids isoleucine and leucine in plasma are preventing transport of plasma dopa into the brain. This is because they share a common molecular transport system and are competing with one another to pass through. I would guess that tyrosine and tryptophan, amino acids with large, aromatic "side chains" would have the same effect if present at similar levels. I seem to remember that all five of these amino acids, including dopa, use the same or overlapping transport systems, unlike the other amino acids like glycine and alanine which enter the brain via different transport systems. In typical dietary proteins, tyrosine and tryptophan are present in lower amounts than phenylalanine, leucine and isoleucine, and would therefore provide less competention for a common transport system.

Think of the presence of separate turnstiles or revolving doors constructed to allow only people with certain body shapes or sizes to pass through. So, if there were only one or two dopa-shaped people and several hundred phenylalanine-, leucine-, isoleucine-, and ten or twenty tyrosine- and tryptophan-shaped people all simultaneously trying to get through the same turnstile, the dopa-shaped people would get in quicker after the crowd of other amino acid folks thinned out.

However, that explanation alone does not seem to fully answer the mysterious ons and offs that folks experience even in the absence of oral dopa intake. It is well-known that dopa is made in other parts of the body, especially the adrenal medulla, as well as in non-brain dopaminergic neurons. It is my understanding that the dopa made in these cells can not get out into the general body circulation where it might otherwise supply some amount of "rescue" dopa to account for an improved pre-off condition. The gradual production of dopa by the few remaining dopaminergic neurons while in the unmedicated state, as suggested by rick and others, seems to me to better account for that phenomenon.

Robert

just speculating...
 

Could we possibly be dealing with a drop in dopamine levels brought on by a depletion of the raw materials triggered by sinemet? For example, Ron takes a sinemet and floods his system with l-dopa. As the l-dopa is used up, it might trigger the adrenals to use the tyrosine or even dopamine itself in anticipation of the oncoming symptoms to produce epinephrine and norepinephrine. It could even be a learned response- i.e. the adrenals think "Oh darn, here comes that paralysis again!" and it sets up a self-reinforcing loop. Sort of a miniature fight-or-flight response.

Transport systems
 

Robert,
Your info. on transport systems is interesting.
My major problem at present is the total off following any on, whether from oral levodopa or a "mysterious" on. I started to take tyrosine about 2 months ago, in the hope that it would facilitate own levodopa synthesis which would avoid dyskinesia. Could this be causing my dreadful offs following an on?? Am I creating a traffic jam?
Concerning body dopamine, this is used as a hormone to regulate heart rate, and in theory should not be able to cross the BBB. However, you are obviously familiar with chemical structure, so compare dopamine which "can't pass the BBB" with levodopa which can. Dopamine is very similar to levodopa, differing only by a molecule of CO2. In fact dopamine is a smaller molecule than levodopa, and combine this with the fact that PWP have dysfunctional BBB's, means that our mysterious ons could be caused by hormonal dopamine leaking into the brain from the body.

Carbidopa too
 

Carbidopa is also claimed to be unable to cross the BBB, but it has been shown that it can cross a defective BBB, and PWP have defective BBB's!! A fact researchers tend to forget. Once in the brain, it would prevent decarboxylation of levodopa to dopamine. However, I can't give an explanation why this should happen at the end of an on, causing the catastrophic off some of us see.
The latest paper by Leenders on PWP's having defective BBB's is below.
Ron

J Neural Transm. 2008 Jul;115(7):1001-9. Epub 2008 Feb 12. Links
Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA.Bartels AL, Willemsen AT, Kortekaas R, de Jong BM, de Vries R, de Klerk O, van Oostrom JC, Portman A, Leenders KL.
Department of Neurology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands. a.l.bartels@neuro.umcg.nl

Decreased blood-brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson's disease (PD). This study investigated in vivo BBB P-gp function in patients with parkinsonian neurodegenerative syndromes, using [11C]-verapamil PET in PD, PSP and MSA patients. Regional differences in distribution volume were studied using SPM with higher uptake interpreted as reduced P-gp function. Advanced PD patients and PSP patients had increased [11C]-verapamil uptake in frontal white matter regions compared to controls; while de novo PD patients showed lower uptake in midbrain and frontal regions. PSP and MSA patients had increased uptake in the basal ganglia. Decreased BBB P-gp function seems a late event in neurodegenerative disorders, and could enhance continuous neurodegeneration. Lower [11C]-verapamil uptake in midbrain and frontal regions of de novo PD patients could indicate a regional up-regulation of P-gp function.

PMID: 18265929 [PubMed - indexed for MEDLINE]
PMCID: PMC24

Ron,
 

Your comment about taking additional tyrosine is very interesting. It could well be that the added tyrosine is indeed creating a "traffic jam" which is preventing sufficient dopa entry to provide sx relief. Is there a chronological connection between beginning the use of supplementary tyrosine and the "super offs" you have experienced? The rate-limiting step in neuronal production of dopa is tyrosine hydroxylation, so our limited remaining dopaminergic neurons need pre-formed dopa to provide for the more rapid step of decarboxylation in which dopamine is the product.

Regarding your statement about dopamine and dopa sharing a transport system, the amino acid transport systems are very specific for amino acids only. Since dopamine is missing its carboxylate group, it is not a substrate for this system.

Also, I am unaware that dopamine is used to regulate heart rate. I think that is one of the roles for epinephrine, or adrenaline, a different catecholamine. Cardiac muscle tissue is very responsive to that hormone, which is provided by the adrenal medulla in the "fight or flight" response.

Robert