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

Well, Ron et al - you swayed me to post on this one. I don't know why I decided to read the forums today, but I am glad I did and would like to respond.

I justt got back from my 8 - year evaluation post Spheramine surgery. Spheramine, as y ou may recall, was the implanting of retina dopamine-producing cells from a donor eye into the brains of advanced PWP's. I was one of the original 6 in this study at Emory in Atlanta.

After 48 months, the sponsors were still singing its praises att maintaining a 43% improvement in Phase I after 4 years! Then the first year Phase II results came out. They haven't been published yet, but it was said oint blank that they did not meet their endpoints - no way - case closed. One of the big sponsors pulled out their s upport, and now the future of Spheramine and even the original company looks bleak.

This is how this relates to your question. I have few but horrible off times. It may only occur one or two times a day, but that's enough to get in the way of being an acceptable quality of life. And my worst off time is often a few minutes after taking my meds. (I take Stalevo and Requip XL).

Compare this, if you will the results of being off ALL meds for 12 hours. This is what is required when I go for my annual evaluations. I am not sprinting by all means, but i can walk unassisted and perform pretty well on the neurological exam (finger tapping, timed walk, rising from a chair unassisted, etc.)

Charlie's answer about us producing dopamine when we rest may be part of the answer, but after 2 hours and walking up steps and everything before testing? I don't get it, but there's an answer somewhere in there, I'm sure!
Peg

Peg, how does your status when off all meds now compare to that before Spheramine?
Robert

Robert
 

Glad you asked that! I could NOT have walked to the testing without assistance (walker, cane or wheelchair), I would fall on the least "pull" test, and would have barely been able to speak. All of that has improved greatky and now my on time (except for dyskinesia) is near perfect, with few off times (maybe 1-2 times a day).

Another question, is why do symptoms exacerbate when in pain, depressed, or stressed?
Peg

This is how it goes with me.
 

If I havn't eaten a bunch of junk the day before, I wake up perfectly peacefully in the morning (I only take a remeron and a clonazepam .5 mg at bedtime.)

I usually eat a protien/carb snack before lights out. I then go about 10 hours between taking meds. last sinemet at 9 PM - 7 AM first meds in the morning.

If I sit quietly I am fine, but 32 minutes (no joke) after I have taken my morning meds my left leg starts to tremor...I must get up and move at that point or it will get worse and become an "Off" time for me. The medication without question does activate my tremor. At 1 hour and 15 minutes after I take my first meds in the morning I am fully on and you can barely tell I have anything wrong with me. If I eat carefully and sparingly, I can keep my meds up and going most of the day without dyskinesia. Sugar causes dyskinesia(among other things) for me. If my meds go off during the day I have nasty leg tremors (tremors is not exactly how I would describe them...more like seismic events in my legs.) It is as if the sinemet I take doesn't all go to the brain, but some gets into my adrenaline system and off I go -literally. I relate to man of your comments and the only thing that beats it into control is a benzodiazapine called Clobazam which you don't have in the States....no idea why. The brand name is Frisium. I only take it when my tremor is nuts or I have to get myself in controll PDQ. It works in 20 minutes.

I make my best effort to be in bed when my last meds wear off. Cuz "off" is not a good place to be. Just a side note....I went to emergency twice, and both times because my sinemet was not working for me. Both times I just had to have 8 or so hours unmedicated and some sleep to be ready to face the day. If I wake up in the middle of the night and don't think I will go back to sleep a few almonds or a spoonful of peanut butter is as good as medication and I do go back to sleep. Fluctuations in blood sugar do play a role ....the queastion of the day is: what does all this mean? Does sinemet raise our cortisol levels?

comparing patterns
 

For myself, a typical 24 hour period goes as follows-
10 PM to Midnight- Shuffle off to bed thoroughly "off" and exhausted. Fall asleep quickly.

1 AM to 2 AM- Awaken to go to bathroom. Am in better shape than when I first went to bed. On a scale of ten, went to bed a 3 and now a 6. If I stay up fifteen minutes I am down to a 3 again.

4 AM to 5 AM- Often awaken to go, either again or instead of earlier trip. Something changes in this period. If it is at 4 AM then I am about a 3 but if at 5 AM I am a 6 or 7.

7 AM to 8 AM: Get up about a 6. Usually have dystonia of left foot for 15 minutes. Take meds and wait. After half-hour have dropped to a 4. About the one hour mark I have sudden need to stretch various parts of body for next 15 minutes. Usually on by one hour mark but can be as long as three hours.

Note- If I take meds at 5 AM and go back to bed it is as though I never took them. (BTW, meds are (1) sinemet CR 200/50 with 6 mg of requip)

10 AM- Second round of meds. Full on (10) by 10 to 11M.

2 PM- Third round. Note- this is a period that I am fragile and can go off big time. Then things stabilize by 3 PM.

6 PM- I cheat and take a fourth round.

9 PM- Start final decline.

Chronobiology
 

AKA circadian rhythms. A lot of things fluctuate over the 24 hour period. For example, cortisol levels bottom out about 3 AM and then quickly shoot up to peak at about 5 AM and begin a slow "ski slope" decline. This awakens us but varies among individuals (morning people and the rest of us, for example). Neurofunction varies too. It is a mistake to evenly space your pills throughout the day because your needs change.

Now if I can remember
 

what I just read, I have some comments.
1. when you take your meds you need to be in at least a sitting position for 20 minutes for your medication to move efficiently into your intestine. More time if your intestines are already loaded up with food, or you havn't had a good "housecleaning" for a day or two. Keeping things moving is right near the top of the list when it comes to making your meds work.

2. when you take meds and then go back to bed, you are a)in a position that causes your meds to be destroyed in your stomach juices, and b)run their course of half-life stuck in your stomach. Your whole metabolic system slows down when you sleep. So don't waste medication on sleep time.

3. I believe that your body needs the break from levodopa meds, they are very wearing on your system. Also I totally agree with
Rick that you don't need the same amount of meds at each part of your day. However I know people who swear by a 4 hour schedule and I wonder if the body doesn't just adapt to what we train it to expect.

4. I have my worst time between 3-6 pm. It is the rare day I get through that time slot without some down time. Naps help if I keep them to 15 minutes. I never would have believed it but I have trained myself to lie on my stomach on the floor and totally zone out to the point of dreaming, then look up because I'm sure I've slept to long and then find I have only had my usual 15 minutes.

5. can't remember what else I wanted to say...it will come back later.

Hi Robert,
There is a weak chronological connection between starting taking tyrosine,(Aug), and suffering terrible offs after meds wore off.(late Sept).
Dopamine does regulate heart rate, in his book, "The Parkinson's Handbook", Dr D. McGoon says dopamine is a body hormone with this effect, often administered during an operation to boost a flagging heart.
I can't find where I said dopamine and dopa share a transport, but I may have inadvertently have implied it.
I have stopped taking the tyrosine, and will let you know what happens.
Ron

motor oscilllations etc
 

Hi Ron and others,
The abstract I posted was specifically looking at the 'on-off phemomenon' as opposed to wearing off and wearing on, which is a different thing . What I really found interesting about this, and apologies for not mentioning it at the time I posted, was the levodopa delivery method used, rather than the conclusions that the investigators drew. I think what Ron and others are experiencing IS this phenomena, which they are finding to be related to the WAY that levodopa is delivered, though their conclusion seems to have fudged that and gone on to describe the way we experience wearing off and on. In fact they also say that when there is a continuous and even delivery of levodopa that bypasses the digestive system, then there are no motor oscillations but this is then lost in their conclusions........so is there a good reason why there are no alternative delivery systems for levodopa? In other diseases, again diabetes, and also MS and others drugs are delivered direct into the blood......... I may be showing my ignorance here, but I would love to know why the system that the researchers have used in this study, and which delivered up to 30 hours free from off/on experiences is not available to people experiencing these random and distressing offs. Maybe there are good clinical reasons why not, whichever way it would be good to understand this better.

Lindy:confused:

a simple experiment
 

The old trick of dissolving a day's worth of standard sinemet in a bottle of water and taking the properly sized sip each hour might yield a clue.

sip at a time
 

Hi Rick,
the soluble option is something I have read about over and again, right through to the best things in which to dissolve our 'gold standard' stuff in, seems to be something that many people here and elsewhere tried, I have tried it myself, but do not rate myself as having an overwhelming need to and found it a bind to keep to a regular schedule. I do not know how much relief this brings for random offs, but my first response to your post was that there would not be any money to be made from it ..... I don't however think that this is what you were getting at, but it does not bypass digestive system either......

Lindy:)

Cracked it!
 

Robert,
You were right, it was the transport log jam. Since I stopped the tyrosine 3 days ago, I don't now need to fear my sinemet wearing off. I now don't get the totally disabling off I was getting. Thanks for your input.
Lindylanka,
For a long time I was very interested in nasal delivery of levodopa.
There is a channel in the nose which connects directly to the brain, and by-passes the BBB. I corresponded with a UK company, who were developing the route using a nasal spray.
see
http://www.in-pharmatechnologist.com...-drug-delivery
also
http://www.ingentaconnect.com/conten...4?crawler=true
A huge advantage is it is much faster acting, not having to go through the gut absorbtion stage. However, there are a few too many hurdles and they dropped it. I even tried a few experiments myself, but you need no carbidopa present, otherwise it would prevent your brain levodopa from being converted to dopamine.
Ron

Transport systems
 

Have a look at
http://myheartmind.blogspot.com/2008...teins-for.html
where it says
"To further complicate matters, amino acids are assigned a particular "truck." Amino acids in the same group compete for the limited space in that transport molecule. For example, the amino acids tryptophan and tyrosine both belong in the same category and must enter your brain together. If tryptophan dominates, your neurons will make more serotonin, the calming neurotransmitter that promotes contentment and is responsible for normal sleep. If tyrosine wins out, then you will synthesize more norepinephrine and dopamine, stimulating neurotransmitters that promote alertness and activity.

Tyrosine is crucial to brain power and alertness in another way. It's also needed for your body to make active thyroid hormones. Therefore, low blood levels of tyrosine are associated with an underactive thyroid gland. An extreme deficiency causes severe mental retardation known as cretinism."

Ron

Bumping this thread up for Ibby for info on problems with sinemet and supplementing witih tyrosine.