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

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

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?

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.

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.

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

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

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.