About Medication

[joopoele]

About medication

As a member of the Science and Ethics group of the Dutch Parkinson association, I had to judge a study that was investigating the usability of a drug made from mucuna pruriens.
The seed powder of Mucuna pruriens has long been used in traditional Ayurvedic Indian medicine for Parkinson-like diseases. The seeds contain levodopa and seemed to work as good as modern medication where ldopa is combined with a decarboxylase inhibitor.

There has been a study (Katzenschlager R J Neurol Neurosurg Psychiatry. 2004 Dec;75(12):1672-7.), but this was not very usable to us because the study has only a very limited number of respondents. Further the main conclusion was negated by an obviously faulty figure that actually proofed that mucuna was the worst alternative while the text stated the opposite.

Still there is something about the mucuna project that I think we can learn from. It is what in recent publications is called the dirty drug concept. A drug composed of different active components may work better than the components separately administered.

In pharmacokinetics three important parameters are used to describe the characteristics of a drug:
- Cmac, which is the maximum plasma concetration
- Tmax or the time to reach Cmax
- Half-life, the time that is needed to reach half of Cmax.

The problem with PD is what they call the therapeutic window. If you take too much medicine you get side effects, if you don’t take enough the symptoms are not controlled adequately. This therapeutic window narrows during the development of the disease. It becomes a problem to keep levels of L-dopa within the therapeutic window.

A method that I use for myself, and that seems to work, is to use a diversity of drugs at the same time. I use levodopa together with benserazide and carbidopa. further I take a dopamine agonist (ropinerol) and I’m planning to use amantadine.

One reason why this concept works is that the medicines I use have different values for Tmax. So the top of the graph is reached at different moments in time. The tops aren’t high enough to cause side effects. An old report (Menek Goldstein a.o http://www.neurology.org/cgi/content/abstract/34/2/227) from the University New York wrote the following on combined us benserazide and carbidopa at Parkinson’s disease:
"The pharmacokinetics of levodopa differs when it is combined with benserazide or carbidopa. Peak dopa levels are higher, occur sooner, but decline more rapidly with benserazide. ..... Benserazide was combined with carbidopa in 38 patients who were experiencing a diminished response to carbidopa, .... Ten of the patients improved on the combination of benserazide and carbidopa, with a 30% decline in disability. .... The combination of carbidopa with benserazide is useful in some parkinsonian patients.

Further the time that is needed to metabolise the drug is considerably different in levodopa and dopamine agonists (Half-life). This spreads the effects of the medication in time.
Another method that in my opinion is equally important is to spread the use of medication evenly throughout the day. By taking less medicine, more often, plasma levels don’t get too high or too low.

I would appreciate some feed-back on this matter. Tell me what is wrong or right in my reasoning. In my opinion patients should actively try and fight this disease. And we have a definite advantage in the fact that we can feel what medication or therapy does to us. Something healthy researchers lack. If you have time please visit http://www.parkinsonhuis.nl/parkinsonregistry/questionaire.htm and fill in the questionnaire and become a member of our patients panel. Every six months your symptoms will be recorded. The aim is to find correlations both in symptoms and patients, and eventually to predict the development of the disease.

[joopoele]

Have you ever done some experimenting with your medication?
Because sometimes my medication didn’t seem to work I’ve done some tests to find out what might cause this annoying phenomenon.
If I eat a copious meal before I take medication it will sometimes take more than 2 hours before the pills take effect. Sometimes it feels like I haven’t had anything at all.
If I eat a small snack, rich of carbohydrates, right after taking my pills I get the fastest response.
I get a better result if I take my pills with enough water.
The reason for this all is that levodopa is metabolised in the stomach. Sometimes there is not much left over when the medicine has reached the duodenum. It is only here where the Parkinson medication is absorbed in the blood.
Duodopa is administered directly into the duodenum, but a clever patient may not need this for a few years.

[jcitron]

Joopoele,

"If I have a copious meal before I take medication it will sometimes take more than 2 hours before the pills take effect. Sometimes it feels like I haven’t taken anything at all."

"If I eat a small snack, rich of carbohydrates, right after taking my pills I get the fastest response.

I get a better result if I take my pills with enough water."

Recently I had started eating a breakfast in the morning just before taking my first dose not realizing what I was doing, and I ended up feeling so sick to my stomach I thought I was going to pass out. To add insult to injury, the medication was taking longer to kick in! This is as you indicated the absorbtion issue with the Sinemet. (Carbo/Levo) So now, after I learned the hard way, I now take the medication on an empty stomach and with plenty of water with no ill effects. This gets progressively difficult through out the day as I consume meals, but I did find that the carbohydrates do help the absorbtion better. I think it's because the higher protein meals tend to stay in the gut a lot longer than the carbs, which burn up quickly.

If I can maintain the empty stomach prior to pill taking, it would be a wonderful thing, but I'm thin enough as it is at 132 lbs (60 kg); down from 147 lbs (67 kg) a few years ago and my doctor wants me to keep eating to bring my weight up. With my increased dose schedule, this has proved to be more difficult.

John

[joopoele]

John,
To survive parkinson's disease you must adapt. I now have five light meals, as I have five moments during the day that I take my pills.
It is not as difficult as it looks. Have a light breakfast at eight in the morning, some crunchy stuff at 11 dinner left-overs at 14.00, again some snack at five and dinner at eight. Plenty of opportunities to gain some weight I would say. Strangely I lost two kilo's.
Joop

[reverett123]

I am an active experimenter and will share what I can.

First and foremost, because it is current and because it could skew any other results, is the matter of electrolyte imbalence. In my case, a routine physical two weeks ago showed low potassium. I began with just 200 mg and was startled by the effect. Twenty-four hours before, I had ended my day as I had been doing increasingly frequently for two years by crawling to bed at midnight - primarily due to balance and lower leg weakness plus freezing. Less than 24 hrs after the first potassium I walked to bed more or less normally and have not crawled since. Further, I have reduced my Requip dosage from 32 mg/day (too much) to 24 mg/day and Sinemet CR (200/50) from 4x/day to 3x. Also, my blood pressure is under better control and my early morning dystonia in my left foot was missing this morning. Pretty good for two weeks.

Some points about this- 1) Despite my study I made the basic mistake of assuming that I was getting sufficient electrolytes. My neuro seemingly was too. Only my sturdy GP was sensible enough to check the basics. So, beware of initial assumptions. 2) The symptoms of electrolyte imbalance are uncannily like those of advanced PD as are some of the other nutrients (B12 in particular). 3) Since it only required 200 mg to make a difference and the daily amount suggested is 20x that, one cannot assume a smooth curve as things gradually worsen. Instead, there is a threshold effect. In my case, that means that for the last several months and maybe over a year I was slipping above and below that threshold. I would have a bad day for no obvious reason just because my diet had slipped the day before. A difficult situation.

Finally, while one might test this at home, caution is advised. If you have any kidney problems (and don't assume you would know) potassium levels can build up to fatal levels. This is one where you need a doc monitoring you system since your heart can stop.

I'll return to topic in a following post, but keep in mind that some of my data may be screwed.

[Ibken]

I've been taking mucuna powder w/ carbidopa (lodosyn)for about a year and a half and lately have been wondering if I'm taking too little or too much of either or both as 'on' time is getting tricky. I also NOW take a Sinemet CR - which helps smooth things out. Sometimes I take a little Sinemet in addition or instead of the mucuna. Add in the food factor and things are further complicated. Oh, also the Mucuna isn't standardized AND my original source has changed/substituted the product. Too many variables and unknowns.

I had not heard of benserazide. Now I am wondering if there is a formulated blend of the two carbidopas w/ l-dopa since that study showed that some patients benefitted from such a mix in the study. And if not, why not! ??

Two weeks ago I added Amantadine and am seeing some improvements in balance and tremor control and have noticed that I'm not sleeping the same.

I know this whole thing is trial and error (mostly that!) as each person is different but lately I am becoming more befuddled about it all. Feeling quite stupid, really. Just can't figure it out!

Like John, weight loss is a problem. I don't have much appetite but dutifully eat to try to gain/keep what I have. The constant need to regiment drugs and food is maddening. Spontaneity has disappeared from my lifestyle, much to my displeasure. :mad:

I will get to your survey when I am able. Too much stuff going on these days so it may take awhile.

Ibby

[reverett123]

Mucuna- Ron Hutton and I tested this one somewhat, both the raw powder and a standardized extract form. It definitely worked, sometimes too well (dystonia) in the case of the extract. It is on my list to retry the powder as I, too, see an advantage in "dirty" drugs. Mucuna has a lot more than ldopa in it. The biggest problem was that it stained everything black.

Acetyl-L-Carnitine plus Alpha Lipoic Acid plus L-Carnosine- I have had measurable success with this combination. Purportedly the combo boosts mitochondrial function. In my case, I used a timed balance on each foot to test before and after. As I recall, time on each side increased by a factor of five within 48 hours.

Panax Ginseng - "Red" processing method - Although this one may have been affected somewhat by my potassium problem, at least two others have reported similar results. A definite lessening of symptoms and purported protective action.

[annefrobert]

Hello,

I am Anne, a french PwP, I was a MD, specialist in gynaecology and oncology surgery before day of diagnosis of own PD in 1999, at 42 years of age.

I have "some ideas" about dopaminergic drugs optimization as,in fact, I have led a huge work on my own, during several years upon the very subject.

In 2001, I had first worked upon mechanisms of drugs addiction and withdrawal troubles as I wanted to confirm my hypothesis levodopa therapy motor complications may present similar mechanisms.
Then with the knowledge I had acquired from excellent works in toxicology and psychopharmacology of reward circuitries, I "naturally" extended then my works upon dopaminergic drugs in nigrostriatal pathways.
I was then contacted by group of frech engineers who had started a manual method for optimization and they asked me to make somthing from it.
I must say all my admiration for al they had done , it was odf great help to me. But nobody inneurology had agreed to listen to them ;
As nothing was referenced in their work and they had no idea about mechanisms, they encourage me to go on. This is how I led new bibliographic research, still on my own, ran a meta-analysis of almost all the international and multicentric essays for each drug, each presentation, each bi-therapy protocol and same with COMT and MAO B inhibitors and have read and worked upon loads of articles upon same subject.
This is how I succeeded after 3.5 years of really tough work to list with scientific references almost all pharmacokinetic data ((Cmax,T max and half life, whole work is about 500-600 references).
Two french neuropharmacologists I met to compare with their knowledge were absolutely astonished to see I had found all the others, and indeed some were not even listed in the US pharmacologists
database at that time, in November2004. A french engineer PwP’s too and working with me in Mediapark the association I have founded in Lyon has then defined mathematics for a computerized application we have now since end of Spring 2005.
-following lines coming soon-

[joopoele]

Reverett,
I’m not familiar with the concept of electrolyte imbalance, thanks for the tip. I will check this out.
Amazing: 32 mg of requip a day. To me Requip works quite well, but to a maximum dose of 15 mg a day or to be more specific, 3 mg per intake. If I take more than 3 mg I get serious side-effects.
Ibby,
I agree that the fact that it isn’t standardized is a serious draw back of mucuna. It increases the amount of variables.
As far as I know there isn’t a formulated blend of the two decarboxylase inhibitors.This may be because the two drugs are patented by different companies.
Bezerazide is a component of Madopar (Dutch name) Carbidopa is a component of Sinemet (Dutch name)
How much Amantadine did you add, and did you omit any Requip at the same time?
Anne,
I’m very curious about the rest of your story
Joop

[Ibken]

I started w/ a liquid Amantadine and took 1 tsp (50) daily for a week, upped to 2 tsp daily the 2nd week and am now - 3rd week - at 1 capsule (100 mg) daily. This was prescriibed by my local GP Doctor. I'm going to be away for winter and will see a neurologist soon. There aren't any near where I live. I've been 'self-mediciating' for the past 3-4 years. I was doing very well until a year ago when I had a small oops-slip while exercising and experienced an over-night change for the worse. I strongly believe that there is a musculo-skeletal factor with PD.

I was thinking the same re: no formulated blends of ben-carb w/ l-dopa - ie different manufacturers. ($$ issue)

I have not taken requip... Someone - Ol' CS? - recently said that Amantadine is like a mild dopamine agonist. I don't know. Have absolutely NO bio-chemical background/understanding. Can't speak that language!

[chasmo]

Sometimes there is not much left over when the medicine has reached the duodenum. It is only here where the Parkinson medication is absorbed in the blood.
Duodopa is administered directly into the duodenum, but a clever patient may not need this for a few years.

I have not noted a mention of protein in this discussion. Any protein injested less then 2 hours before taking your SInemet or less than one hour after taking it will greatly diminish its effect.
There is a Scandinavian company that has a duodenum pump that continually
dispenses minute amounts of levadopa into the duodenum. It appears to work pretty well.
My friend Nkki O'Brien, takes liquid sinemet on an hourly basis. That regime works well for her.You cannot even tell she has PD when she is on, which is just about all the time. OFF She needs a wheelchair!

Charlie

[reverett123]

The protein problem seems to vary with the individual. Somewhere along the line I read something by Dr. Lieberman saying that only a minority (25% ?) had to worry about it. I do not remember the actual processes involved.

For myself, protein is good. I do much better if I start off with meat and eggs. A couple of possible explanations- 1) Protein provides the building blocks for production of dopamine, so having a surplus helps; 2) Meat is also a good source of potassium, so maybe I was benefiting from that. (You see why this is a mixed blessing. I have to doubt everything that I had thought figured out.); 3) Protein stabilizes blood sugar levels; 4) There may be something to the idea that your blood type relates to your dietary needs.

Regarding the advantages of slow, continuous delivery of ldopa into the system- one of the reasons I want to revisit the mucuna question is to experiment with the water bottle and mucuna mix as a delivery system. The constant spiking of ldopa in the system is not good. Mixing a set quantity into a bottle of water in the morning would allow one to minimize that.

Another factor about mucuna is that for those of us without insurance it sure is cheap. Twenty bucks will last you two to three months.

This brings up a question I have been wondering about. When I was trying mucuna powder, I assumed a certain percentage was ldopa - ten percent as I recall. The literature suggested a range of five to fifteen. Simple math gave me the equivalent to the Sinemet I was taking and the mucuna did, indeed, have a similar effect.

Why? The mucuna had no carbidopa to preserve it against degradation. Why did the simple math equivalent work? What am I missing here? Should it not have been wiped out by enzyme action long before it made it to the brain?

[wendy s]

I have been wondering lately (as my sinemet and mirapex don't seem to be lasting as long) which is worse - having variations in the amount of dopamine available OR taking too much sinemet. ie should I increase the number of doses in a day and increase my risk of dyskinesia later but keep the dopamine more level. Or should I put up with the somewhat off periods so I don't have to take so much sinemet, but that will cause whatever problems uneven dopamine causes.

Anne, I'm waiting eagerly for the rest of your post, hoping you have some information that will help me make the most of my present meds so I don't have to change anything. Thanks for all your research.

[Ibken]

Well put. That is my question, too....to dose or not to dose. I tend to err on the too - little side...I guess it depends on how bad the dyskinesia gets. And since adding Amantadine 2+ weeks ago, I am even more confused. Wouldn't it be nice to just prick your finger and get an instant l-dopa reading to better gauge our doses? Anne, I'm looking forward to your post, too.

Rick, I often take my mucuna as you are thinking of doing. I weigh out the powder (ahead of time), put it in a small bottle with a chip of lodosyn. When it's time to 'take' it, add a little water and shake and then sip evenly over the next hour or so...3-4 sips, maybe. Somewhere I read that l-dopa/mucuna isn't stable after mixing w/ water and I don't know for how long, so maybe the water bottle idea needs experiment - as usual...:winky:

ibby

[reverett123]

My understanding is that the better choice is to maintain a constant level. That is the logic behind the pump systems.

The mucuna lasts about a day but needs to be kept out of sunlight. An opaque bottle does the trick. I intend to mix up a day's worth each morning and hit it on a regular basis. Trial and error.

You will find that the solution turns black as the solution degrades.

[joopoele]

Charlie,
I’ve tried this one out and it is almost what you would call a
”Monkey sandwich” in dutch or a myth in English. If I take the protein after I’ve taken my medication I experience no trouble at all. I test this every day with icecream yoghurt meat cheese etc.
The duodopapump is widely used indeed.
Levodopa does not dissolve very well in water so you will have to shake it very well, which of course isn’t a problem for us.

Reverett,
“The constant spiking of ldopa in the system is not good.”
What would you do if you were a human body and for some reason there was a sudden increase of levodopa in your blood. Of course you would try to break it down, to metabolize it. This in turn would cause Homocysteine levels to rise and vitamin B12 and folate levels to drop.
“The mucuna had no carbidopa to preserve it against degradation.” This is what puzzles me too.

Wendy,
“which is worse - having variations in the amount of dopamine available OR taking too much sinemet”
This is really a problem for me too. I take as little medication as possible but sometimes this brings my body in a cramped state which also cannot be healthy.

Joop

[annefrobert]

Had an awful day yesterday, excuse me about the delay in this answer, here is the story to give you informations.
I am under continuous subcutaneous infusion of apomorphine, 24h round the clock treatment, a treatment to be promoted for many,with strong but very possible education on my opinion, as optimized use may lead to best motor results.
This is no surprise as, this technique is the only one with intra-jejunal duo-dopa to deliver continuous dopaminergic stimulation, though a "must" in terms of respect of functioning and regulation..

Results are great in my case -huge akinesia and narrow window before reaching level where dyskinesia are triggered, a well-known problem in IPD, early optimization may prevent, but if this I know by now and may easily demonstrate, unfortunately no one has taught me on time, I have learnt by myself and understood the mechanisms when too late for me.
Apomorphine permits me to go from 56 in "best Off UPDRS" -to 6 in '"best on",
(see below a report of the tests).

I have ordered next fills to pharmacy 12 days ago and was told they would be a few days of delay but then, a delay again...
From delay to delay, yesterday was the crucial limit, as I would have not enough fills to end today.
A call to the pharmacy yesterday morning told me the product had not arrived yet and that the pharmaceutical laboratory would no deliver anybody until friday.
To me, stop of infusion means awful suffering with most distressful impossibility to breathe.
Should I describe with all details what any of you may imagine about the stressful black day it has been then with my "mental brain" thinking clear, looking for solutions, applying them and repeating operations again and again as one after the other led to failing results and with my "emotional brain" reaching because of these repeated failures, a typical parkinsonian mess that quickly led my body to be submitted to strongest internal vibrations and dyskinesia throwing me from chair to ground for hours till finally a solution was found?
The only solution for me today is to take a taxi to go to Grenoble, a 1h30 drive, and go to the hospital where DBS-STN has been co-pioneered by neurosurgeon Pr AL Benabid and neurologist Pr P.Pollak, who follows me.
I have asked nurse and phamacist to call his unit yesterday for me and everything has been arranged, the pharmacists of the hospital have been told about my case and will provide me enough treatment for one week.

I am aware that such a solution has been found after several hours of search and with involvement of several persons because of the ability I have kept til now to develop huge motivation to reach goals, a very atypical one when , conversely most of us suffer from apathy, and that an other big part of the whole has been possible only upon my name, because of my reputation in own country for on-going contribution to french PwP's and implication in improving IPD social and sanitary problems.

But I worry about all the other persons under same treatment you can't switch in one day as many others and when Laboratory Aguettant we called yesterday only answered no more Apokinon fill was avilable, delay in production, delay in delivery and that's all of it, no more, not one word with either a regret, an excuse, nor an offer of help, the taste of compassion, the smell of empathy.
Nada, niente, rien, nothing.

So, unfortunately for this thread, as we have zero help for PwP's in France, neither state nor association giving care and help to people but only fund raising and as the only SOS Parkinson here is to call or mail Anne Frobert,(see "anne frobert parkinson" on google search...), I'll be very occupied today ....
Very very sorry about this delaying my participation, a big frustration to me as I was so happy to give you answers, to present you a good view upon optimization, explain how much the mechanisms of dopaminergic treatment effects are misunderstood by all, how it is possible to change things and turn them a better way.
But to carry on I need to stay alive, no?
So thanks for your patience for a couple of days

Joop, I send you a private mail yesterday here on Neurotalks.
I will try, before living to Grenoble, to post a small presentation I started to prepare the night before but rained unfinished yesterday.
Anne

REPORT:
"Best off" UPDRS scale test is performed after stop of all treatment for several hours ( more than 8 hours duriing my test),a dreadful experience I went through, at 56 I am like a statue made of stone, can't move one finger, breath, talk , swallow, open eye lids ....most awful situation of total dependance where own body is reduced to the most painful prison and only mental functions are perfectly clear. I observed from this very advanced point of view of "IPD seen by its inside" that I could talk to myself in french, english, spanish and german, could explain modulation of dopaminergic receptors response with short time and long time duration effects, depotentiation and significant decrease in membrane-bound NMDA receptors...all this was perfectly clear in mind but Icould ont communicate.
Such an awful experience exposes you to all the hardness of your physical degradation and and to the huge distress to feel then the most absolute lack of power to fight against.
I have made afterwards the suggestion to Pr Pollak neurologists may change the name of "best Off" to "worst Off" in respect of patients for the high level of physical and moral suffering this stop of treatment irreparably induces.
Levo-Dopa pulls me out of this hell on earth, back in half an hour with dispersible Madopar to "On" stage with "best On" with UPDRS testing at 6. I recognize honestly Dopaminergic stimulation works particularly well upon cases of my type, mostly severe akinetic form with very young onset around 21-23, though diagnosis made only 9 years ago at age of 42 -another story-
Here is all the miracle of the "famous golden standard molecule" but...
I have reported in previous thread how bandwrapping pulled me out of it too, to UPDRS scord of 12 in few seconds, the testing of it upon my "best off" stade having been initiated by Pr Pollak who performed by himself the clinical examination , calculation of results and reported the observation in my file in hospital-another story too-

[reverett123]

Anne is rushing toward Grenoble at the moment, but asked that I post this link to a slide presentation about her Optimization work. It should run automatically.

http://www.parkemedia.org/pps/NTopt.pps

[joopoele]

Anne, This is an amazing presentation. It is what I wanted to say. I made an article on the subject in dutch ( http://www.parkinsonhuis.nl/archief/requip2/index.htm ). It isn't half as complete as your presentation I must admit, but you can see we're on the same tune.
Joop

[jcitron]

Ann,

I know that you're not responding here at the moment, but I hope everything works out soon for you. There's nothing like being in the off state for long periods.
Your presentation was very interesting.

John

[wendy s]

This is so interesting, Anne. Thank you so much for somehow thinking of the rest of us when you are in such terrible shape. I really hope that by now you are getting some relief in the hospital.

My husband and I spent quite a bit of time looking at the presentation. The best piece of information is that I may not need as much sinemet at one time as I take now. Maybe it doesn't take as much to get me above the threshold. I've wondered what taking a half tablet would be like - would I only get half the relief?

I phoned my neuro's office to discuss changing from my sustained release sinemet to regular so I could cut them in half. The nurse I talked to was very helpful, and once she understood what I wanted, told me that sustained release becomes regular if you chew them. I took my third dose at my usual 3:00 pm - chewed the whole thing because I still had a bunch of people to see and was afraid the half dose might not work well enough. I felt great until about 8:00 - right now at 8:45 I'm stiffer on my left side than I've ever been, really very uncomfortable. I'm going to wait until my usual 10:00 to take a sustained release tablet for the night. Tomorrow, it's half doses all day to see what happens.

The treadmill often loosens me up, so I'm off to walk for a mile and hopefully loosen up a bit.

[chasmo]

I am so sorry to hear of your difficulties. I know how bad and scary akinesia can be. This too shall pass.
Have you discussed a lead relocation with Dr. Benebid???
Perhaps that would help, or a third IPG into a different part of the brain?

In any event I will pray for you.

Charlie Black , YAhoo groups, DBS Surgery group founder.