Motor fluctuations not an inherent sign of progression

[Conductor71]

I have been searching for studies to substantiate my opinion on levodopa and its negative perception here (at least in the states). Yes, it is still addictive and causes unwanted movements, but it is not inherent to the drug itself but to the oral delivery route. All I ever see written is how levodopa is only efficacious for five years and that it fails due to progression. Where are the studies supporting this?

We each metabolize levodopa differently depending on:

-gastric emptying latencies
-body weight
-genetic responses to medicines
-erratic blood plasma levels
-how drugs alter our brain structure and other neurotransmitters, hormones,etc.

The blood plasma levels are the key player in on/off. If you find that you need to take more meds than your peers, it could simply be your metabolism to the drug. Still, doctors and other PWP will act as if you are at death's door. I still have the same clinical benefit from levodopa that I did four years ago despite taking on another symptom. I choose to overlap my doses to stay "on" as much as I can.

Some key findings. Note they are all European. Wonder why that is? Wonder where the studies are for the claims it is all due to disease progression?



“On-Off” Phenomena Related to High Plasma Levodopa.

Blind evaluations of transient attacks of dysphonia revealed an association between episodes of neurological deterioration and exceptionally high plasma concentrations of levodopa shortly after ingestion. These results indicate that “on-off” phenomena can be toxic reactions to levodopa rather than deteriorations due to inadequate intake or absorption of the drug.

Levodopa peripheral pharmacokinetics and duration of motor response in Parkinson's disease.


Wearing off occurred when the plasma levodopa level had fallen to approximately 50% of peak concentration, irrespective of the duration of the motor response. Whilst the amplitude of motor response to levodopa is likely to be modified by alternations in dopamine receptor stimulation and sensitivity as the disease progresses, it is proposed that the duration of response is primarily determined by levodopa peripheral pharmacokinetics rather than by central pharmacodynamic factors associated with dopamine storage capacity.


Clinical and pharmacokinetic comparison of oral and duodenal delivery of levodopa/carbidopa in patients with Parkinson's disease with a fluctuating response to levodopa.[/b]

There was a threshold plasma concentration of levodopa associated with the "switch on or off" effect. In addition, rapid attainment of this critical plasma concentration was associated with a quicker onset of action and a more prolonged clinical response.

Just food for thought.

Laura

[lurkingforacure]

Originally Posted by Conductor71

I have been searching for studies to substantiate my opinion on levodopa and its negative perception here (at least in the states). Yes, it is still addictive and causes unwanted movements, but it is not inherent to the drug itself but to the oral delivery route. All I ever see written is how levodopa is only efficacious for five years and that it fails due to progression. Where are the studies supporting this?

We each metabolize levodopa differently depending on:

-gastric emptying latencies
-body weight
-genetic responses to medicines
-erratic blood plasma levels
-how drugs alter our brain structure and other neurotransmitters, hormones,etc.

The blood plasma levels are the key player in on/off. If you find that you need to take more meds than your peers, it could simply be your metabolism to the drug. Still, doctors and other PWP will act as if you are at death's door. I still have the same clinical benefit from levodopa that I did four years ago despite taking on another symptom. I choose to overlap my doses to stay "on" as much as I can.

Some key findings. Note they are all European. Wonder why that is? Wonder where the studies are for the claims it is all due to disease progression?



“On-Off” Phenomena Related to High Plasma Levodopa.

Blind evaluations of transient attacks of dysphonia revealed an association between episodes of neurological deterioration and exceptionally high plasma concentrations of levodopa shortly after ingestion. These results indicate that “on-off” phenomena can be toxic reactions to levodopa rather than deteriorations due to inadequate intake or absorption of the drug.

Levodopa peripheral pharmacokinetics and duration of motor response in Parkinson's disease.


Wearing off occurred when the plasma levodopa level had fallen to approximately 50% of peak concentration, irrespective of the duration of the motor response. Whilst the amplitude of motor response to levodopa is likely to be modified by alternations in dopamine receptor stimulation and sensitivity as the disease progresses, it is proposed that the duration of response is primarily determined by levodopa peripheral pharmacokinetics rather than by central pharmacodynamic factors associated with dopamine storage capacity.


Clinical and pharmacokinetic comparison of oral and duodenal delivery of levodopa/carbidopa in patients with Parkinson's disease with a fluctuating response to levodopa.[/b]

There was a threshold plasma concentration of levodopa associated with the "switch on or off" effect. In addition, rapid attainment of this critical plasma concentration was associated with a quicker onset of action and a more prolonged clinical response.

Just food for thought.

Laura

This makes me wonder what we would see if there were another delivery means for levodopa....we were told a few years ago that "someone" was working on a patch for levodopa but the problem was that it was burning the skin and they were trying to resolve that.

We have also joked here, and at our doc's office, about snorting levodopa, that would sure hit fast, and you wouldn't have to worry about toxic levels in the blood. But, it may have the same problem with burning the skin in the nasal passages...and we are too scared to try! How much would one whiff? And how long would it last? I've never read of anyone trying this but if anyone has, please step up and let us know.

[moondaughter]

I'm going to ferment some fava juice.....

[soccertese]

even though some of the info in these older articles might be out of date, i find them informative.
http://www.parkinsons-information-ex...ve/neuro4.html

[Conductor71]

Originally Posted by soccertese

even though some of the info in these older articles might be out of date, i find them informative.
http://www.parkinsons-information-ex...ve/neuro4.html

Thanks for this. I am finding particularly with our options, new is not always better.

Laura

[soccertese]

i think of getting l-dopa into your brain like chinese checkers, you have to saturate all the body's supply of the active dopa Decarboxylase as quickly as possible so l-dopa can get to the bbb asap so i wonder how much of the equation is also balancing carbidopa?

http://en.wikipedia.org/wiki/Carbidopa

how quickly do cells produce more Decarboxylase as the enzyme becomes more inactivated in the presence of more l-dopa? does the system "overshoot" with wild fluctuations of carbidopa/levadopa?

[johnt]

Regarding alternative delivery methods, see the thread:
"DIY easy high dose anti-oxidant therapy" started by moondaughter,
http://neurotalk.psychcentral.com/thread165607.html

Moondaughter provides a link to a video which shows how to create tiny liquid droplets with an oil skin (liposomal encapsulation) using an ultrasonic cleaner (cost about $30). These can get things across the BBB that would normally be blocked.

In the thread, I describe my experiences with dopamine (or, rather, my proxy for it: banana): some benefits, but the lack of a pure dopamine source meant that I had to take large quantities of the liposomal preparation, leading to feeling nauseous, and the worry that toxins in the banana would get through the BBB.

Pure levodopa should be possible to encapsualate.

It would probably be undesirable to encapsulate carbidopa. This is because its property of reducing the conversion of levodopa to dopamine, is only desirable outside of the brain. Inside the brain, we want the levodopa to convert to dopamine. Thus, we require that the carbidopa does not get into the brain. This is the case, ordinarily, because it cannot cross the BBB.

John

[ol'cs]

I believe that early dopa therapy is correct for SOME of us but perhaps not others. After all, pd is a "continuum" of symptoms, according to which particular brain structures are "affected"
After 15 years from dx, this particular "case" of pd receives still the best amelioration from pd with dopa. Sure, precipitous offs. Happen, as well as troublesome dyskinesia, and dystonic manifestations, which I attribute to the drugs. However, in this case anyway, I would be non functional without dopa.

He

Originally Posted by Conductor71

I have been searching for studies to substantiate my opinion on levodopa and its negative perception here (at least in the states). Yes, it is still addictive and causes unwanted movements, but it is not inherent to the drug itself but to the oral delivery route. All I ever see written is how levodopa is only efficacious for five years and that it fails due to progression. Where are the studies supporting this?

We each metabolize levodopa differently depending on:

-gastric emptying latencies
-body weight
-genetic responses to medicines
-erratic blood plasma levels
-how drugs alter our brain structure and other neurotransmitters, hormones,etc.

The blood plasma levels are the key player in on/off. If you find that you need to take more meds than your peers, it could simply be your metabolism to the drug. Still, doctors and other PWP will act as if you are at death's door. I still have the same clinical benefit from levodopa that I did four years ago despite taking on another symptom. I choose to overlap my doses to stay "on" as much as I can.

Some key findings. Note they are all European. Wonder why that is? Wonder where the studies are for the claims it is all due to disease progression?



“On-Off” Phenomena Related to High Plasma Levodopa.

Blind evaluations of transient attacks of dysphonia revealed an association between episodes of neurological deterioration and exceptionally high plasma concentrations of levodopa shortly after ingestion. These results indicate that “on-off” phenomena can be toxic reactions to levodopa rather than deteriorations due to inadequate intake or absorption of the drug.

Levodopa peripheral pharmacokinetics and duration of motor response in Parkinson's disease.


Wearing off occurred when the plasma levodopa level had fallen to approximately 50% of peak concentration, irrespective of the duration of the motor response. Whilst the amplitude of motor response to levodopa is likely to be modified by alternations in dopamine receptor stimulation and sensitivity as the disease progresses, it is proposed that the duration of response is primarily determined by levodopa peripheral pharmacokinetics rather than by central pharmacodynamic factors associated with dopamine storage capacity.


Clinical and pharmacokinetic comparison of oral and duodenal delivery of levodopa/carbidopa in patients with Parkinson's disease with a fluctuating response to levodopa.[/b]

There was a threshold plasma concentration of levodopa associated with the "switch on or off" effect. In addition, rapid attainment of this critical plasma concentration was associated with a quicker onset of action and a more prolonged clinical response.

Just food for thought.

Laura

[Conductor71]

Oh, I quite agree. I am grateful every moment for Sinemet. I was looking at the bigger picture. It seems that every description I read about PD treatment says or implies that Levodopa stops working or you always end with horrid dyskinesia while on mega doses of Sinemet. Where is the data? We hear how meds lose efficacy due to disease progression; well I am sure that plays a part there are in fact no studies that show this and in fact autopsies all but prove there is no correlation between amount of med taken and severity or progression of PD, yet there is a pervasive fear in drug naive PWP that is perpetuated by neuros who treat them. Clinically, a paper has been published on neuros who levodopa phobic and find every excuse not to prescribe.

I am saying it is troubling that many doctors do not bother to know their own corpus of lit better; worse, if they do, they let these misperceptions unchecked. Seems if patients were better informed they might experience less anxiety and stress on coping with this disease; and really it is vital to consider this sort of stuff before opting in for DBS.

Just my 2 cents!

Laura