In early PD, can changes to L-dopa dosage take 2 weeks to take full effect?
 

While "researching" for a post/comment over at HU, I came across some interesting text related to a levodopa/carbidopa product called Syndopa.

Here is part of what it said: "There are two types of responses seen with the administration of Syndopa Plus Tablet: The short-duration response which is related to the half-life of the drug. The long-duration response depends directly on the accumulation of effects over at least a two week course, during which ΔFosB accumulates in nigrostriatal neurons. When used in the treatment of Parkinson's disease, this response is seen only in early therapy, as at that stage the inability of the brain to store dopamine is not yet a concern."

This was of great interest to me because it explained something that I experienced recently. A couple of months ago my neuro increased my levodopa dose. For the next 2 or 3 weeks nothing happened, and then suddenly my tremor virtually disappeared, and has remained that way since then.

I was already aware of my ability to store dopamine for short periods of time. For example, when I wake up in the morning I have no tremor, even though it has been about 12 hours since my last dose of levodopa. But the "accumulation of effects over at least a two week course" was something that I had never heard of before.

I'm going to spend some time "researching" this further, starting with the protein ΔFosB. When I first saw it I thought it was a misprint, but when I googled it I found that it was real. And there is a lot of information about it, so it's probably going to take me a while to try to get on top of it.

Is anyone already familiar with all this, and if so, can you point me to an article/paper that explains it all?

I've done a search of neurotalk and found something potentially interesting [1], but it's not at the more introductory level that I'm hoping to start with.

Thanks.

[1] Impact of grafted serotonin and dopamine neurons on development of L-DOPA-induced dyskinesias in parkinsonian rats is determined by the extent of dopamine neuron degeneration, T Carlsson et al. Brain, Feb 2009.

jeffreyn,

Thank you. It's an interesting topic.

In my own reading, I have occasionally came across claims of a long term response to levodopa, but I never really bought into them. I have never, knowingly at least, experienced anything that couldn't be explained by the standard pharmacokinetic models, plus dopamine storage in vesicles.

I'm 13 years post diagnosis, and some 15 hours since my last dose, but I still experience good performance in the morning before taking my drugs. When I do get around to taking them, I will start by getting worse, especially my tremor, before they kick in, and the tremor is greatly reduced.

However, the case in favour of the long duration response certainly looks more persuasive when you actively seek out the case for it.

Unfortunately it's behind a paywall, but Anderson and Nutt have written about the long duration resonsponse to levodopa [1]:

"The antiparkinsonian response to levodopa is characterized by an immediate motor improvement lasting hours and a more sustained response lasting days. These two responses have been referred to as the short-duration response (SDR) and the long-duration response (LDR). The LDR represents a substantial component of the clinical effect of levodopa ..."

Unfortunately it's behind a paywall, but Nagao et al. write [2]:

"Over a mean treatment period of 16.6 ± 4.4 years, annual increase in motor disability was 2.3% of the maximum score. The long duration response composed 49% of total levodopa response during the first decade of treatment, and this proportion was significantly higher soon after commencing levodopa (p = 0.001). Higher pre-treatment motor score (r = 0.60) and lower MMSE (r = 0.60) were the main predictors of a larger long duration response. There was little correlation between long and short duration responses."

References:

[1] "The long-duration response to levodopa: Phenomenology, potential mechanisms and clinical implications"
Elise Anderson, John Nutt
Parkinsonism and Related Disorders, Sept 2011
https://www.prd-journal.com/article/...087-3/fulltext

[2] "Inferring the long duration response to levodopa in Parkinson’s disease"
Kanae Nagao et al.
Parkinsonism and Related Disorders, Sept 2018
Inferring the long duration response to levodopa in Parkinson’s disease - ScienceDirect

John

took me 3 months!
 

When I first began taking sinemet it was 3 months+ before I felt the whole impact- but then I had been symptomatic for 16+ years previous to taking an pd med- now 24+ years of sx cycling back and forth with the seasons.

My theory is its best to take minimum dose but not to the point of under medicating. With early onset it just seems important to resist flooding receptors- is this a flawed perspective? I used to start my first dose of the day at 7 AM but now can wait till 9-10 AM..also find that the last dose taken in late afternoon carrys me really well into the night

What is counter intuitive is that as the sinemet/mucuna become less effective smaller doses function as well or better as higher doses unless I go too long without keeping the med effect fairly continuous.

MD

homeostasis through adaptation
 

This discussion makes me wonder if the "premise" of "half-life" could be expanded to include the possibility that some absorption of levadopa can have a longer term life...and adapted into the endogenously functioning neurons... even if only for a while...

Can nutrient act to deficiency like a cast does to a broken bone??/


MD

A couple of references
 

I have found another reference that seems to provide support for a role for the ΔFosB protein in the levodopa LDR.

"These data suggest that the L-DOPA-induced ΔFosB-like proteins have ongoing transcriptional​ effects for more than 2 weeks after treatment discontinuation.​ Such effects may account, at least in part, for the long-lasting effects on ​brainfunction produced by L-DOPA treatment."

Time course of striatal ΔFosB-like immunoreactivity and prodynorphin mRNA levels after discontinuation of chronic dopaminomimetic treatment (2003):

[PDF] Time course of striatal DeltaFosB-like immunoreactivity and prodynorphin mRNA levels after discontinuation of chronic dopaminomimetic treatment. - Semantic Scholar

I've also found an open access "Author Version" of johnt's second reference (see above):

Inferring the long duration response to levodopa in Parkinson's disease - Open Access Repository

I remember reading an article some time ago about storage of levodopa in muscle tissue of pigs. Of course I can't find it now, but I did find this one on rats. It appears that levodopa is not rapidly decarboxylated in muscle so has a longer half life than in blood.

The effect of carbidopa on plasma and muscle levels of L-dopa, dopamine, and their metabolites following L-dopa administration to rats. - PubMed - NCBI