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

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

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

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