LEVODOPA VERDICT: Start Early/Late = Same Outcomes

[PDConscience]

"Doctors often delay prescribing levodopa, or L-dopa, to Parkinson's patients for fear that the drug might have toxic effects that produce jerky involuntary body movements over time.

"But patients started on L-dopa nearly a year earlier than a second group did not develop significantly different rates of involuntary movement, results from the new trial show.

"'The current study bolsters our confidence that levodopa is safe even in early Parkinson's disease and that patients should not fear it,' said Dr. Michael Okun.

"There's disappointment here as well. While levodopa isn't toxic, it also doesn't appear to provide any protection against progression of Parkinson's in the brain, said Dr. Susan Bressman.

"'The theory is if you get those extra 40 weeks of exposure to levodopa and it's neuroprotective, the earlier group will be in a better place and the late group will never catch up,' Bressman said. 'They'll always be a little worse because the first group got more of this neuroprotective effect.'

"But both groups wound up in the same place by week 80 of the trial, with essentially the same rate of disease progression, the Dutch researchers found. The drug didn't provide people in the earlier group any extra protection.

"At the same time, neither group suffered greater rates of jerky movements or levodopa-related fluctuations in motor response, discounting concerns over toxic effects."

Article: usnews.com/news/health-news...

[park_bear]

A very important study. Link here:

nejm.org/doi/full/10.1056/N...

" this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect. "

[Hikoi in reply to park_bear]

Yes, the study found this too just as PD conscience wrote. But the important thing i think is that delaying meds does not delay side effects as many here have found and I have witnessed.

[condor39]

This is really important, and should be required reading

[Astra7]

Thank you. I have been wanting to clarify this for years as some people are so adamant we should delay meds I feel almost guilty when I take them.

Despite this and the Ghana study a lot of people and organisations say the opposite without any evidence.

[Hikoi in reply to Astra7]

Even though the guru himself (Dr Stanley Fahn) says delaying meds is not necessary we people and organisations keep spreading the myth that we only can use meds for a few years before they stop working. I guess its going to take many years to change that thinking.

[Tribselyov]

But.... I think being asked to take a medicine three times a day as opposed to no meds, if offering no impact on the natural history of the disease... adds to the psychological impact of a disease and leads to psycho-medical dependency. A preferred regimen: self-dependency with emphasis on aggressive exercise, which does alter the impact of PD.

[Hikoi in reply to Tribselyov]

Psycho medical dependance

I sort of understand but don't think dependency is a choice. If its not medicine dependance it seems to be dependance on carers which is a huge burden. and they burn out. Would you say a diabetics who uses insulin should avoid because it is Psycho medical dependance? - I wonder how else you or I would you address my shortness of breath which happens when my dopamine is low? It's not that easy I don't think. Exercise is good but many people me included need meds to exercise and no matter what not everyone will find it has an impact on their PD and if it does for how long?

[Tribselyov in reply to Hikoi]

I fear misunderstanding. The study (and my comments) relate to early stage disease: the go-go stage. At that time, exercise should be given higher priority than meds. I can help myself. Later on, we are more medication dependent which is accompanied by more psychological dependency. Let’s delay both and get our endorphin response this Sunday morning.

Delayed hope makes the heart grow sick! (From Mishlei)

[park_bear in reply to Tribselyov]

Taking meds or supplements at certain times very quickly becomes routine. I take these substances because they make an obvious difference that allows me to engage in a vigorous exercise program. The idea that there is some kind of "psychological dependence" is mythical thinking.

[Hikoi in reply to Tribselyov]

rcpe.ac.uk/sites/default/fi...

As an aside, just read this. See third to last paragraph. So much we dont know!

PS its Monday here alrady lol

[Astra7 in reply to Tribselyov]

I agree. I went to an integrative GP when first diagnosed and she had me taking about 15 things. In the end I stopped seeing her and whittled it down to a few as my life was just becoming a constant timing and taking of things at specific times etc. Now I take meds to help me work and play tennis and am not as obsessed with checking every health fluctuation and trying to work out what caused it. In other words I just try to get on with life with it being in the background not the forefront of life.

[JerMan22]

I exercise a lot. Wouldn't be able to without my LD/CD. Know that for a fact.

[Kwinholt]

I second that !! Same for me as it is for jerMan22. And know that for a fact too........ Karen

[Gioc]

we know this from 2014 that thanks to this Italian study in part, (certainly financed also with the tax money of my region, Lombardia IT).

parkinson.it/farmaci/non-va...

academic.oup.com/brain/arti...

But where's the good news? . Knowing that levodopa, sooner or later, will stop working does not make me happy. My neurologist's advice was to take levodopa without any delay, but I often hear differently here in Italy. There is not a homogeneous modus operandi in spite of the researches, so how can I confidently listen to everything that is said by the authoritative sources on whose door there is written "We are science, the only possible truth", and have conflicting opinions between them? At a television program in which a theologian priest declared that the extraterrestrials do not exist. Rubbia, the Nobel Prize winner for physics, was invited, perhaps with the idea that he would scientifically confirm this thesis. Suppressingly he said "we do not know, but it is very likely that they exist given the greatness of the universe". This example to say that if science slips into a truth based on the authority of its most important members it will close the door to innovation and will increasingly resemble the field of art criticism; which is a useless thing.

When researcher makes a discovery in the field of brain it is good to compare it to the complexity of cellular and brain life that is enormously complex like the universe and go humbly forward without closing any door with the consideration that we already know everything.

[Hikoi in reply to Gioc]

GioCas

Does levadopa really stop working or does our body loose the ability to use it ? Splitting hairs maybe, but i guess the former feeds into people thinking delaying will give them a better chance to use levadopa longer in the disease though the research is showing that isnt true, see your second link.

We certainly dont know everything just as our drs dont but accepting some ‘truths’ wont mean we do know it all I guess.

[Tribselyov in reply to Hikoi]

Hikoi,

I like the concept that we have a lessened reserve of dopamine.. which is further attenuated by exogenous supply.... but that is just my working model

[Hikoi in reply to Tribselyov]

Yes I thought that was a useful explanation too. I wonder if its correct, perhaps ‘Science of PD’ will know or at least have an opinion.

But we need a certain amount of nerones to get or convert dopamine from ldopa dont we? As we get less and less neurons we can tolerate less and less l dopa ....?

[WinnieThePoo in reply to Hikoi]

Why are any neurones required to convert levadopa to dopamine? The enzyme decarboxylase is required.

[Hikoi in reply to WinnieThePoo]

I am no scientist and bow to your knowledge. All i know is we need dopamine neurons to produce dopamine. How that happens I read and forget. Please explain to me what dopamine neurons do?

[WinnieThePoo in reply to Hikoi]

I'm no expert either. But fairly confident on this one. Dopamine neurons do indeed produce dopamine - neat. But dopamine can be made by enzymes like decarboxylase from levadopa. This is why Sinemet was a breakthrough. Dopamine itself can't pass the blood brain barrier, so putting dopamine into the blood stream doesn't help deliver it to the part of the brain its needed in. Levadopa CAN pass the blood brain barrier, and then, in the brain be converted to dopamine. BUT, it is naturally converted to dopamine before it gets to the brain. If you ingest only levadopa (like Macuna Pruriens followers) most of the levadopa is converted to waste dopamine in the gut and that dopamine in the blood stream can't get to the brain. Either you have to ingest huge quantities of levadopa, which tends to make you vomit, or you also ingest carbodopa (which doesn't cross the blood brain barrier) which suppresses the enzyme from converting levadopa to dopamine in the main body, and leaves more levadopa free to cross into the brain and be converted to dopamine there - where it can do its job. So less levadopa for the same effect with carbidopa - less vomiting. Hence the name Sinemet - latin for "without chucking up"

The ingested levadopa, converted to dopamine in the brain is added to the naturally produced dopamine (by those neurons).

Now, straying into pure personal speculation, I wonder if the "wearing off" issue, is that dopamine neurons do not just randomly produce buckets of the stuff - they produce it in response to demand / need. So does there come a point where the replacement therapy has too much random dopamine slopping around, which overwhelms the "on demand" stuff produced by the neurons, and leads to diskinesias, tremors and other problems? The problems with early stem cell graft experiments in humans, (20 years ago?) seem to fit that model. As do the concerns of the Japanese stem cell team. The stem cell neurons produce dopamine, but not in a responsive way like native dopamine neurons do. They just deliver a big slop of the stuff directly where it is needed, without all the ingestion / digestion issues.

Sorry, longer than I meant it to be

(Thats why the GDNF trials at Bristol look more hopeful of a proper cure to my eyes)

[Hikoi in reply to WinnieThePoo]

Thank you, I like that you have wrnitten it clearly and in straight forward language! i have copied so I can refer to it as I need too.

[Gioc in reply to Hikoi]

Hikoi

Precisely, but if we examine the history of research and discovery we see that things go another way. We have a major conflict of interests between the status quo and innovation with obvious disproportion of forces in the field towards the status quo. This does not facilitate progress. Few people, no more than 20, have pushed technology, in the history of men with their research, to the point where we are, often opposed to the point of paying with life. Not to mention the humanistic field. So it would be civilized that the research be protected from this "conflict of interests" between those who have an interest that things remain as they are and those who innovate with a discovery.

[Hikoi in reply to Gioc]

I think the status quo evolves and changes over time. As an example:

The knowledge that levadopa doesnt stop working so much as the person cant use it effectively is quite new knowledge that challenges current thinking ie the status quo. This new knowledge challenges thinking until it is accepted and eventually it will become the status quo. This is the way of scientific advancement.

[Gioc in reply to Hikoi]

unfortunately or fortunately there is always a WHO with intention and ability that takes care of making things progress. Sometimes good innovation imposes itself on the status quo sometimes not, but it is always the people who cause the events. Sometimes knowledge is lost simply because it is not evaluated or put into relation with other data, see here on HU how many promising research is presented and to which it is not continued with an experimentation on man in order to establish their validity. It would seem a system to protect some interest. "Accepting" some scientifically proven results seems to me more like a verb inherent to an individual state of mind than to real science whose results are invariable beyond emotions that should not influence scientific progress.

[Hikoi in reply to Gioc]

Yes I agree with most of what you write in the first part at least. I’m not into conspiracy theories and I havent noticed the many promising research ideas suggested here on HU.

[StayPosEvryDay]

I can only speak from my personal experience. Diagnosed at age 61. At this time working as business adviser also endurance athlete (trail running, cross country skiing, biking). Now, age 72, I am still working as a business adviser and limit exercise to 1/2 to 2 hours per day - same activities with more hiking and less trail running, Started Carb/Levo 3 X day at age 62. Now take 1 C/L 25/100 and 1 C/L ER 25/100 7 X or 8 X times per day. Prior to exercise that includes interval training I take 1 extra C/L during exercise period. Also vape high grade medical marijuana, Sativa strain, prior to exercise period. Believe that marijuana is metabolized with oxygen at cellular level and delivered to cannabinoid receptors in a way that helps with Parkinson symptoms (for me - severe right hand/arm tremor). Plus, the "high" from the THC gets you in the zone for a more enjoyable workout and connects you more to Nature. After my workout I can go up to 4-5 hours without C/L and C/L ER. I know other endurance athletes without Parkinson's who train with a touch of cannabis. I only use it before exercise and not every day. The only change that I have experienced with 10 years of C/L is the onset of dystonia affecting my feet about 3 years ago when I wake up in the middle of the night. If I can't relieve it through relaxation techniques I chew a C/L followed by some water. The only dyskinesia related issue that I experience is a pronounced right arm swing when walking. I am sharing my personal experience because I opted for a C/L regimen that would allow me to pursue my life on my terms despite the warnings of dyskinesia down the road. As many others have commented - exercise is probably the most important thing you can do plus a healthy diet. Also, keep your connection to he natural world and your appreciation for life, relationships and don't open the door to negative thinking. Stay in the now today and look forward to tomorrow.

[PDGal4]

I fourth (or fifth, I’ve lost count) that I could do zero exercise without C/L. My main symptom is slowness and stiffness, and I cannot sustain repetitive motion without medication. Like StayPosEvryDay, I’ve learned through experience that I need to take an extra half dose of C/L before exercising. No med marijuana available where I am (yet). I am somewhat heartened to read these studies that opting to take C/L early on is no worse dyskinesia-wise than not as I am starting to experience some dyskinesia and am happy not to have to second guess my med decision.

[Tribselyov]

Again, the Dutch study dealt with when to start meds in early disease. In late disease, we are more dopamine deficient and need exogenous supply.

[Hikoi in reply to Tribselyov]

Tribselyov,

I take you are not on medication yet. How will you decide it is time? Late disease is 15-20 plus years to me, complex 8-10 Early disease diagnosis to 5 years. Thats how I think of PD so I wouldnt be waiting until late disease for medication. Most people need it in the first couple of years in my observation.

[Tribselyov in reply to Hikoi]

I am on azilect daily.

I take one sinemet q am; for last year (now 6+ yrs with PD.).

Meds do not influence our course; just symptoms.

If I have evening function, I take another. I also take a second one at the tenth hole when playing golf.

Everyone has a different course; I would rather shuffle a bit rather than take meds.

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