Parkinson's Movement
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Dyskinesia: Lessons from Africa

I have posted this as there are many voices against medication on here but many of us see meds as a life saver despite the problems. It's primary purpose is not to convince those who are convinced meds are bad. It's more to support those who are taking them and to give some reasons why they have made a good decision.

During the past decade, a number of large drug trials suggested that beginning levodopa therapy should be delayed to reduce the risk of motor complications in patients with Parkinson's disease. But is the cause the length of time exposed to levadopa? This research result is interesting.

Over 4 years researwches investigated a large group of patients with Parkinson's disease in a sub-Saharan African country (Ghana), where access to medication is limited and begining levodopa therapy often happens many years after onset. They were investigating whether motor complications (dyskinesia) is primarily related to the length of time on levodopa or to other disease-related factors.

Two groups were compared, one in Italy and one inGhana. Although levodopa was introduced later in Ghana the length of time from having Parkinson disease to motor fluctuations and dyskinesias was similar in the two populations.

The results show that motor fluctuations and dyskinesias are not associated with the length of time on levodopa therapy, but rather with longer disease duration and higher levodopa daily dose. Hence, the practice to withhold levodopa therapy with the objective of delaying the occurrence of motor complications is not justified.

ncbi.nlm.nih.gov/pmc/articl...

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Hikoi, The greatest concern is NOT levadopa, but it's most common companion/s which is/are a couple of the most commonly prescribed DOPA decarboxylase inhibitors (DDCIs) Carbidopa/Benserazide (prescribed mainly to counter effects of nausea from levadopa therapies and for modest enhancement of LD bioavailability).

"Both drugs irreversibly bind to and permanently deactivate pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, and PLP-dependent enzymes. PLP is required for the function of over 300 enzymes and proteins. Virtually every major system in the body is impacted directly or indirectly by PLP. The administration of carbidopa and benserazide potentially induces a nutritional catastrophe."

"During the first 15 years of prescribing L-dopa, a decreasing Parkinson's disease death rate was observed. Then, in 1976, 1 year after US Food and Drug Administration approved the original L-dopa/carbidopa combination drug [Sinemet®], the Parkinson's disease death rate started increasing. This trend has continued to the present, for 38 years and counting.” PubMed, Oct2014: ncbi.nlm.nih.gov/pubmed/253...

Hence, a rational person's reluctance to imbibe is justified (at least until a credible study contradicting these dire findings emerges).

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interesting: "Carbidopa is postulated to contribute to the increasing Parkinson's disease death rate and to the classification of Parkinson's as a progressive neurodegenerative disease. It may contribute to L-dopa tachyphylaxis." tachy - rapidly diminishing response to successive doses of a drug, rendering it less effective. The effect is common with drugs acting on the nervous system.

It reads to me that without carbidopa, Parkinson's would not be progressive!

My neuro counters with the statement that the progression of the disease requires higher doses and not that the med is less effective.

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Whacky

I get that but I do have still unanswered questions.

The research papers I have seen to date are written by Hinz or his colleagues. Hinz has a vested interest in this as he sells the treatment that fixes the problem that he has identified.

His interpretation could not yet be called fact could it? It is his theory. He writes Carbidopa is postulated to contribute to the increasing Parkinson's disease death rate .... Postulated is not proven, who else in the scientific research world agrees with his theory about carbidopa?

Another question about the apparently increasing death rate that is used as proof of the dangers of carbidopa. where it says the death rate it is actually only reporting on the death rate in the USA. So is this a problem everywhere?? NO no, in fact quite the opposite. In a similar time frame the death rate apparently decreased in Other countries. Here are a couple of papers on it.

Trends in mortality from Alzheimer’s disease, Parkinson’s disease and dementia, England and Wales, 1979–2004 concludes that

"Mortality rates of Parkinsons Disease declined by 22 per cent for males and 32 per cent for females!"

webarchive.nationalarchives...

Another report in 2009 titled Does Parkinson’s disease increase mortality? was based on two studies from the UK and four trials from Western Europe. It concluded

"The survival of PD patients is similar to the normal population during the first decade after presentation. This is followed by ‘a modest rise’ beyond 10 years. ‘Even with very long-standing dis- ease and follow-up over more than 20 years there is only a moderate ... increase in mortality .....‘This is reassuring and suggests that current standards of best medical management of PD have indeed significantly improved survival compared with the prelevodopa era.’ "

onlinelibrary.wiley.com/sto...

So what is the cause of the increase in Parkinson deaths in the US but not elsewhere?

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Thanks for going to the trouble of doing this research and I agree - Hinz is the source of these allegations and he is not impartial in this matter. He is also not an impartial source for the effectiveness of his treatment, which must be custom tailored to each patient and is not easy.

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My interpretation of: "We conclude that motor fluctuations and dyskinesias are not associated with the duration of levodopa therapy, but rather with longer disease duration and higher levodopa daily dose. Hence, the practice to withhold levodopa therapy with the objective of delaying the occurrence of motor complications is not justified."

Interpretation - I conclude that motor fluctuations and dyskinesias are associated with the longer disease duration and higher levodopa daily dose. Hence, the practice to withhold levodopa therapy with the objective of delaying the occurrence of motor complications is justified.

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Roy I think it's a bit dangerous to use my personal write up of the findings to decide what the paper proves. We all interpret words to fit our particular world view but I don't see how you can really claim that this research supports holding off treatment when it does the exact opposite.

What it does suggest is that holding off treatment does not delay dyskinesia. They found that people who started treatment late got dyskinesia in 6 months rather than maybe 5 or six years. That is if they were going to get it. Not everyone does.

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Roy,

I've read your interpretation several times, but I still can't figure out how you came to that interpretation. Surely the main reason someone would be on a "higher levodopa daily dose" is exactly because they are in the situation of having a "longer disease duration".

Or do you believe that the reason someone would need a higher daily dose over time is because the levodopa doses become less effective over time (tachyphylaxis)? I think that most movement-disorder-specialist neurologists would argue that the reason someone would need a higher daily dose over time is simply because the disease has progressed.

Can you share with us how you arrived at your interpretation?

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Thanks so much for this, Hikoi. This is really important news and will save patients a lot of suffering if it is heeded. I was always suspicious of the levodopa causes intolerance theory. I the dopamine agonist makers had a vested interest in promoting this idea and pharmas are not above using the scientific literature to promote their interests.

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The problem with your suspicions of the 'levodopa causes intolerance' theory is that you - again - continue to ignore the problems posed by its constant companion (since 1999) - the DOPA decarboxylase inhibitors (DDCIs) Carbidopa and Benserazide.

"Concomitant L-dopa/carbidopa preparations have been positioned by the manufacturers to permeate treatment to the point that prescription L-dopa as a single ingredient is no longer available (Table 1). Prior to 1999, three pharmaceutical companies distributed a US FDA-approved brand name prescription forms of L-dopa as a single-ingredient drug: Bendopa® (Valent Pharm Intl); Dopar® (Shire plc, St Helier, Jersey); and Larodopa® (Hoffman-La Roche Ltd, Basel, Switzerland). There is no public documentation explaining the reasoning behind the virtually simultaneous discontinuation of these drugs by the three companies.

"When these drugs were approved, each was described as a decarboxylase inhibitor. Documentation submitted in 1997 noted significant central and peripheral PLP depletion after limited ingestion time of carbidopa. Now the full mechanism of action of PLP is known, giving rise to more serious concerns." ncbi.nlm.nih.gov/pmc/articl...

Of course, if you're simply looking for reason to be content with your favorite LD/DDCI combo, you should ignore all of this.

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IF you want L-dopa only you could just take mucuna or other L-dopa supplements available in the marketplace that do not contain carbidopa

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NO - it is YOU who are ignoring Hikoi's point that Hinz and associates are the only ones making this claim. Show me something from an unaffiliated researcher.

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Bear, If I thought you'd actually read it, I might refer you to the link I already provided you and suggest you actually glance at it. The full report (not just a selected snippet) is referenced with numerous studies conducted in recent years - both affiliated and unaffiliated - supporting the conclusions made.

There has yet to appear anything contradicting the havoc wreaked by the binding to/deactivation of the all-important pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, and PLP-dependent enzymes by the routinely prescribed DOPA decarboxylase inhibitors (Carbidopa, Benserazide).

The modest, short term benefits conferred by this drug (if any) in return for long term costs to one's total physiology is a trade I personally feel better not making. You however appear to remain in a state of bliss with your combo therapies so, as already suggested, you should just ignore all this and run with your choices.

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Whacky I have read it.

This isn't about modest short term benefits, it is about long term quality of life for me.

As to the studies I wonder how many are done in Hinz own labs? There are mice and rat studies which are not conclusive for humans. I will look again later.

The effect of using carbidopa beserizide on the body is one matter which studies may well support but they may disagree on degree and long term effects , it is rather technical for me so I find them difficult to read.

The conclusions Heinz makes especially connecting carbidopa use to an increased death rate is another. I haven't seen any other report that agrees with this r that advises stopping carbidopa/benserazide.

Among sufferers of PD are scientists, chemists etc. I haven't heard of people with PD who understand all this refusing sinimet.

I am open to knowledge and interested in this but nothing so far has give me confidence in Heinz conclusions.

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Still waiting for you to post a link to one of these alleged unaffiliated studies supporting Hinz's conclusions.

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Hi

have you ever take a look to this :

2016. Do we need a new levodopa? ncbi.nlm.nih.gov/pubmed/273...

Please. let me know what do you think about.

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As someone who suffered month long disability due to dysregulation of the postural blood pressure regulation system as a result of taking 15 days of a low dose Dopamine Agonist ("DA"), I can tell you that DAs are NOT the solution.

"Comparison of various L-dopa/DDI dosages against placebo therapy found a significant lower nigrostriatal radiotracer enrichment as marker for PD progression in the 600 mg L-dopa/carbidopa daily dose arm after nine months compared with placebo (Fahn, 2006). This outcome indicates that neuronal death promoting effects of L-dopa/carbidopa particularly appear after higher L-dopa dosing, when probability of nutritional deficiency and antioxidant depletion goes up."

-so it may be that lower doses of levodopa are not so prone to causing the sort of problem set forth in the article.

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"The previous literature documents this increasing death rate, but no hypothesis has been offered concerning this trend. Carbidopa is postulated to contribute to the increasing Parkinson's disease death rate and to the classification of Parkinson's as a progressive neurodegenerative disease"

postulated: suggest or assume the existence, fact, or truth of (something) as a basis for reasoning, discussion, or belief.

This is a paper written to start a discussion about the possibility that Carbidopa is the cause for an increased death rate of PWP. This is NOT a study and to use it for a reason to not take Meds is very suspect.

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I totally agree. After I was diagnosed I met a man maybe 38 at least 15 years my junior in lowes hardware. I should say I approached him. He was shaking so badly he could barely hold himself still. I asked him if he had pd. He said yes. I asked him what he was on. He said nothing. His dr didn't want him to become immune. I looked at him and wanted to cry. He said I can't even button my shirt. He told me he couldn't work cus he was a computer specialist. I said to him what about quality of life. He agreed. I immediately gave him my dr name as I was still working and completely understood his circumstances. I have never had any tremors but I had many other symptoms and without the Meds I would not have been able to work the next 5 years. I had to stop as I was taking Meds every 2 hours and couldn't function anymore enough to work. That was 2 years ago and I am still awaiting disability.

If you had diabetes would you not take or delay insulin? That is the only way I've been able to justify taking 8-10 doses of sinnemet a day. Good luck to all. I personally would rather have 10 years of quality of life. Which I have to say I have passed now and am having unbearable gi problems which none of my Drs can help me with.

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PD dries out the GI tract from one end to the other. For the dry mouth I take Cevimeline. To prevent constipation I take docusate, an over the counter stool softener.

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I'm familiar with the data. However, each of us is different. My understanding is that medications for PD are used to alleviate specific symptoms, not for addressing addressing a specific cure for which there is no medication yet. If the medication does not take care of your cure or your symptoms it is best 2 work on either tolerating what symptoms you have or behaviors such as exercise or Diet see if that helps. There is no Stigma for person taking medication that makes their life smoothie and happier.

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ditto:"If the medication does not take care of your cure or your symptoms it is best 2 work on either tolerating what symptoms you have..."

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Thank you for posting this. When I think of the shape I was in before starting Carbidopa levodopa the change is quite dramatic. My Parkinson's manifested with gait and balance problems and lots of pain. I could not walk any distance without great effort and now I do 5 mile hikes with a thousand foot elevation gains. I regularly ride my bike at least 10 miles. The best outcomes I have seen are when people use the meds judiciously and go in big for exercise. I would be sunk without the meds.

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Enodah,. You are doing great. That is what the medications were meant for to enable this to do the activities so necessary for daily life.

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I agree with you. and live the same way.

This seems to be a haven for anti drug PWP. Which is okay they have their right of opinion. When i first started on this site i was blasted for suggesting that meds were a good thing. so hard i stopped posting. So now i just post and let it be.

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My neurologist has recently told me that a study done 18 months ago indicated that the synapses die if they do not receive enough dopamine. He wants me to take sinamet so my synapses are 'bathed in dopamine'.

I will ask him for a reference to the study next time we meet.

This fits with why smokers have such a lower rate of PD.

I did take it for a few days and it was wonderful, but I have stopped while I follow up my integrative GP's findings that my copper level is 150 times higher than it should be. Here's hoping that's the answer to all my neurological problems!

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Diagnosed 8.30.2010, age 59, had symptoms for several years before. Finally got the right medication and dose that works for me. I've been taking 25/100 carb/levo oral dissolving tablets for 3-4 years now. Back then 1 1/2 tablets 4 X per day was all I needed to function. I'm up to 18-19 tabs per day and wearing off up to an hour before my next dose.

We are all different in our response to meds. If we can cut back on our meds without sacrificing our quality of life, is something most of us would like to do.

At 18-19 tabs per day my dyskenesia is very apparent. There have been days where my pill count is 12-13. Dyskenesia on these days is greatly diminished to almost non-existent. Was I over medicated at 18-19 pills per day? Yes I would say so. Will I be able to function at 12 pills per day or less, only time will tell.

I am taking Tasigna, 200 mg, once daily. Today is day 90 on Tasigna. My doctors have stated four months on medication needed before one sees results. I will post my results sometime after October 1.

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That long-term use of C/L does not induce dyskinesia, but that increasing the doses does.

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