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Parkinson's Movement
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Improving the Bio-availability of Levodopa

This is a simplified version of my research into how L-Dopa is metabolised in humans and my current understanding of how its duration in the blood may be very significantly improved simply by drinking a glass of Grapefruit juice per day.

Earlier this month, I posted a detailed scientific article on the metabolism of L-Dopa and the possibility that Cytochrome P450 enzymes could be impacting the bio-availability of L-Dopa in the blood. The post generated quite a few replies and comments, but many of you said that you had difficulty in understanding the document. I agree that the subject is extremely complicated, with its own particular jargon, but due to the controversial nature of my conclusions, to be credible it also had to be detailed.

First, some background about who I am and how I came upon this idea. I am an experienced research scientist (chemistry/physics), now retired from a leading international research centre. I have published many scientific articles during my career but, importantly, never in this field. One year ago, when I was first diagnosed with Parkinson’s disease, I knew absolutely nothing about this subject. I put a lot of effort into learning about Parkinson’s disease, and after a few months I began to understand some aspects of the pharmacology and pharmacokinetics of drugs used to treat it.

In a subject as intensively documented as this, there are very few obvious gaps in the knowledge available to researchers. There are however, as in all scientific fields, areas where the accepted wisdom fails to stand up to detailed scrutiny. This is particularly true in a field which is not an exact science such as this. Being new to this field, I initially thought that I must have misunderstood something. However the more I looked into it, the more I became convinced that some aspects of the established wisdom did not add up. I felt the need to do more detailed research to try to find out what might be wrong. Since I am no longer employed by a recognised institution and have no experience or realistic credibility in this field, it was not my intention to publish articles on this subject. However, in the light of what I may have stumbled on, I feel it is important to share this with people with Parkinson’s disease.

Trying to prove an alternative to the established wisdom is a very big challenge. But in this case, if it turns out to be true, it could be very helpful for people with Parkinson’s disease. For a scientist who believes there really is a problem to be solved, it becomes an obsession. Paradoxically, being new to the subject is a great advantage for a research scientist. He is not boxed in by past experience of research that wasted time and effort and didn’t end well. So there are no areas he can’t go into. “You can think outside the box, because you don’t have one”. That’s why young scientists are often more creative than more experienced ones.

Good and bad enzyme inhibitors

My intuition led me to look into research on enzyme inhibitors and to focus on the most important system in drug metabolism, Cytochrome P450 enzymes. If the overlooked process in the metabolism of L-Dopa was indeed a CYP enzyme, I realised that I would have strayed outside the box. CYP enzymes are the killing fields for drug developers because they are the most important source of drug-drug interactions and a major issue for drug safety. But I was to discover an even more controversial issue. The only practical route to improve the bio-availability of Levodopa in the face of CYP enzymes would be to explore whether the source of the biggest safety issues in drug-food interactions, Grapefruit, could be transformed into a very positive benefit for people with Parkinson’s disease. This is a very uncomfortable place to be.

A summary of the research

It is recognised that Levodopa is strongly metabolised by two main enzymes, DDC and COMT. There are drugs available to inhibit these enzymes and are regularly prescribed. Even so, its bio-availability and half-life in the blood remains poor. I suspected that there might be a third enzyme that kicked in when the other two were blocked. If this were true, it would not take much effort for a specialised laboratory to identify it and propose a solution. So why was there no published research on this and no drug available to deal with it?

When I looked at the likely candidates for a hypothetical third enzyme, one clearly stood out and with it the reasons why big pharma will not touch it. It’s called CYP3A4 (sorry for the jargon). CYP3A4 is the most potent drug-degrading enzyme in the intestines and the liver. CYP enzymes are also the cause of drug-drug interactions that have very serious implications for drug safety. Any drug that unintentionally inhibits CYP enzymes, even though it may have been designed for something else, comes with a long list of safety warnings on drug-drug interactions that seriously limit its use. For drug-drug interactions to occur, you must take two drugs within a short time scale time, often for completely different conditions. One drug is “boosted” (I prefer to say “protected”) by the action of the other drug on the CYP enzyme.

Warnings relating to Drug-Drug Interactions

A significant number of drugs carry warnings against taking two apparently quite unrelated drugs simultaneously. These warnings relate to serious drug-drug interactions. Patients are not normally given any explanation for this, they are just told not to mix them!

In the vast majority of these cases, the link between the two drugs (let’s call them Drug A and Drug B), is in their opposing reaction to a very common enzyme, a protein called CYP3A4 whose role is to protect organs from toxins getting into the blood. Both of the drugs are chemically attracted to the same enzyme, usually in the intestine or the liver, so that the enzyme can degrade them into smaller non-toxic products, but as you will see, with two very different outcomes.

Drug A follows the normal process. It binds to the enzyme, is degraded by it and is finally released in a degraded state. The enzyme remains active and available to degrade other molecules of the same drug. As a result, less of the active drug gets into the bloodstream and that which does is progressively cleared from the blood by the liver. The drug dose is calculated to take this process into account and is much higher than if it were not degraded by the enzyme.

Drug B also binds to the enzyme and is partially degraded by it, but then the process takes a very different path. One component of the degraded Drug B is a chemically active species, and instead of being released, it reacts chemically with the enzyme and permanently deactivates it. The enzyme is said to be irreversibly inhibited. A new supply of enzyme protein must then be regenerated by the cells that express it and this can take many hours or days. During this post-inhibition period, if drug A is ingested, it will no longer be degraded to the same degree by the enzyme and very much more of it can get into the bloodstream where it will remain for a longer period. Consequently when Drug A is co-ingested with Drug B, the former is overdosed and this can have serious consequences.

The most serious interactions of this type occur when Drug A is rapidly metabolised by an enzyme and therefore has a very low bio-availability and when Drug B strongly inhibits the same enzyme. The pharmaceutical industry takes this very seriously and tries to avoid making drugs that can be involved in accidental drug-drug interactions by this process. In some cases however, two drugs are deliberately prescribed together so that by inhibiting a given enzyme, Drug B protects and improves the bio-availability of Drug A. In the treatment of Parkinson’s disease, the DDC enzyme inhibitor Carbidopa, is co-administered with Levodopa, and a COMT enzyme inhibitor is also available to improve the bio-availability of Levodopa.

What has this to do with Parkinson’s disease?

Even when the two important enzymes, DDC and COMT are inhibited, Levodopa still has a very low bio-availability and is rapidly eliminated from the bloodstream. This unexplained observation raises the question of whether a third enzyme takes up the task of degrading Levodopa and becomes dominant when the other two are inhibited. This opens up a clear research opportunity to identify the enzyme concerned and to find a solution to improve the low bio-availability of Levodopa for Parkinson’s disease patients.

The most potent enzymes that degrade more than 70% of all drugs are the Cytochrome P450 type. CYP3A4 is most active in the gut (70%) and the liver (30%). Here the % relates to the fraction of total CYP enzymes in each organ, bearing in mind that the liver has 100 times more CYP3A4 than the gut.

There is no direct experimental proof, but significant and credible indirect evidence, that CYP3A4 degrades Levodopa. This uncertainty concerning the interaction between Levodopa and CYP3A4 still needs to be clarified experimentally.

Why has this not been researched before? It surely has been investigated by the pharmaceutical industry, but not pursued because of the high risk of drug-drug interactions that would likely make this line of research unprofitable. It is therefore unlikely that a commercial CYP3A4 inhibitor would ever be developed to inhibit CYP3A4.

Are there any natural inhibitors?

The answer to this question can be found in numerous drug safety warnings. Grapefruit juice is the most extensively researched food product known to cause drug-drug (or in this case drug-food) interactions mediated by CYP3A4. Many drugs that carry a safety warning to avoid drug-drug interactions also warn against the consumption of Grapefruit juice prior to, or simultaneously with the use of the drug. These grapefruit-juice induced drug interactions are very well documented. Grapefruit juice contains a very potent natural CYP3A4 inhibitor and therefore should be given the same consideration as any other drug.

One glass (250ml) of grapefruit juice is proven to totally and irreversibly inhibit CYP3A4 in the intestine. When consumed on a daily basis, the amount of CYP3A4 in the liver is also reduced. When CYP3A4 is inhibited by Grapefruit juice, more than 24 hours (up to 3 days) are needed before the enzyme activity is totally renewed, so a daily dose causes a cumulative effect in the liver. This extends the time a drug remains active in circulation in the blood.

So where does this leave Parkinson’s Patients?

I am fairly certain that Levodopa is metabolised by CYP3A4 and becomes the dominant metabolic pathway when DDC and COMT enzymes are inhibited. However, I could be wrong so this still needs to be proven experimentally. It could be a significant cause of the low bio-availability and short half-life of Levodopa in the blood.

The potency of grapefruit juice as an inhibitor of CYP3A4 is proven. If the above hypothesis is correct, grapefruit juice could be used to increase the bio-availability and extend the half-life of Levodopa in the blood, especially if taken in conjunction with DDC and COMT inhibitors. Because of the proven safety issues associated with Grapefruit juice in relation to many other drugs, this could turn out to be a very contentious issue indeed. In its favour, grapefruit has no safety issues for people in good health are not medicated. In fact it’s good for you.

In the meantime, I am carrying out my own personal trial with the support of my GP and getting good results. He even suggested that the subject would make a good subject for a research thesis in pharmacology.

IMPORTANT

If you are taking other drugs for unrelated conditions, you should first discuss the matter with your Doctor before drinking grapefruit juice on a regular basis and consult in detail the reference by D.G. Bailey on grapefruit-induced drug-drug interactions.

Ref. : D.G. Bailey et al.

Grapefruit–medication interactions: Forbidden fruit or avoidable consequences?

CMAJ. 2013 Mar 5; 185(4): 309–316.

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

The full scientific paper lays out in detail the evidence for this summary. If you would like to read it, you can find it here: researchgate.net/publicatio...

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wriga,

Good work!

You mention that you are running a n of 1 trial. Do you have more details?

You probably don't have the equipment to measure levodopa plasma levels directly. But, you can measure the efficacy of the treatment by measuring the pharmacodynamic effects. You should choose a time to run the test when most of the previous doses of levodopa have worn out, probably the first thing in the morning. I find that in these situations doing the side-to-side tap test every 10 minutes, from 30 minutes before the dose of levodopa is taken to four hours after, gives a suitable test. The difference between the area under the curve whilst on levodopa and whilst on levodopa plus inhibitor gives a good measure. Placebo? Significance? They can wait for another day!

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How long does it take from drinking a glass of grapefruit to irreversibly inhibit CYP3A4?

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Good question. I allow 30 minutes in the morning before taking levodopa.

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CDD oil which many find helps with movement issues as well as sleep, anxiety and depression is also a powerful inhibitor of the cytochrome p450 site.

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As a research scientist you might also find useful ideas in the work of William Walsh walshresearch.org

He’s looking at nutrition and mental illness but the conversation is about illness and health resulting from the under abundance of key vitamins and minerals such as B vitamins, zinc, copper.

We are ultimately talking about managing neurotransmitters. It’s all about Dopamine, Seratonin, Norepiepherine, and methylation.

Walsh has treated over 30,000 patients and has an abundance of hard science backing his work. I know his work is very important for folks with Bipolar Disease, Autism, Depression, and ADHD.

I personally suspect it is also relevant to Parkinson’s disease, and the success some are having with high does B1 supports that notion.

I’m personally getting great benifit from CBD oil, high does B1, and adding Mucuna with green tea when I’m off. But this is all verynew for me so I’m still tweaking and learning.

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Thanks

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Following

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Well done! I look forward to periodic updates.

For those interested, here is a list of drugs that are metabolized by CYP3A4:

pharmacytimes.com/publicati...

Here is some additional important information on the subject:

medsafe.govt.nz/profs/puart...

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Thanks PB,

CYP1A2 is also inhibited by Grapefruit

Thats an update on Bailey.

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Great links. The potential for contraindications is really pretty large.

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Do you know how I can blow up those 3 charts? The ones that list the drugs?

Following your links and ended up at a URL called DrugBank which has this tidbit,

"The risk or severity of serotonin syndrome can be increased when Amantadine is combined with Levodopa."

drugbank.ca/drugs/DB01235

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Right-click on the image and select copy image. Start up "paint" and paste the image. Then select resize and resize to 200%.

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For the charts just click to open them in the doc before you print. As I remember it works for me but could be confused with another doc.. I'm travelling in UK now, so no PC. Amantadine is herbal levodopa as I recall. With GJ, you may need to reduce dose of L-Dopa over time as half life increases. If you get good results, reduce the dose and tell us. Being quantitative will help us all.

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Amantadine is Not herbal Levodopa. Amantadine is a anti flu medication. Herbal Levodopa is called Mucuna Pruriens. How could you not know this?

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Hello malayappan

Thank you for correcting my reply.

I was indeed mistaken, I did not have my documentation with me and was thinking of the herbal L-Dopa, Atremorine made from fava beans. Of course I know about Mucuna and I take it daily.

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Thanks MB,

I have read that serotonin syndrome can be caused when patients get overdosed with C/L. Do you know what the mechanism is? To avoid overdose, I reduced my dose of MP by half when I started taking GJ and I'm at less than half my previous dose now 500mg/day Levodopa content down from 1200mg/ day and with much better results.

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I don't know the mechanism of action except that it is always induced by pharmaceuticals. I was surprised to see that in that drug website because so many people take both C/L and amantadine together.

You've reduced your doses to pretty low levels and with the half-life levodopa being about 60 minutes and the half-life of Sinemet being about 90 minutes, you're probably safe, but, as you have explained, taking GJ obscures your dose of C/L, so when you add in MP, the rate/dose of L-dopa you're accumulating is just a guess, i.e., is it possible that after a few months of GJ, you're ending up with more L-dopa than when you cutback?

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wriga, do you think/know if GJ, being a fierce inhibitor of 3A4 that it might diminish the amount of 3A4 , overall and indefinitely, for as many consecutive days as GJ is consumed? And/or, how much levodopa taken for, say, 6 hours after class of GJ is metabolized? Could be none?

Thanks.

Marc

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Hi Marc,

I will try to answer both posts in one. One thing I have learned in this PD voyage is that when doctors propose to change the dose of prescription drugs in any sense, they are making their best guess. This may be called an expert opinion, but it's no better than a guess, not even an informed guess, because facts are scarce, and quantitative facts are practically inexistent. I come from a career in exact science, we don't guess, we build an exact model to represent a hypothesis and we try to prove it by measurement. If the measurements fit the model, both qualitatively and quantitatively, the hypothesis becomes fact, if not it's false or at best an approximation. No opinions, no guesses. Concerning levodopa and GJ, we have no hard facts, just guesses. So in the case of GJ and levodopa we are in uncharted territory. We don't yet have a decent model. My opinion is just a hypothesis until we can get some more facts. We have a few facts : GJ knocks out CYP3A4 in the gut and it may have a cumulative knockout effect in the liver measured once only after 6 days. What happens after 6 weeks is unknown. We dont know the optimum dosage. The combination of knocking out DDC and CYP3A4 at the same time with carbidopa and GJ is unknown. My best guess is that it could "tame" the levodopa metabolism in a big way, smoothing the dose levels in the blood, but could also require big cuts in dosing levels. But its only a guess. We don't have any facts.

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Thanks.

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My general impression in the use of GJ is that the bio-availability of ldopa taken with madopar is more constant and linear rather than peaking and then disappearing in a little over three hours. But for some reason it is not useful to reduce the dose of ldopa for now.

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Thanks for your feedback Gio,

we need this from as many GJ users as possible to buid up the data of how GJ works for different people. I found that I could reduce the daily dosage of L-Dopa after about a month, but I'm also trying to find the minimum dose possible for MP.

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I have only been on Grape juice continuously for about ten days, previously I tried it in a discontinuous way, to see.

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Gio,

Did you mean Grape juice or did you mean Grapefruit juice?

Art

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We've always talked about Grapefruit ...

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The second: Grapefruits juice. Thank you.

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Wow. Thanks for all of your work on this. I don't understand much of it, but I'm glad to have your expertise on our "team." This is a dumb question, but do you think grapefruit confers any benefit upon those of us not taking levodopa?

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Hello Jim,

It could have a modest but positive effect on Ropinirole by inhibiting CYP1A2. It seems to reduce nausea. And of course on MP. My experience is that most effect is on Levodopa.

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Hi Wriga, Isn't there a risk of Levodopa overdose? Another problem is that many pwp use antidepressants with which grapefruit juice interferes.

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Hi Fed,

Coming back to your question of overdose of L-Dopa when taking GJ. I think there is a risk.

I think this could be higher with people taking Carbidopa or other DDC inhibitors along with GJ as this would give levodopa a very easy passage through the gut. I take Mucuna and Green tea, so the DDC is not fully inhibited, and I've cut my levodopa intake to less than half.

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Good morning Wriga, I've been taking GJ since I read your post. After how many days can an improvement be verified? It is my intention to reduce the consumption of Leodopa. Thanks.

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I saw an improvement in a few days, followed by a decline. I suppose the body tried to fight the change. Then a steady and consistent improvement over 6 weeks that still continues today. Just one glass a day keeps Dr Parkinson away.

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Hello Wriga, I would also like to ask you if grapefruit can interfere with supplements.

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Depends what you mean by supplements. With MP yes, cos its Levodopa. Read Bailey to understand more. I can't give answers to every suppl. Bailey and my description in terms of Drug A and Drug B explains the principle. Think in terms of more GJ over time means less CYP3A4 and therefore more Levodopa or any other drug metabilised by it getting into and staying longer in the blood.

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wriga,

Another good piece. Good theory. Just by the odds, 3A4 likely plays a role. Being as the goal is to increase the dose/availability, then shouldn't it be avoided by those who are, in general, trying to take as little levodopa as possible? I imagine grapefruit juice drinkers drink it once a day, but take levodopa throughout the day, so would this cause a spike adjacent to that one dose and make it unknowable? Not enough to matter?

Marc

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Hi MB,

My takeaway is different. After several days of GJ, one glass in the morning before food or meds, the inhibition of CYP3A4 stabilises, and it lasts more than 24h. You may need to reduce the dose of Levodopa to avoid a high peak, but the decline of Levodopa after the peak should be slower. My goal is to make it last as long as possible with good results at the lowest possible dose. I think the e morning dose just stabilises the hepatic CYP3A4 at a lower level throughout the day. Now I don't feel any difference before or after the dose of L-Dopa. I feel just stable throughout the day. My next step is to try just two doses per day: am and pm.

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OK, I'm glad it's working well for you.

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Thanks Albert, a great job. I too am experimenting with GJ with the madopar and will keep you updated on my impressions. At the moment Ldopa seems more stable, both in the duration and in the peak side effects of doose which are more attenuated. Results to be confirmed. Thanks you very much Gio

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Hi Gio,

I'm very pleased its working for you. I'm doing well also, just one glass of GJ in the morning. It lasts at least 24h. Now after 6 weeks, I'm still improving. Have reduced the dose of MP to 500mg L-Dopa /day. Feeling fine. Tremor almost gone, no pain at all, no tiredness.

Wriga

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Eh yes,Albert.

Very good. I probably having a fast metabolism, everything remains more difficult. With the GJ, a glass a day, the ldopa seems "tamed". The result is to be put to "hard test" as appropriate. If it exceeds it is a great thing, almost comparable to the b1 as a utility.

Thank you very much.

Gio

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Thanks so much. My husband has started on gj so we ll keep you posted!

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That is all very impressive but L-Dopa does nothing to slow down the progression of Pd, so why take it? It has serious side effects and we have to take more and more of it to et the same temporary effect.

Rather do Fast walking, it is capable of reversing the symptoms of Pd, as it has with me.

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Thank you is not enough Wriga! You and Dr. C. have a prominent role in our therapy and fight against PD. So glad we have an individual of your caliber and scientific background. We lucky, indeed.

I believe GJ has also worked for my husband. He is on MP and his daily dose is between 300-430mg L-dopa. His first dose is 280mg L-dopa and his second and last one of the day, around 4:00 pm, is 150mg. He was diagnosed one month before you, March 2018. GJ does work!

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Thanks for your confidence and feedback Despe.

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Wriga,

This is my latest observation: On the B1 (50 ml) injection days (Mon and Thurs) and shortly after GJ consumption and 30 min later L-dopa intake, my husband's hand tremors become extremely intense and very frequent to the point he complained about hurting from the intensity and frequency. Today, he is a lot better after his morning GJ and L-dopa. Another symptom he has had since he started GJ on an empty stomach is stomach aches.

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Hi Despe,

Thanks for sharing this observation. I have started to get stomach upsets recently, not everyday and not painful, just annoying. I think I'll change to drinking GJ with breakfast instead of on empty stomach and keep you informed. I had very unpleasant stomach tremors before though and these sometimes come back.

.

Saw my Neuro today and told her about my research into GJ, L-Dopa and CYP enzymes. She tried to put me in my place and said she didn't approve of patients taking supplements especially GJ. When I asked why she just said GJ was not recommended. I gave her the publication and the summary translated to French. I told her I had a PhD in Chemistry and the relation between GJ, enzymes and L-Dopa was all explained in the paper. That was too much, she said she wouldnt have time to read it and gave it me back. She added that her Neuro training didn't really cover much in pharmacology and she always kept to the accepted protocols for meds. That's what we are up against.

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Wriga,

Thank you! You didn't really expect your Neuro to accept your research on GJ, did you? Again, thank you for sharing her reaction on GJ.

Basically, I believe that your upset stomach and my husband's is due to GJ on an empty stomach. He used to take GJ WITH his L-dopa but again on an empty stomach. He will most likely start taking L-dopa with his previous supplements protocol (Vit C, Quercetin with Bromelain, Citicoline and NAC) followed by a cup of green tea. An hour or more later he takes his breakfast. I will ask him to drink his GJ with his breakfast. I hope that will ease his stomach ache.

Yes, please share your new protocol with your GJ and breakfast. If you stop taking GJ on empty stomach, how will you be taking your MP? We are our own doctors, sad.

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I thought you'd come back with that question. I asked my Neuro to prescribe me Carbidopa/L-Dopa, which she did as it's the standard treatment. Want to compare MP + green tea with C/L. Carbidopa should be a better DDC inhibitor than Green tea. I will then have both DDC and CYP3A4 inhibited which may work better. I will intially take one half 10/100 C/L and just one MP capsule (instead of 2) 30 mins after breakfast, then same after lunch and dinner. My intention is to build up to 3 x 10/100 C/L per day and no MP to compare the results.

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The thought of having my husband start very low dose of C/L has crossed my mind several times, but still hesitating. It is kind of hard to find the ideal MP dose, but also the same dose can work some times and others not. I suppose it's the same problem with synthetic L-dopa. I also entertain the idea of having the doctor prescribe an MAO-B inhibitor while he continues with MP. Next month, we will be seeing a MDS at Vanderbilt for a second opinion. The doctor at Mayo was not a MDS but a neuro. Couldn't get an appointment with a MDS during our visit at Mayo, a 5-day stay.

Sounds like a good plan starting C/L at a low dose. Let us know how it will work for you.

PS. May I ask what brand and strength is your MP? Taking a test and comparing notes, hahaha. :)

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I take Solbia MP extract, 200 mg capsules at 50% L-Dopa = 100mg. I think they come from Spain. But it says Swisse on the bottle.

I dont have an issue with side effects from C/L. My issue is with the peak dose and rapid fall in L-Dopa in the blood. If GJ helps smooth this out then C/L could be better than MP. That's what I want to test.

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Thanks, Albert. Anything or any combination that brings longer period relief is worth trying. I hope Dr. Mischley will help us later this afternoon during our initial consultation.

It's B1 that we are more concerned. . .

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Neurologists do tend to get stuck in their paradigms. One of my research doctors told me he could tell when a doctor he hadn't met went to medical school based on how they prescribed medication. Once they learned it one way they rarely change. And, yes, it is what we are up against.

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Thanks Julie,

To be honest I didnt expect to be taken seriously by her. Despite my best diplomacy, she took it as an inversion des roles rather than a chance to work together to maybe learn something new. My GP has been much more open and even wrote her a note to prepare the ground. It wont stop me continuing tho, we have to own our PD and take responsibility for it

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Hi Despe,

I was initially concerned about GJ and B1 both taken orally. I wouldnt expect an interaction between IM injected B1(avoiding the gut and first pass through the liver) and oral GJ.

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The only way to find out if GJ interacts with B1, even if injected, is to take a break of HDT for about 10 days then start again.

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Hi Despe,

If the GJ inflames slightly the stomach and causes stomach pain, the tremor may increase as a result. My trembling sometimes returns and is always related to the burning of the stomach especially in exchange for the season, then the burning passes and even the tremor goes almost to zero. I think almost every inflammation affects tremor, fever, and burning of the stomach are my favorites. 😊

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Thanks Gio for your tip on GJ. He didn't have GJ this morning on an empty stomach, will have it later after breakfast. Tremors have worsened, more frequent and intense.

It's the HDT that we are still fighting. :) Up, down, stop, what?

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I had a crisis of tremors and I stopped HDT for a week and it calmed down. Also his dose of L-Dopa seems low if he is only on MP and without a DDC inhibitor. Green tea helps but the dose of Dopa that gets to the blood is very low, 2-3 %. More L-DOPA with GJ should help. You don't have to increase the amount of GJ.

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Albert, his MP is 150mg L-dopa (2X15%) three times a day. Tried different combinations of MP strength but it seems that the higher the L-dopa the less effective it is. He is doing better at this strength, at least I think so.

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dear Despe, I have two points of reference, if my trembling increases so much is matter of inflammation, fatigue or infection. If it occurs more at the end of the dose of LDopa something has interfered with its absorption. Thiamina does not act from one day to the next (it has a longer cycle) and frankly with injections it is difficult to overdose for me. my main symptom of thiamine overdose is agitation, ie I am well awake at night and very rarely palpitations, i.e. some beats more. Just suspend a week every three and everything goes well quickly. But I only use three things, Thiamine, LDopa and occasionally antacid, the GJ is in trial. This is my experience, if you read Wriga we talk about taming LDopa, which has been a big problem since it was discovered.

nature.com/articles/466S6a

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Dear Gio,

I read the link. Very interesting indeed. Nothing in the market to "tame" L-dopa. :( , that is true!

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Could it be that GJ influences the action of Thiamine..??

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Hi dadcor,

I also asked myself this question and I failed to find any answers. As a precaution, I reduced my dose of thiamine to 1g when I started taking GJ . I have since gradually increased it back to 4g over 6 weeks.

All I can say is that I am doing much better on GJ than I was before.

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dadcor,

Dr. C seemed to think so and advised against its use at the same time as B-1.

Art

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Albert, this study of yours is wonderful , I advise everyone to study it even if they do not intend to make use of it since gives a full understanding of the kinetic pharmacy of levodopa and how to "tame" it to its own use in a simple and effective way.

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Hi Gio,

What do you mean by "taming" levodopa? I like the expression but maybe I'm giving it my own meaning.

Also what kind of L-Dopa do you take and have you been able to reduce the dose you take or extend the time between doses?

This question goes for anyone else who's trying GJ. All replies will help to build up the data on GJ and Levodopa.

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Excuse me Albert, I take here this expression:

nature.com/articles/466S6a.

“Levodopa: the story so far”

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Hi Gio,

Thanks for that very interesting article that everyone should read. I think we have the same meaning of "taming levodopa".

It still leaves open the question of what causes the short half life of L-Dopa even when using DDC and COMT inhibitors.

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I take madopar plus madopar extended relase and give me a slight foot dystonia at the peak dose, with the CJ after a few days it would seem much less pronounced and I can even delay the next dose. If I stop taking it it is immediate the return to dystonia.

My impressions is that LDopa seems more stable, both in the duration and in the peak side effects that is more attenuated. Results to be confirmed.Gio

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Thanks wriga. This is very useful.

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I'm pretty sure this has been mentioned previously by other posters, but it seems that a major problem with levodopa is getting even distribution throughout the day to help get even response in terms of symptom control and this is the reason for ER/CR versions, which although effective for some people, not so for everyone.

I have mentioned previously that with something like mannitol, maybe it is possible to dissolve your daily dose in a drink and sip throughout the day to prevent the high mannitol spike after dosing that can cause the unwanted gas.

In the case of levodopa, maybe it is possible to do something similar such as in the following study in order to even out the dose delivery to the system. They used ascorbic acid in the study, but grapefruit juice is also a source of ascorbic acid.

ncbi.nlm.nih.gov/pubmed/778...

Art

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Following

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Hi Wriga!

Very interesting this study of yours.

I started GJ 2 days ago and i'll keep you update. So far i've seen slight improvements, but to short to advocate to GJ. My usual meds are C/L (sinemet) 25/100 4x day. I try to replace one C/L dose with MP every time i can, 2 capsules 400mg MP at 15% L-Dopa (120 mg L-Dopa total). I also do 2 x 100mg Amantadine (parkadina) and 1 x 100mg Safinamida (xadago).

My question is, will GJ interfere with this two meds? Should i stop during the GJ trial? I also do Omega3 capsules, coconut oil, vitamin D, and still trying to find my optimal dose for B1.

By the way, i'm 45 years, first symptoms about 11 years ago, dx 10 years ago. My main symptoms are tremor, lost of arm swing, some brakidnesia, some foot dystonia. Two days of GJ and my arm swing is much better. But still, i think i'm going pretty well, since i have run my first half marathon 1 month ago :)

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I tried eating 1 grapefruit for breakfast for 2 weeks now. I noticed significant reduction of ON time even in the early afternoon which used to be my best period. I am going to stop this experiment and I will report on the result in 4-5 days. BTW I take 2 Rytary 4 times a day and 1 Sinemet with my first and the last dose of PD medication.

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Will follow

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Thanks for this feedback felixned.

All information on the use of GJ is useful. Maybe there is an active reagent in Ritary ER other than C/L that is sensitive to GJ.

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I have some experience with GJ's effects, not on levadopa, but on a drug used for cancer and organ transplant patients. There may not be a direct correlation, but it could be useful to take a look at this n=138 study. It might give us some insights and suggest other questions to find answers to.

For example, this paper says that the "effect of grapefruit juice begins within a few hours of ingestion and wears off gradually after a few days". Also, "Consuming 8 ounces of grapefruit juice increases sirolimus levels by 350%." oncologynurseadvisor.com/ho...

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Kudos to you but especially to Wriga!

Perhaps instead of an 8oz glass every day, take it every 2-3 days??

PS. Does it matter if it's pink or yellow GJ?

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Clearly, I missing something. I admit, I've yet to figure out the the purpose of drinking GJ.

It increases the bioavailability of levodopa by inhibiting the enzyme that metabolizes it. I get that. Isn't drinking grapefruit juice the same as increasing the dose except by an unknowable amount?

Let's say, for example, a PWP is taking 3 Sinemet a day and wants to lower their dose. So, they eliminate 1 Sinemet and begin drinking a glass of GJ every day. Little or no metabolism occurs with levodopa that's consumed within 8 or 10 hours of GJ and since the regeneration of 3A4 takes 2 or 3 days, (which means that much of the levodopa which is consumed during time is not metabolized) isn't it possible the person ends up with a net gain of levodopa? I suspect that G J increases the availability of the 2 remaining Sinemet by considerably more than the one that was eliminated.

I can see if you're paying out-of-pocket for C/L and you want to stretch the value of your dollar, but If 2 pills plus G J is giving the same or more benefit as 3 pills, it can only be because there's equivalent levodopa of 3 pills??

The grapefruit juice doesn't make it "better" levodopa, it just simply causes there to be more of it.

Help.

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Marc,

Look at it this way: GJ is good for you, natural Vitamin C. :)

Art made a comment about Dr. C. not recommending GJ with B1. Tomorrow B1 injection, I asked my husband not to drink GJ. See how it works without GJ. Unfortunately, we are no doctors or nutritionists so trial and error IT IS.

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For me, the interst in trying this comes from "taming" levadopa. If one were to take a dose of levadopa (say 200 mg just to keep it simple). That 200 mg dose might end up getting 125 mg of levadopa actually into your blood supply (just guessing). And maybe within 2 hours it's gone. Levadopa doesn't hang around in your bloodstream very long because that CYP3A4 is not just in your gut but also in your liver. That's how levadopa gets removed from your bloodstream.

But now we've had GJ before taking just a 100 mg dose, which delivers only 85 mg (guessing) into your blood. So that's less of a whammy right away. Here's the important part: GJ reduces the CYP3A4 in your liver too, so it takes longer for the levadopa to be removed from your bloodstream. Maybe 4 hours instead of 2. In other words, it's less of an initial spike and a longer and gentler decline. Put another way: by keeping a lower level, but longer, in your blood, you need less at the start. If all it did was get more into our bloodstream, but didn't keep it longer in the blood, then yes, all it would be good for would be to lower the cost. Although, for some, large doses of levadopa can cause digestive problems, and it could help there too.

This is what I'm currently getting - somewhat - from Rytary, but I'm hoping that this will be even better. Worth a try say I. :)

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JAS 9, boiled down, I think you're saying the same thing I said, which is, the grapefruit juice causes less levodopa to be metabolized causing the serum level both be higher and last longer (than it would be without GJ) the net effect of which is you have more levodopa in your system - so my question is, what's the difference between that and taking more Sinemet?

I haven't given any thought to the spike issue, but with grapefruit juice, (say) 90% of the levodopa is floating around instead of 10% the net effect of which is you have introduced more levodopa into your system than you would've with a pill?

Is it possible that G J creates more of a spike?

Marc

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PS. The other concern I raised is the amount that levodopa is increased isn't knowable.

And, if the increase isn't knowable and if it's possible or likely that the increase is substantial, which I believe it is, doesn't that risk moving a person closer to dyskinesia, unknowingly, than they might be if they were able to keep track of the dose?

In other words, if you are taking 8 Sinemet a day and you cut that down to 5 and add grapefruit juice, is it possible you getting the equivalent of 10 Sinemet a day?

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That's what I'm wondering, it's not "a lower-level longer," it's a higher-level, longer.

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IMO should follow the concentration of LDopa over time ie the pharmacinetics in the presence of GJ, keep in mind that the circuits are two, peripheral and over BBB. See graph of ldopa permanence in the peripheral system. What complicates the use and the different benefits even more.

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Thanks JAS9,

Your take on the reducton of the CYP3A4 in the liver on the slower clearance of L-Dopa is also my interpretation as the greatest potential advantage of GJ. Sure the quantity that gets through the gut will be higher so the spike will be higher for the same initial dose. My interest is not in reducing the dose to save $, but to keep the supply of dopamine more constant for the wellbeing of our neurons.

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