Update on Grapefruit Juice Experiment... - Parkinson's Movement

Parkinson's Movement

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Update on Grapefruit Juice Experiment - Day 44

TheLordsWeapon
TheLordsWeapon

Good morning all,

Currently drinking one 8 once glass of GJ first thing in the morning half hour before I start my first of four daily c/l dosings which starts at 7am each morning.

I've been testing with GJ for 43 days now, just completing a full week of being able to take 200mg c/l four times a day, that's down from 250mg four times a day. I've also completed one week of tapering off Requip from 2mg ER to currently 1mg non-ER once a day, next week I will try going off Requip all together.

"Off" times are now about 40 minutes when they use to be 60-90 min, and c/l daily dose is down to 800mg from 1000mg total per day going from 250mg to 200mg doses four times a day, I will try reducing c/l another 50mg to 150mg four times a day starting next week, I will also be stopping Requip dosing 100% starting next week.

Also saw my PCP yesterday, he commended me on the testing and results I've been getting and said to keep it up and report back to him every month on my ongoing GJ testing, he also said that medical testing "HAS NOT" been conducted extensively on GJ and to be very careful since it has been known to have the opposite effect compared to my results.

Will keep you all posted, Jesus Christ is with us, we would never have made it this far without him.

God Speed!

36 Replies
oldestnewest

I would go there with you, except that when I once did, I encountered the problems with statins and other calcium channel treatments I was having for other co-occurring conditions and very quickly had to deal with some very dangerous consequences...I think the complextity of the effect of GJ, which are sometimes multiple and complicated, at different time frames in the equation expanding some effects and then very soon thereafter working in the opposite direction depending on the medications involved, really can become problematic if not taken into account with an expert. If you have a simple medical picture, that's one thing. But if you have more than one condition or treatment or metabolic process, beware. Caution. Simple is not the usual situatation. Anticipation of the possible complications is not within the vision or the mindset of the simple outlook. Just my two cents.

Thanks for the update and dosing details. These results are very encouraging so far. Just be careful not to cut your meds too fast. I don't see the point in cutting both C/L and Requip at the same time. If you get a bad reaction, you won't know which one is causing it.

Better to change one at a time.

A

White rather than pink, unsweetened, frozen concentrate.

Interesting results so far. I'm on day 9 of drinking 200ml/day and so far see no obvious results. I haven't reduced any meds yet and my "off" periods are still 45 minutes long. Possibly I'm feeling a little better in my "on" periods, but that's subjective. Thanks for being my guinea pig or canary in the mine, etc.

sharoncrayn
sharoncrayn in reply to JAS9

Apparently, results with the CYP3A4 inhibitors (like naringenin in grapefruit juice) take time to impact the transfer of L-dopa to the brain.

johntPM
johntPM in reply to JAS9

JAS9,

Are you on taking any anti-PD drugs other than levodopa/carbidopa? If you are on entacapone or taking Stalevo (levodopa/carbidopa/entacapone), you are taking a COMT inhibitor. Inhibiting COMT slows the metabolism of levodopa. So there is less benefit to taking GJ, which slows the metabolism of levodopa too. If you are on agonists (e.g. ropinirole) these are, as far as I know, unaffected by GJ, so again the incremental benefit of GJ is reduced.

sharoncrayn
sharoncrayn in reply to johntPM

Just for the sake of discussion:

COMT is an enzyme. A COMT inhibitor "prolongs" the effect of L-Dopa by blocking that enzyme which can to some extent make a portion of the L-Dopa useless. Unless you routinely have liver tests done, COMT inhibitors are rarely prescribed by any competent PD doctor.

Generally a CYP3A4 inhibitor increases the effectiveness of carbidopa. So we might assume it increases the effectiveness of a drug such as Stalevo.

Finally, Cabergoline is a synthetic ergote dopamine agonist.

johntPM
johntPM in reply to sharoncrayn

Entacapone is a COMT inhibitor. It is frequently prescribed either on its own, assuming that a dose of levodopa is taken at roughly the same time, or as part of Stalevo (levodopa, carbidopa, entacapone).

Liver tests are required for tolcapone, another COMT inhibitor, but not entacapone.

jeffreyn
jeffreyn in reply to sharoncrayn

John is right, Sharon.

You should update your knowledge of entacapone (and opicapone).

sharoncrayn
sharoncrayn in reply to jeffreyn

To repeat myself:

COMT is an enzyme.

Entacapone, Tolcapone, etc... are COMT "inhibitors" that "prolong" the effect of L-Dopa by blocking that enzyme which can to some extent make a portion of the L-Dopa useless.

Sure, in preclinical studies neither drug caused a problem, yet in CTs Tolcapone..did. Therefore, in the US, very, very, very few physicians will prescribe Tolcapone for obvious reasons.

As for Entacapone, in the US, RARELY is it prescribed as a lone drug. It just isn't. Nor is Stalevo.

Should an individual taking any "drug" COMT inhibitor have a liver test? In general most US physicians would say yes to stay on the conservative side. We simply don't have sufficient evidence beyond the CTs (with very limited populations) or the various rat studies (comparison between the 2 drugs) to suggest they aren't needed.

As for Opicapone, it is a very new COMT inhibitor. Way too new to draw any conclusions that you shouldn't have a routine liver test.

In summary, we need a lot more study and analysis of COMT inhibitors related to PD. What I am concerned with is whether or not these inhibitors actually enhance PD patient's dyskinesia. IOW, our main concern shouldn't be perhaps the liver toxicity issue, but the enhancement of PD symptoms.

JAS9
JAS9 in reply to sharoncrayn

I am also concerned that people trying this GJ idea are not aware that (if they don't pay attention to overmedication symptoms and reduce their C/L accordingly) they might well be increasing the level of L-dopa in their brains. And that, of course, might increase dyskinesia. I've gone through C/L reduction cycles, so I know what to look for. I'm being very cautious.

johntPM
johntPM in reply to sharoncrayn

You write:

"As for Entacapone, in the US, RARELY is it prescribed as a lone drug. It just isn't. Nor is Stalevo."

The situation in the UK is different.

Using NHS data for 2018 gives: 48,489 prescriptions for entacapone on its own and 168,190 prescriptions for levodopa/carbidopa/entacapone (such as Stalevo and its generics). Assuming that people who are on it do so for the whole year (12 prescriptions), that suggests that about 18,000 PwP are on entacapone one way or another, which is about 15% of PwP in England.

See neurotalk.org/parkinson-s-d...

This describes how to access the raw data.

sharoncrayn
sharoncrayn in reply to johntPM

I am sure you are aware of this finding regarding Stalevo, but some may not be...

It highlights IMO the importance of extended duration CTs. You may already have prostate cancer, and have had PC treatment(s), so all of this concern maybe irrelevant to you.

I have no idea if the FDA ever followed up on this CT. I should have since it presents some interesting theories on inhibitors if the findings prove valid.

STRIDE-PD

The STRIDE-PD trial was a double-blind, randomized, parallel group, controlled clinical trial conducted at 77 centers in 14 countries, including the United States, the release notes. The primary endpoint was time to onset of dyskinesia in PD patients between treatment groups. A total of 745 PD patients were enrolled, and 541 completed treatment, 265 receiving entacapone/levodopa/carbidopa and 276 receiving carbidopa/levodopa only.

Mean treatment duration was 2.7 years, ranging up to 4 years. The average age of patients was approximately 60 years, the age at which prostate cancer is most commonly diagnosed, the alert points out; most were white (95.2%) and male (62.7%).

“An unexpected finding in the trial was that a greater number of patients taking Stalevo were observed to have prostate cancer compared to those taking carbidopa/levodopa,” the alert notes.

Specifically, 9 of 245 men (3.7%; 95% confidence interval [CI], 1.69% – 6.86%) had prostate cancer in the entacapone/levodopa/carbidopa group vs 2 of 222 men (0.9%) in the carbidopa/levodopa group, for an incidence rate of 14 cases per 1,000 with entacapone/levodopa/carbidopa compared with 3.2 cases per 1,000 with carbidopa/levodopa.

The odds ratio for the occurrence of prostate cancer in men taking entacapone/levodopa/carbidopa was 4.19 (95% CI, 0.90 – 19.63) vs carbidopa/levodopa.

Duration of entacapone/levodopa/carbidopa therapy before a diagnosis of prostate cancer ranged from 148 to 949 days, with a mean of 664 days. Previous trials of this entacapone/levodopa/carbidopa therapy did not indicate any such increased risk for prostate cancer, but most of these trials were conducted for less than a year, the alert points out.

The additional drug in this combination, entacapone, is also sold as a single-ingredient product (Comtan), also used to treat PD symptoms, and likewise has not been previously associated with an increased risk for prostate cancer.

“The agency is exploring additional ways to better understand if Stalevo actually increases the risk of prostate cancer,” they write. “This communication is in keeping with FDA’s commitment to inform the public about its ongoing safety review of drugs. The agency will update the public as soon as this review is complete.”

Hidden
Hidden in reply to sharoncrayn

There have been several newer studies which show no increased incidence of prostate cancer with entacapone...

E.g.,

ncbi.nlm.nih.gov/pubmed/297...

ncbi.nlm.nih.gov/pubmed/256...

encepp.eu/encepp/openAttach...

sharoncrayn
sharoncrayn in reply to Hidden

You may want to read the complete study(s) before pronouncing your judgement. For example, the VA study using the VA data base found no significant change in the incidence of PC due to entacapone, but we have no idea whether it related to the STRIDE CT in terms of using Stalevo. They never mention whether they cross referenced for Stalevo. I doubt seriously that they did. If you recall, the STRIDE CT examined the use of Stalevo, NOT entacapone as a stand alone drug. I believe this distinction is extremely important for several reasons.

Further, when they did find PC in the E cohort, they found a much higher level of PC disease severity. Not a problem? Obviously it is.

Hidden
Hidden in reply to sharoncrayn

"I believe this distinction is extremely important for several reasons."

Please, do tell.

sharoncrayn
sharoncrayn in reply to Hidden

"Please, do tell."

You must be kidding me.

Orion's clinical trial examined Stalevo exclusively. They were not interested in evaluating entacpone (because they don't own the patent) as a stand alone drug. The alarming incidence of PC in this relatively small CT population involved Stalevo, not entacapone as a stand alone. So, FOCUS on Stalevo use, not some other drug.

So why did the VA team who undertook the VA database study choose not to cross reference within a "stratification cohort" strategy the use of Stalevo amongst other important strata?

Because they didn't even know what a stratification cohort strategy means or its importance in drawing conclusions from a basically questionable data base.

Really Sharon? the VA database is extremely vunerable to coding errors over a 15 year time period for a variety of reasons. The US Va has about 170-175 medical centers and almost 1,750 outpatient clinics and 11,000-12,000 doctors plus thousands more Nurse Practitioners. And how many VA coding clerks know what they are doing?

Lots of garbage in; lot and lots of garbage out.

sharoncrayn
sharoncrayn in reply to johntPM

Aug 6, 2019

John,

Went back and looked at David J Brooks (MD, neurologist,London) aggregation study of information and studies on Stalevo which was published in 2008. Obviously done well before the STRIDE CT. Any chance you know him or can reach out to him to ask him what his assessment was of the STRIDE CT. If 15% (or whatever) of PD patients in the UK receive Stalevo as of 2018, It appears that the UK physicians who treat PD did not consider these findings significant for males over 55, or your Public Health Service didn't. or something else.

Or did they? and the UK database doesn't stratify the prescriptions by age and gender which would indicate they (the physicians) are selective (very doubtful but possible).

As you are aware, I am a cancer drug biochemist so this situation is of interest to me in a peripheral sense. Entacapone as a single doesn't interest me because nothing I can find allows me to trace prescriptions on the basis of a connection to Sinemet at a level of 200 for Entacapone (which is consistent across all Stalevo prescription strengths).

Either way, just let me know.

Thanks.

S

JAS9
JAS9 in reply to johntPM

I take no prescribed meds other than my C/L. I'm also fairly conservative about what supplements I take. Just to be thorough, let me list them: B1, vegan DHA, magnesium, methyl B12, methyl folate, fisetin, Alma extract. Most days I get enough sun while walking, but if not I take D3 and ubiquinol (co-Q10). Also most days I eat 1 cup of blueberries. I'm vegan. Thanks for your concern, though, and I hope others are paying attention.

wriga
wriga in reply to johntPM

Hi JohnT, I hope you are doing OK. I have suffered with the heat in France, doing better now.

I beg to differ on 2 points.

There is an established cascade effect associated enzyme inhibitors. When you inhibit one or more metabolic pathways, the non-inhibited pathways become more important. So, inhibiting DDC and COMT, means that the CYP3A4 Metabolic pathway, which btw, I admit is still not proven scientifically, should become the dominant metabolic pathway.

In the case of Jas9, either he is not far enough into the inhibition process in the liver, or his genetic variant of CYP3A4 is of the type that is not very active.

Ropinirole is metabolized by CYP1A2, which is also inhibited by Grapefruit juice. However its half-life is much longer than that of levodopa, so inhibiting CYP1A2 should have a positive, but not strong effect on its therapeutic lifetime.

johntPM
johntPM in reply to wriga

wriga,

Good to hear from you. Stafford had two days of sun, then rain.

I am in agreement with your statement that "inhibiting DDC and COMT, means that the CYP3A4 Metabolic pathway, which btw, I admit is still not proven scientifically, should become the dominant metabolic pathway."

However, and this is where we may differ, I think (I have no proof) that it is likely that there is a law of diminishing returns in place. For instance, someone on L/C/E would have less to gain from GJ than someone on just L/C

What we need is a calculus of inhibition. From a pharmacokinetic view point we are concerned with the area under the curve (AUC) and the half-life. We need to know how extra inhibitors "add" together.

John

wriga
wriga in reply to johntPM

Sure, both concepts are valid. The problem remains that the half-life of levodopa is still short with DDC and COMT inhibition. I've yet to see the AUC's of levodopa with different combinations of inhibitors. It would likely discredit some of them.

I'm now in contact with a Senior Consultant Pharmocologist from Sweden who wants to do a proper medical "Proof-of-Concept" on CYP3A4 inhibition on levodopa. We are preparing the case together. It will be a tough battle to get it through all the committees and safety, regulatory and funding bodies. We have to get some important people on board if it is to fly. Hope to have more news in the autumn.

sharoncrayn
sharoncrayn in reply to wriga

I wish you the best of good luck. I hope we can look back and say things are progressing to the point that we have much better information.

Tough battle> You can say that again!

sharoncrayn
sharoncrayn in reply to wriga

From my background, I think you have to look beyond just CYP3A4 and consider the entire spectrum of P450 enzymes. Do these enzymes (as a total family) also cause the low bioavailability of Levodopa? I would think so.

Another issue is whether the interaction with the P450 enzymes differs between synthetic levodopa and a natural form, such as found in MPuriens (when it hasn't been extracted to the point of absurdity). I believe it does, but it is just a hunch. It is entirely possible the half life with MPuriens extends beyond just an hour or so, which is the typical half-life of the synthetic. More than likely.

Finally, how does one differentiate between the variety of grapefruit Juices and where they come from ? Certainly, a difference exists between pink and the non-pink.

sharoncrayn
sharoncrayn in reply to wriga

I'll add another question to the mix:

What are the active constituents of grapefruit juice that are responsible for its actions on the CYP enzyme systems and Pgp? We have 10 or 11 to examine and test and that isn't even considering possible combinations.

Unfortunately, enzyme chemistry ain't as simple as calculus.

sharoncrayn
sharoncrayn in reply to wriga

Re: CYP3A4

It is the dominant pathway for 50-60% of the drugs we use today. This class of inhibitors acts to prevent "degredation" by the enzyme. Therefore, this enzyme and its conversion is extremely important and that importance is reflected in the literature. If you believe it is "still not proven scientifically", that is strictly your opinion.

Re: Grapefruit Juice

The scalability of Grapefruit Juice as a COMT inhibitor in comparison to the scalability of a drug class COMT inhibitor (such as we have talked about) is like day and night. Absolutely no comparison even though it does have an effect. Quite a bit of garbage on the internet about Grapefruit Juice, without much evidence in a real CT, which is repeated over and over as gospel by our "faux" pharmacologists. Garbage in; garbage out.

Re: Ropinirole half life vs. L-dopa's half life:

Since Ropinirole's half life is about 5-6 hours (depending on the individual and their other meds), Grapefruit Juice even with its low scalability probably has an effect (when taken sufficiently, 8 ounce glass of pure juice) for up to 24 hours. The question is: does Grapefruit Juice really inhibit all CYP enzymes in the cytochroma P450. We don't have any human study that gives us the answer. Therefore, your comment is an "assumption".

On the other hand, we basically agree that the half life of L-dopa is extremely short, which is IMO its primary problem for treating PD patients.

Re: Ropinirole in the US vs. EU

Requip is no longer available in the US; Requip XL is still available. Glaxo's decision apparently. Many CTs over the years (since 1990s) on this drug, but Glaxo seldom published the results. When published, UPDRS scores were decreased in the Requip cohort, but not remarkably and "off" times were reduced. Again, nothing dramatic.

Glxo also is looking at this drug in relation to to its impact on end stage renal disease.

What was published re: RLS and Requip in terms of CTs goes back the late 1990s. I don't know what the prevalence of RLS in the PD population, but I assume it isn't significant.

NO simple answers IMO.

jeffreyn
jeffreyn in reply to sharoncrayn

Sharoncrayn said: "If you believe it is 'still not proven scientifically', that is strictly your opinion."

I think wriga was referring to the CYP3A4 metabolic pathway just in relation to levodopa (i.e. not the CYP3A4 metabolic pathway in general).

Sharoncrayn said: "The scalability of Grapefruit Juice as a COMT inhibitor ..."

I think the subject was grapefruit juice as a CYP3A4 inhibitor (i.e. not as a COMT inhibitor).

sharoncrayn
sharoncrayn in reply to jeffreyn

Thanks for correcting my incorrect abbreviation. Too many things going on today in my world to double check and proof everything.

Thankfully, I have you to do it. Your check is in the mail.

jeffreyn
jeffreyn in reply to sharoncrayn

No charge, H2H.

wriga
wriga in reply to sharoncrayn

Sharoncrayn,

Sometimes I despair !

For the benefit of the forum, I replied publicly to a comment made by a forumer, JohnT, whom I know and respect, about the subject of CYP3A4 inhibition and it's likely impact on the levodopa half life. John has researched this subject himself and has even tried to quantify its impact using his tapping program. Furthermore, John has read all my research articles and we have had private discussions about them.

The multiple interjections by Sharoncrayn, the doubt she casts on my opinion and the questions she asks quite simply demonstrate that she has not read any of my research articles or the discussions about them on this forum. The answers to ALL of those questions, where they are relevant to the present discussion, are to be found in those articles. What she calls an "assumption" on my part concerning the inhibition of CYP3A4 by Grapefruit juice, has been the subject of a great many scientific articles and books, many of which are referenced in my articles and stored in my archives for further consultation. My research has been systematic and detailed. My conclusions have always been measured. Those who have read my papers and comments know this. This subject has been abundantly discussed and criticised on this forum so I will not facilitate the task of finding those discussions by providing links as I have often done before.

My apologies to TheLordsWeapon for hijacking his post, which I appreciate.

Have a nice day everyone.

jeffreyn
jeffreyn in reply to wriga

Wriga said: "What she calls an 'assumption' on my part concerning the inhibition of CYP3A4 by Grapefruit juice ..."

Sharon is a bit of a nuisance I agree, but the above statement is actually incorrect (IMHO).

What she was referring to (IMHO) is the following statement made by you: "... inhibiting CYP1A2 should have a positive, but not strong effect on [Ropinirole's] therapeutic lifetime."

The way comments and responses are displayed on this forum makes it difficult to match them up sometimes.

wriga
wriga in reply to jeffreyn

Hi Jeyffreyn,

I realise that you are trying to be helpful, but Sharon has introduced quite a few inaccuracies into the discussion. Let me just put a few things straight.

- Carbidopa is not metabolised by CYP3A4.

- CYP3A4 does not inhibit the COMT enzyme.

- Sharon is right that the CYP3A4 enzyme metabolises 50% of all drugs, BUT,

- the metabolic pathway whereby levodopa is metabolized by CYP3A4 or any other CYP enzyme, remains a hypothesis for the medical profession until a "Proof of concept" has been validated and published. This has not yet been done. I personally believe there are strong arguments in favour of this hypothesis,. These are detailed in my research articles.

- Grapefruit juice is a proven and potent CYP3A4 inhibitor, equally if not more potent than drug-class CYP3A4 inhibitors. There are hundreds of pages of published research papers that have been devoted to this subject, mainly because of safety concerns relating to drug-drug interactions (see par ex ref. Bailey in my recent articles).

- the main CYP3A4 inhibitor in grapefruit juice is not naringenin, but the furanocoumarins, bergamottin and 6', 7' dihydroxybergamottin.

- I don't claim to be a pharmacologist and even less a faux pharmacologist. That's why I am in discussions with a Senior Consultant Pharmacologist and practicing clinician about how to go forward. My bio is given in my research articles.

sharoncrayn
sharoncrayn in reply to wriga

Give me a clue as to where your research articles are...

--- should I have somehow known? Apparently I should have ESP.

As to whether this forum is a research forum is certainly questionable...

--- certainly not where I have come from; obviously from where you have come from.

I am truly sorry if I questioned you authority on this subject....

--- I am just a stupid Ph.d. in biochemistry from a bunch of diploma mill universities in the US equivalent to Oxford and Cambridge.

Please put your ego back in your hip pocket when addressing me....

--- just let me know where I can find all your research on this subject.

wriga
wriga in reply to sharoncrayn

Thanks for replying Sharon, we Parkinson people would dearly like to talk to someone with a PhD in biochemistry more often. Especially if he or she is open to listening to what we have to say. We live with our disease every day, so we know a lot about it. Not in terms of biochemistry, but in terms of what our body tells us. Apart from that we are just patients, we know our place. The doctors have the degrees, we have the disease.

I'm what's known as a Patient Researcher. When Parkie came to mess up my life, I decided to do the only thing I knew. Doing research in a field I knew nothing about.

I've done this before. I was trained as a chemist, but then did research in neutron science. I stumbled on what I now call the "Levodopa anomaly". This is not a physical phenomenon like a bump in the earth's magnetic field. It's a medico-social phenomenon based on the observation that a chronic disease like Parkinson's is treated with a drug that lasts only 2-3 hours and for 40 years, nobody has bothered to find out why. Patient researchers don't have a status, we're still just patients who should know their place and accept what the Doctor tells us, but we don't. We don't have an ego, the medical profession, with a few exceptions, doesn't want to talk to us. A few of us rebel and start to question how we are being treated. I didn't like how levodopa messed up my life as much as the disease itself. It took me just 6 months to find out why. Not because I'm brilliant, but because it was pretty obvious that there was another enzyme other than DDC and COMT degrading it and that enzyme was not being addressed. I cannot imagine for one moment that Big Pharma did not know this years ago, but we patients were never told about it. Ask yourself why ?

Inhibiting CYP3A4 has given me my life back. It's not perfect, but it's now manageable.

You are quite right to say that this is not a research forum. It is a patient's forum, but there are many knowledgeable patients here who take a keen interest in research because they think more could be done.

If you click on my profile, and look up the posts I have made, the more recent ones discuss the subject of the metabolism of levodopa and inhibiting CYP3A4. There you will find links that take you to my research. This has not been published in any peer-reviewed journal, because patient researchers should not be encouraged to do this kind of stuff.

I look forward to discussing this with you once you have read what I have written.

I invite you to criticise what you read. I know it's not perfect, but so far no researcher has bothered to counter it.

Does it affect meds for hypothyroidism?

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