Mella Finds Hypometabolic State in Chronic Fatigue Syndrome Plus Rituximab and New Drug For ME/CFS?

Cort

Founder of Health Rising and Phoenix Rising
Staff member
(This blog is based on a post on Phoenix Rising describing Dr. Mella’s Oct. 10th talk in Arendal, Norway and a typically tortured Google translation of part of that talk.)

Another Hypometabolic Signature Found

Naviaux’s paper has clearly sparked a lot of interest. Certainly, antecedents hovered in the background; metabolism has actually been a niche topic in ME/CFS for years. Lemle proposed that a hydrogen sulfide induced state of hibernation or hypometabolism caused the low energy problems in chronic fatigue syndrome in 2011. The Aussies have been doing metabolomics research for quite some time. Their 2014 review paper argued it could be helpful in ME/CFS.

Metabolomics is not a niche topic anymore. The Japanese, who have also done metabolomics research, recently released a metabolomics ME/CFS study (to be covered soon).

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[/fright]Last month Hanson reported finding evidence of a hypometabolic state in ME/CFS, and now Fluge and Mella have apparently found it as well. The metabolites they've found suggest to them that low energy production is a central feature of this disease.

Problems producing energy appear to be fundamental and extend to the immune cells - something Ron Davis has proposed. Fluge and Mella reportedly found reduced levels of phosphate – the P in ATP – in immune cells in ME/CFS. That suggests the reduced killing ability of NK and T-cells could be caused by poor energy production. That makes sense given that some immune cells need to power up to kill pathogens.

Fluge and Mella also have evidence suggesting that metabolic problems may be loading ME/CFS patients with lactic acid – a by-product of anaerobic energy production. (If aerobic energy production is impaired or insufficient, the less-efficient, dirtier and lactic-acid producing anaerobic energy production process kicks in.)

These Norwegian researchers believe ME/CFS patients have two problems with lactic acid; they're producing too much of it, and are having trouble getting rid of it. Mella noted that he produces lactic acid but he can get rid of it quickly - people with ME/CFS cannot. Lactic acid remains a puzzling subject - some researchers find it increased and others do not. That variability may reflect a subset issue.

Rituximab Update

If my calculations are correct, the trial is a bit over halfway done, and we should expect it to end sometime in the summer of next year. At that point, Fluge and Mella will crack the code, and by late 2017 (optimistically) or the first half of 2018, we should know the results.

We've seen some promising Phase III trials go bust recently. Because the larger Phase III trials include more types of patients, they often have less positive results, and Mella warned that this was possible in Rituximab as well. If the results don't apply to ME/CFS overall, then the goal will be to find out which patients it’s effective in and target them. Mella noted that different mechanisms can produce the same symptoms in autoimmune diseases, and he expects this is true in ME/CFS.

According to the translation, Mella stated that they can be "reasonably sure" that a subset of the patients responded. Whether enough people respond to make the trial statistically significant is another matter. Rituximab could be effective in some patients, but not in enough to result in a significant overall response.

(Dr. Patrick in Canada believes he may have found a biomarker that will help identify which patients respond to Rituximab. Dr. Peterson is reportedly testing that biomarker in his patients. )

Mella also cautioned that even if the Norwegian trial is successful, each country will have to put on its own trial. (As it is now, Rituximab would be available off-label to doctors willing to prescribe it, but the drug is very expensive.) The U.S. – the most difficult place to get drug approval – will need its own trial.

According to clinicaltrials.gov. the NIH, one of the biggest clinical trial producers in the world, is currently recruiting for no less than 49 Rituximab trials, mostly in cancer but also in lupus and other autoimmune disorders.

How the NIH, after the IOM and P2P reports, and its statements that ME/CFS constitutes a serious, unmet need, could find a way not to fund a Rituximab trial in the face of a successful Norwegian trial is unclear, but if any group can find a way, surely the NIH can. If the NIH waits for the results of Fluge/Mella’s trial before proceeding, we might be looking at a U.S. Rituximab trial beginning in 2019 with the results in 2020 or 2021.....

It’s remarkable to continue to see the NIH with its 30 plus billion budget continue to sit on its hands while a small country like Norway produces a large Rituximab trial.

Another Drug Possibility…..Cyclophosphamide

Chemotherapy may end up being very good to chronic fatigue syndrome. Fluge and Mella have been giving twenty-five people who didn’t respond to Rituximab or who relapsed after getting it, a shot at another chemotherapeutic drug called cyclophosphamide. Cyclophosphamide is used to treat cancer, autoimmune diseases, and amyloidosis.

A quite toxic drug, Wikipedia reports that it's side effects usually limit it to the beginning phases of treatment in autoimmune diseases. It’s typically used only when first-line treatments such as Rituximab don't work. Like Rituximab it’s an immune suppressant.

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Cyclophosphamide_iv.jpg
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Not all immune suppressants are the same; etanercept (Enbrel) didn’t work for Mella and Fluge. Cyclophosphamide findings have, interestingly, excited some hospitals…

Fluge and Mella are using cyclophosphamide in the lower doses associated with autoimmune disease treatment. They reported that while some people get worse at first, it does appear to work in some ME/CFS patients. Like in autoimmune diseases, the positive effects show up months after taking the drug. Approval for a second trial with severely ill ME/CFS patients has been received.

“Toxic Blood?” (or Another Good Reason Not to Donate Blood)

The idea that something in ME/CFS patient's blood may be turning off the mitochondria or natural killer cells or what have you is not a new one. Although no new studies have come out, reports indicate that the natural killer cell problems in ME/CFS apparently disappear when NK cells from ME/CFS patients are put into a healthy person's blood. Conversely, healthy NK cells poop out when put into ME/CFS patient's blood. Fluge and Mella are finding that healthy muscle cells act strangely when cultured with ME/CFS patient's blood.

Fluge and Mella are also finding that the blood vessels of ME/CFS patients are producing too little nitric oxide. Nitric oxide is a gas produced in the walls of the blood vessels which allows them to enlarge and increase blood flow. If you produce too little nitric oxide, your blood vessels will be so constricted that getting enough blood to the muscles during exercise or other blood requiring activities will be impossible.

Nitroglycerin tests indicate that ME/CFS patient's ability to produce nitric oxide is still present, suggesting presumably that either the signal to produce NO is not being sent or is being ignored, or that the cells that produce NO are being shut down in some way.

(Fluge and Mella filed a patent in 2014 to use a nitric oxide donor in conjunction with Rituximab in ME/CFS. Their understanding of the role that blood flows play may date back to this patient. After checking into a hospital for chest pains, she found that a nitric oxide donor (Imdur) improved her symptoms in much the same way as Rituximab had - except that the results were immediate. They got moderate results in six patients and suggested that using supplements with relatively high doses of L-Arginine 5 g twice daily combined with L-Citrulline 200 mg twice daily might suffice as well.)
Finding some factor in the blood that turns things off could be very helpful. It could a) directly point to a cause, and b) to clear treatment options that block the factor or stop it from being produced.

Fluge and Mella's Journey

Fluge and Mella’s range has become so large, that it’s totally inappropriate at this point to think of them as Rituximab researchers; they're after the source of ME/CFS itself. They're looking at the immune system, blood flows, exercise metabolism, and genetics and have developed a model which incorporates all of it.

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Fluge_Mella..jpg
[/fright]They've experimented with at least three different drugs. They'll be presenting the data from the Rituximab trial in an open source format so that it's available to other researchers. A 150-person Biobank that is storing blood taken before and after ME/CFS patients receive Rituximab could reap diviidends. We’re lucky to be the focus of two such creative and persistent researchers.

Other researchers – most of whom I would guess were not interested in ME/CFS prior to their work - have clearly been excited by it. Their international partners draw from the Charite University Hospital in Berlin, UCL London, Arizona State University and Institute of Immunology Rikshospitalet and Biomedisn UiB.

Fluge and Mella are going to make their first trip, so far as I can tell, to the U.S. for the IACFS/ME conference where Dr. Fluge's plenary address will focus on how the Rituximab trials have helped him and Mella understand the cause of ME/CFS. At the Patient Day we'll get a trifecta; Fluge, Mella and Dr. Peterson on "Rituximab and Emerging Treatments". It's a rich time for them and for us.
 
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Moss

New Member
Thanks for the neat write up on this Cort!

Does anyone know of a link/place to donate to Fluge and Mella's work. I would like to donate to them as a thank you.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
Good question. Here's where they've gotten their funding from - these are all in Norwegian kroner.. $10 million kroner - $1.5 million U.S.

The whole study has cost about $5 million U.S. You've got to give it up to Norway and ME/CFS orgs for funding such an expensive study....

I imagine that you could donate to them through the Kavli Foundation or Me and You (???).

Some of funding: 10 million, previously from health care, regional health contributed by salaries of staff, ME and You, ME Association, Kavli Foundation has provided four million, 1.8 million. This is the support of our partners at Oslo University and the University of Bergen, plus private sponsors.The whole study costing 32 million, especially expensive expenses for medicines and labor costs.
Thanks for the neat write up on this Co

Does anyone know of a link/place to donate to Fluge and Mella's work. I would like to donate to them as a thank you.
 

tatt

Well-Known Member
really excited about this as I've always felt that my problems are heavily related to energy production. Also vitamin D deficiency is linked to low levels of phosphate in the blood and fixing my less than optimal levels of vitamin D is one of the things I credit for keeping me from being bedbound.

It's that time of year when people in the UK and a lot of America stop getting enough sunshine to make vitamin D so back on supplements for me.

Wonder if my gp would prescribe Viagra to try to help the nitric oxide thing :)
 

Monica

New Member
Good question. Here's where they've gotten their funding from - these are all in Norwegian kroner.. $10 million kroner - $1.5 million U.S.

The whole study has cost about $5 million U.S. You've got to give it up to Norway and ME/CFS orgs for funding such an expensive study....

I imagine that you could donate to them through the Kavli Foundation or Me and You (???).

You can donate to ME-forskning.no
Click the menu to see english version.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
really excited about this as I've always felt that my problems are heavily related to energy production. Also vitamin D deficiency is linked to low levels of phosphate in the blood and fixing my less than optimal levels of vitamin D is one of the things I credit for keeping me from being bedbound.

It's that time of year when people in the UK and a lot of America stop getting enough sunshine to make vitamin D so back on supplements for me.

Wonder if my gp would prescribe Viagra to try to help the nitric oxide thing :)
Someone in Los Angeles got a NIH grant to study the use of Viagra in ME/CFS a long time ago. Some people were upset over that study because they thought it was demeaning but it made sense = viagra opens blood vessels all over the body. THe study never got published, however.

I just added this to the blog regarding NO

  • Fluge and Mella filed a patent in 2014 to use a nitric oxide donor in conjunction with Rituximab in ME/CFS. Their understanding of the role that blood flows play may date back from her. After checking into a hospital for chest pains she found that a nitric oxide donor (Imdur) improved her symptoms in much the same way as Rituximab had - except that the results were immediate. They got moderate results in six patients and suggested that using supplements with relatively high doses of L-Arginine 5 g twice daily combined with L-Citrulline 200 mg twice daily might suffice as well.

http://www.healthrising.org/forums/threads/fluge-mella-take-out-patent-on-nitric-oxide-treatment-for-me-cfs.2829/
 

Seasprit

Member
really excited about this as I've always felt that my problems are heavily related to energy production. Also vitamin D deficiency is linked to low levels of phosphate in the blood and fixing my less than optimal levels of vitamin D is one of the things I credit for keeping me from being bedbound.

It's that time of year when people in the UK and a lot of America stop getting enough sunshine to make vitamin D so back on supplements for me.

Wonder if my gp would prescribe Viagra to try to help the nitric oxide thing :)
 

Seasprit

Member
Genetic testing and micronutrient studies can be very useful in honing in on individual core problems that may be the tipping point for our various conditions. I just found out through a micro-nutrient study that I am deficient in most B vitamins which also concurs with genetic test results that I am positive for the MTHFR genetic mutation which prevents normal Vit. B assimilation and use.
 

Carollynn

Active Member
Please, dear fellow patients, don't jump in with taking Arginine supplements just yet! Arginine itself fosters reactivation of herpes viruses. If any of the HHV's are part of your "pathogenic cocktail," or you suspect they are, avoid Arginine until more of these studies are done. In this promising study, a variant of Arginine has been pharmaceutically created to inhibit viral replication. As the abstract sums up, "rurther exploration into the breadth of viruses inhibited by peg-ArgI, as well as the ability of peg-ArgI to suppress arginine-associated virus-mediated pathophysiological disease processes is warranted." https://www.ncbi.nlm.nih.gov/pubmed/27192555

Interesting that the study involves cellular metabolism.
 

ShyestofFlies

Well-Known Member
Someone in Los Angeles got a NIH grant to study the use of Viagra in ME/CFS a long time ago. Some people were upset over that study because they thought it was demeaning but it made sense = viagra opens blood vessels all over the body. THe study never got published, however.
Actually a vasodialator would make anyone with the POTS/CFS (subset?) overlap worse wouldn't it? So that could of definately interfered in any study like that. I think POTS is typically treated with vasoconstricters. But it's hard to find doctors who believe in POTS too from what I have heard.

I have many dysautonomia symptoms and haven't been diagnosed yet, but I presume that they won't be able to use the vasoconstricters on me because of my Raynaud's which means they'll probably throw up their hands and say they can't really do anything, drink more water and put salt on everything haha.

It's interesting that many people have been saying for years they felt that there was a flaw in their body's abilities to make and use energy and now they are finding evidence of that. We of course had no one to really know for sure on a cellular level as patients as long as people have claimed that, but there is a level of satisfaction hearing that might actually be occuring.

I'm pretty sure most of us wouldn't contest that at all even if we never felt that way because it seems to make so much sense (without delving into the science stuff because I can't really understand it).

I also had low levels of vitamin D but "fixing" it didn't seem to change a single thing. I take high doses but not the super high ones I've seen tossed around (about 5000-10000 iu a day). I wonder if we have more than a problem of absorbing vitamin D but using it as well.

The gut studies going on now/recently concluded are also interesting with their connection to inflammation which depending on who you ask "there is no proof of inflammation in ME/CFS" haha. (I do take a little joy when people get proven wrong with their ignorance).
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
Actually a vasodialator would make anyone with the POTS/CFS (subset?) overlap worse wouldn't it? So that could of definately interfered in any study like that. I think POTS is typically treated with vasoconstricters. But it's hard to find doctors who believe in POTS too from what I have heard.

I have many dysautonomia symptoms and haven't been diagnosed yet, but I presume that they won't be able to use the vasoconstricters on me because of my Raynaud's which means they'll probably throw up their hands and say they can't really do anything, drink more water and put salt on everything haha.

It's interesting that many people have been saying for years they felt that there was a flaw in their body's abilities to make and use energy and now they are finding evidence of that. We of course had no one to really know for sure on a cellular level as patients as long as people have claimed that, but there is a level of satisfaction hearing that might actually be occuring.

I'm pretty sure most of us wouldn't contest that at all even if we never felt that way because it seems to make so much sense (without delving into the science stuff because I can't really understand it).

I also had low levels of vitamin D but "fixing" it didn't seem to change a single thing. I take high doses but not the super high ones I've seen tossed around (about 5000-10000 iu a day). I wonder if we have more than a problem of absorbing vitamin D but using it as well.

The gut studies going on now/recently concluded are also interesting with their connection to inflammation which depending on who you ask "there is no proof of inflammation in ME/CFS" haha. (I do take a little joy when people get proven wrong with their ignorance).
I think in a lot of people with POTS the blood vessels in their lower body are too dilated - but it helped with this woman and some others. Nobody ever said we were particularly consistent :). I imagine this is another instance of subgroups...
 
Hi Cort,

Just a few words about hypometabolic states. In the early 1990's I used to do indirect calorimetry on my patients (direct calorimetry is expensive and complicated). I have all the paperwork in a box somewhere. Hundreds of patients were assessed. This was how hypothyroidism was diagnosed and monitored in the past. 85% of predicted basal metabolic rate (BMR) was considered to represent severe hypothyroidism.

Interestingly, in my non-hypothyroidism CFS patients, I found that the average BMR for my CFS patients was 70-75% of precticted, and some patients had even lower results. There were a few who were the opposite, with BMR's around 105-110% of predicted. The later may reflect the earlier stages of CFS, when critical metabolites are lost.

Thus, the majority of my patients are severely hypometabolic, worse than one would ordinarily see in hypothyroidism.

I believe that calorimetry should be resurrected in ME/CFS research, given what we are finding by other means. It would provide the best objective evidence of what the various new markers are predicting, but no one that I know of currently knows how to do calorimetry these days.

The second point is something I may have stated before, which is that there is excess free phosphate in red blood cells in ~99% of my patients. To me, this signals less ATP because ATP is broken down to ADP and free phosphate. As there are no mitochondria in red blood cells, then reduced glycolysis or a hypometabolic state in red blood cells must be the reason why.

Sincerely,

Dr John L Whiting
 

verbatim102

New Member
Does anybody know of a natural alternative to Rituximab? Surely there must be something that can down regulate B cells without having to take a toxic drug like Rituximab.
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
Hi Cort,

Just a few words about hypometabolic states. In the early 1990's I used to do indirect calorimetry on my patients (direct calorimetry is expensive and complicated). I have all the paperwork in a box somewhere. Hundreds of patients were assessed. This was how hypothyroidism was diagnosed and monitored in the past. 85% of predicted basal metabolic rate (BMR) was considered to represent severe hypothyroidism.

Interestingly, in my non-hypothyroidism CFS patients, I found that the average BMR for my CFS patients was 70-75% of precticted, and some patients had even lower results. There were a few who were the opposite, with BMR's around 105-110% of predicted. The later may reflect the earlier stages of CFS, when critical metabolites are lost.

Thus, the majority of my patients are severely hypometabolic, worse than one would ordinarily see in hypothyroidism.

I believe that calorimetry should be resurrected in ME/CFS research, given what we are finding by other means. It would provide the best objective evidence of what the various new markers are predicting, but no one that I know of currently knows how to do calorimetry these days.

The second point is something I may have stated before, which is that there is excess free phosphate in red blood cells in ~99% of my patients. To me, this signals less ATP because ATP is broken down to ADP and free phosphate. As there are no mitochondria in red blood cells, then reduced glycolysis or a hypometabolic state in red blood cells must be the reason why.

Sincerely,

Dr John L Whiting
How interesting! Thanks for passing that along. To think evidence has been there in one form or the other for all this time. The more we look back the more we see hints.

Do you know anything about the metabolic chambers being used in the Nath Intramural study? I wonder if they will show anything?
 

Ian Barnes

New Member
Does anybody know of a natural alternative to Rituximab? Surely there must be something that can down regulate B cells without having to take a toxic drug like Rituximab.
Fasting for two to three days resets the immune system, breaking down white cells so that they regrow. Repeated fasts would likely be needed over a number of months to get some effect.

See http://www.medicalnewstoday.com/articles/277860.php and http://www.lifespan.com/reset-immune-system-start/2/

Then there's Low dose Dextromethorphan (about 5mg per day), contained in some over-the-counter dry cough treatments, it's a cough suppressant but also has some remarkable systemic effects.

Also look into TCM mushrooms and herbs such as Reishi and Astragalus.
 

dejurgen

Well-Known Member
"Fluge and Mella also have evidence suggesting that metabolic problems may be loading ME/CFS patients with lactic acid... ...Lactic acid remains a puzzling subject - some researchers find it increased and others do not. That variability may reflect a subset issue."

=> This remembers me of an interesting blog of yours relating to the lactic acid problem: http://www.healthrising.org/blog/2015/09/25/walking-marathon-me-cfs-case-study/

The nice things I remember are:
a) Compared to healthy people the lactic acid rise show a very different and delayed timing. This potentially could be used as a tool to first define a subclass of ME/CFS patients showing this response and then investigate time-delayed onset such as seen in PEM.
b) Even better: price of diagnosis is dirt cheap.
 

dejurgen

Well-Known Member
"Nitroglycerin tests indicate that ME/CFS patient's ability to produce nitric oxide is still present, suggesting presumably that either the signal to produce NO is not being sent or is being ignored, or that the cells that produce NO are being shut down in some way."

=> In the article about NIH funding Matthias pointed to Nature paper http://www.nature.com/articles/srep34990. In Figure 1 there is this arrow from Arginine to Citrulline in the Urea cycle. Going from Arginine to Citrulline produces 2 NO molecules as a byproduct. The study shows people with CFS have significantly less Citrulline.

This could be an indication that Arginine breaks significantly slower down to Citrulline and hence significantly lower NO production as a byproduct. I have no clue how important this pathway is in the total production of NO.

The paper also states "the higher oxidative stress levels in the plasma and serum in CFS" and repeats the concept of higher oxidative stress several times.

If memory on chemistry class serves me well, H202 (a major or even the major building block to various Reactive Oxygen Species (ROS)) has some "O" too much and NO is keen on accepting some "O". So H202 + NO leads in very short times to H20 and N02?

Combined: one source of NO production is somewhat inhibited and oxidative stress is a "good" source of NO destruction?

I even dare to state this hypothesis:
A) All sort of strong exercise/exertion causes increased H202 production from the cells after sufficiently long time even in healthy people. It increases more sharply at the onset of fatigue.
B) H202 is one of the signaling molecules involved in potentially causing mitochondria going to Dauer (Naviaux shortly mentions it as a potential signaling molecule). Mitochondria in defensive mode produce extra H202 to signal other mitochondria and cells to go in defensive mode.
C) Lots of H202 crashes the amount of NO in the blood quickly.
D) Far less NO in the blood causes severe vasoconstriction, just like is observed/measured time and again after people with ME/CFS exercise.
E) Severe vasoconstriction to the brain is enough to cause long periods of too low bloodflow to the brain. Severe vasoconstriction to the brain combined with low bloodvolume (that many of us have) and gravity has a multiplying effect causing even more severe reduction of bloodflow to the brain.
F) Long lasting severe reduction of bloodflow to the brain (on top of already low average bloodflow to the brain) causes a cascade of problems and costs us a few days to recover or in other words: Post Exertion Malaise?
 

Cort

Founder of Health Rising and Phoenix Rising
Staff member
"Fluge and Mella also have evidence suggesting that metabolic problems may be loading ME/CFS patients with lactic acid... ...Lactic acid remains a puzzling subject - some researchers find it increased and others do not. That variability may reflect a subset issue."

=> This remembers me of an interesting blog of yours relating to the lactic acid problem: http://www.healthrising.org/blog/2015/09/25/walking-marathon-me-cfs-case-study/

The nice things I remember are:
a) Compared to healthy people the lactic acid rise show a very different and delayed timing. This potentially could be used as a tool to first define a subclass of ME/CFS patients showing this response and then investigate time-delayed onset such as seen in PEM.
b) Even better: price of diagnosis is dirt cheap.
I think both Dr. Unger at the CDC and the Dr. Nath at the NIH will be looking for lactic acid. I would be really surprised not to see at least a subset pop out...
 

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