OMF Kynurenine trial

Rrrr

Senior Member
Messages
1,571
Likes
734

bctjr1993

Senior Member
Messages
135
Likes
309
Location
Kansas City, MO
I take 13 gms a day of BCAA's and get a big energy boost from them and they also help to lessen my PEM. My understanding of how they are working is in the mitochondria.

This diagram is from the Fluge and Mella study that found the Pyruvate Dehydrogenase enzyme to be impaired in ME/CFS. Leading to the creation of lower levels of ATP.

In the pink box you see Ile* (Isoleucine, a BCAA) and Leu* (Leucine another BCAA). Both are feeding the krebs cycle by creating more Acetyl-CoA. These BCAA's were found to be low in ME/CFS. Val* (Valine) in the purple box, the third BCAA, feeds the krebs cycle directly. So by increasing BCAA's, the krebs cycle should create more substrates to create more ATP and energy.

View attachment 37504
Source

BCAA's might also have a role in helping if there is an IDO metabolic trap. I haven't looked into that though.
Interesting! When I googled what BCAAs are, this was part of the article about them on WIkipedia: "Recent studies have also shown that BCAAs reduce the levels of circulating free fatty-acids (FFA) in the blood.[22] FFAs compete for binding sites on albumin with tryptophan, and when levels of FFAs in the blood are decreased, levels of free tryptophan also decrease as more is bound by albumin. During exercise, levels of free tryptophan entering the brain are increased, causing an increase in 5-hydroxytryptamine (5-HT), a contributor to the sensation of fatigue. Through their reduction in levels of FFAs in the blood, BCAAs can help to reduce the levels of free tryptophan entering the brain, and help to reduce the sensation of fatigue as a result of exertion.[23]"
 

ljimbo423

Senior Member
Messages
4,115
Likes
10,632
Location
United States, New Hampshire
Interesting! When I googled what BCAAs are, this was part of the article about them on WIkipedia: "Recent studies have also shown that BCAAs reduce the levels of circulating free fatty-acids (FFA) in the blood.[22] FFAs compete for binding sites on albumin with tryptophan, and when levels of FFAs in the blood are decreased, levels of free tryptophan also decrease as more is bound by albumin. During exercise, levels of free tryptophan entering the brain are increased, causing an increase in 5-hydroxytryptamine (5-HT), a contributor to the sensation of fatigue. Through their reduction in levels of FFAs in the blood, BCAAs can help to reduce the levels of free tryptophan entering the brain, and help to reduce the sensation of fatigue as a result of exertion.[23]"
This could be another reason or even the main reason BCAA's help some of us. Although I think Robert Phair said his metabolic trap hypothesis was independent of blood levels of tryptophan.

That it was inter-cellular levels of tryptophan that determine weather someone is in the metabolic trap.
 
Messages
193
Likes
462
When I read a lot of these theories say whether its about autoantibodies or this specific chemical or that, I can't help but be troubled by the inconsistency that these things didn't seem to show in the 'metabolomic' or 'big data' experiments. Do these experiments really have such limitations as to not get to the crux of the issue ?
serotonin is mentioned for example, a chemical which everyone has heard of. It bugs me because I feel like we are getting somewhere and have gotten past the 'complete mystery' phase that we were stuck on for so long.
 

Wishful

Senior Member
Messages
3,820
Likes
6,843
Location
Alberta
It bugs me because I feel like we are getting somewhere and have gotten past the 'complete mystery' phase that we were stuck on for so long.
I don't think we're past the 'complete mystery' phase yet. Funding is still going to all sorts of hypotheses. They haven't announced that "ME is a <neuroimmunological or mitochondrial or whatever> disease" yet.
 

Badpack

Senior Member
Messages
381
Likes
960
Bergquist is doing the study. They also said that they have done a study with Kynurenine and migraine before. Again, i couldnt find any data. If anyone knows something, please share with us.
 

ZeroGravitas

Senior Member
Messages
100
Likes
500
Location
UK
Do these experiments really have such limitations as to not get to the crux of the issue ?
serotonin is mentioned for example, a chemical which everyone has heard of.
@HTester has suggested that excess serotonin production happening in only a relatively tiny population of cells, for example "serotonergic raphe neurons" [paper], could cause the kind of chaos throughout the body that we see. With effects mediated through central nervous system dysregulation.

You wouldn't expect to be able to see a signal in the blood from only those important few cells being metabolically trapped. (Or even in a CSF draw?) The gut would swamp that signal with the relatively huge amount of serotonin produced and used there. Even if a broader population of cells in different tissues were directly impacted, I'm not sure you'd expect to see a clear signal in a serum test, due to compartmentalisation of metabolites within cells.

("Reading_Steiner" = Steins;Gate anime fan...?)
 

Wishful

Senior Member
Messages
3,820
Likes
6,843
Location
Alberta
You wouldn't expect to be able to see a signal in the blood from only those important few cells being metabolically trapped.
That's why I see little point in studying samples from PWME's bodies. I believe that the core dysfunction of ME is hiding in some little clump of brain cells. The direct markers of that might be short-ranged, so even taking cerebral fluid might not reveal the markers. If I was distributing funding for ME, I'd fund research that does high definition scans of the brain: fMRI, EEG, or whatever else there is. If we had someone who could reliably trigger temporary remission, we could do a before/during/after scan to identify the areas involved.
 
Messages
38
Likes
114
I contacted Dr. Phair about getting an update on the kynurenine trial, he said "I am only peripherally involved (and officially, not at all involved) in that trial." and "Usually, trials require no reporting until they are complete." He did advise me to contact the OMF or Dr. Bergquist for an update. I emailed the OMF and got the generic we are pursuing many paths for a cure and provide updates whenever possible followed by a request for a donation. Also, I emailed Dr. Bergquist twice, once in English and once in Swedish (using google translate); I haven't received an email back yet. Following the last two year’s patterns of updates, you wont hear anything until around the first of May.
 

Badpack

Senior Member
Messages
381
Likes
960
@Possibly James May thanks for the effort. Yea, kinda sad. They only release news when there is another fundraiser. What a strange coincidence...

They mentioned someone did a study with kynurenine and migraine. The study design should be the same but i also cant find it. So if someone has information about it. Please share if you can.
 
Messages
38
Likes
114
@Badpack,

I was able to find this trial on injecting L-Kynurenine to induce headaches in healthy volunteers. The protocol stated was "intravenous infusion of L-kynurenine using the following doses 50 microgram/kg, 100 microgram/kg, 150 microgram/kg, 300 microgram/kg, 500 microgram/kg, 1 mg/kg and 5 mg/kg over 20 min on 7 different days with at least 1 day in between." The only inclusion/exclusion criteria that stood out was no pregnant/nursing women and no one with a cardiovascular disease. Unfortunately, I can't find any results on the trial.
 

Badpack

Senior Member
Messages
381
Likes
960
A normal 75kg person would need 3,75mg to 375mg. Quite a spread they tested there. the water solubility of kynurenine is 2.08 mg/ml. So more than 5mg daily wouldnt be very feasible for s.c. use. So the only option is i.v. Which they used.

Nothing you could/should do at home sadly. So we kinda have to wait and see i guess.
 

Learner1

Senior Member
Messages
5,614
Likes
10,041
Location
Pacific Northwest
Vitamin B6 deficiency increased kynurenine


Deficiency of vitamin B6, a cofactor of the key enzymes of KYN – NAD pathway, shunts KYN metabolism from formation of NAD towards production of xanthurenic (XA) and kynurenic (KYNA) acids.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229017/
Pyridoxal 5′ phosphate (PLP)4, the active form of vitamin B-6, is involved in a wide variety of physiologic processes including gluconeogenesis and the synthesis of sphingolipids and neurotransmitters. It also functions as a cofactor for many enzymes required for amino acid metabolism...

...In this issue of the Journal, Ulvik et al (3) use these data to identify a new serum marker for examining functional vitamin B-6 status. To achieve this, they measured several metabolites in the tryptophan-to-kynurenine pathway. As shown in their Figure 1, tryptophan is metabolized to kynurenine via either indoleamine 2,3 dioxygenase (IDO1 or IDO2) or tryptophan 2,3 dioxygenase (TDO). Other than 3-hydroxykynurenine (HK), all subsequent metabolites require a vitamin B-6 (PLP)–dependent enzyme for generation. They show that ratios of HK to metabolites downstream of PLP-dependent enzymes [xanthuranic acid (XA), 3-hydroxylanthranilic acid (HAA), and kynurenic acid] correlate with PLP concentrations better than HK alone. The relation was strongest at the lowest PLP concentrations, and importantly, the ratios normalized after vitamin B-6 supplementation was instituted...

...For example, the immunomodulatory capacities of IDO are in part driven by kynurenines directly suppressing inflammatory T cell responses (5). This same mechanism likely supports tumoral immune escape in IDO- and TDO-expressing cancers. Both kynurenine and quinolinic acid (another kynurenine metabolite downstream of PLP-dependent enzymes) directly support tumor cell proliferation by activating β-catenin signaling in colon tumors (6). This pathway also promotes tumor growth through activation of the human aryl hydrocarbon receptor in other tumor types (7). Kynurenine itself also has vasodilatory properties and perhaps acts as a compensatory mechanism in atherosclerotic coronary disease (8). Finally, several of the kynurenine metabolites have neuromodulator effects that are predicted to play important roles in both psychiatric and neurodegenerative disorders

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498264/
 
Messages
193
Likes
462
@HTester has suggested that excess serotonin production happening in only a relatively tiny population of cells
("Reading_Steiner" = Steins;Gate anime fan...?)
yes but I prefer the original material more, I read half of it in japanese last year, I have a lot of time ....

I have looked at a few things and I am getting the idea... it could be something like metabolic trap in a specific function to do with preventing autoimmunity or CDR.... so lots of autoantibodies appear or mito fragments or something... then later on the autoantibodies cause constriction of blood vessels in combination with the dynamic changes to the cellular respiration, produces a difficult cellular environment which causes fatigue ... and somehow inflammation is also involved. Its likely some sort of cascade effect, and is potentially quite complex to figure out, and as you said about, not easy to test certain things, so much has to be done in theory.
 

junkcrap50

Senior Member
Messages
1,087
Likes
2,193
What' the latest with this trial? Have they begun it? Is this the reason for Whitney's mysterious "Year of the Cure" and "cure" references on facebook?