OMF to launch clinical trials on Mestinon & Kynurenine, post-COVID19 study

I hope they are aware that Mestinon is contraindicated in some diseases that could be mistaken as ME/CFS such as slow channel congenital myasthenic syndrome, a genetic disease.
https://rarediseases.org/rare-diseases/congenital-myasthenic-syndromes/
Summary The congenital myasthenic syndromes (CMS) are a diverse group of disorders that have an underlying defect in the transmission of signals from nerve cells to muscles. These disorders are characterized by muscle weakness, which is worsened upon exertion. The age of onset, severity of presenting symptoms, and distribution of muscle weakness can vary from one patient to another.
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Kinetic Defect in AChR: The Slow-Channel Syndrome
......
This syndrome does not respond to, or is worsened by, pyridostigmine but is improved by relatively high doses of fluoxetine (Prozac) which blocks (plugs) the acetylcholine receptor ion channel and thereby reduces the length of channel openings.
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It is also the drug implicated in GWI - soldiers took high doses as a preventative nerve agent measure. Below are some of the side effects listed from a GWI article. Mestinon/pyridostigmine does not just effect acetylcholine as acetylcholine drives Muscarinic and nicotinic channels ........
https://www.ncbi.nlm.nih.gov/books/NBK222848/
Side effects of PB are generally related to the large doses given to myasthenics; in surgical patients, adverse reactions are controlled by simultaneous administration of atropine (Williams, 1984). Adverse reactions may be muscarinic or nicotinic (also see Chapter 5), both reactions are due to increased acetylcholine (ACh). Muscarinic reactions include nausea, vomiting, diarrhea, abdominal cramps, increased peristalsis, increased salivation, increased bronchial secretions, miosis, and heavy perspiration. Nicotinic effects are chiefly muscle cramps, fasciculations, and weakness (Williams, 1984).
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The clinical trial info linked above by @cassava7 may only be one dose, but I gather from patient stories of visits to Dr. Systrom that many patients end up on Mestinon as a potential treatment.


I guess what I'm trying to say is that I would like to see ME/CFS clinical trials be more honest on potential mechanisms, possible benefits, and the risks. Just as several folks on the recent Intravenous Cyclophosphamide in ME/CFS thread have educated us that Cyclophosphamide even if somewhat beneficial in the trial it has side effects and long term risks that make it's use in ME/CFS in clinical practice unlikely.
 
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There's something upstream of kynurenine that's wrong and increasing it won't (shouldn't) help. This is all theoretical so my word is as good as theirs, they are not doing intracerebral dialysis measurements on humans any more than I am, nor are there any results for imaging.

Tryptophan is protective against neuroinflammation, and its supply is being immediately exhausted at the neuronal level, thus the downstream kynurenine is low. This happens in a lot of infections: "Tryptophan depletion as a mechanism of gamma interferon-mediated chlamydial persistence", for instance.

The problem is it has nothing to do with anything, and L-KYN could make patients worse.

Quickly, from here:

"Interestingly, acute systemic administration of L-kynurenine, the enzymatic product of IDO, precipitated an anhedonic [me: reduced feelings / pleasure] and anxiogenic [anxiety-inducing] effect in naïve mice without effect on eLMA."

"Finally, our data found that the EBV dUTPase protein modulates tryptophan, serotonin, and DA metabolism and use in vitro and in vivo. The EBV dUTPase may alter kynurenine catabolism in microglia in vitro, suggesting that there is an increase synthesis of quinolinic acid."

So the question becomes, would you treat Chlamydia or chronic active Epstein Barr virus patients with... L-kynurenine? No.
 
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wigglethemouse said:
I hope they are aware that Mestinon is contraindicated in some diseases that could be mistaken as ME/CFS such as slow channel congenital myasthenic syndrome, a genetic disease.
https://rarediseases.org/rare-diseases/congenital-myasthenic-syndromes/



It is also the drug implicated in GWI - soldiers took high doses as a preventative nerve agent measure. Below are some of the side effects listed from a GWI article. Mestinon/pyridostigmine does not just effect acetylcholine as acetylcholine drives Muscarinic and nicotinic channels ........
https://www.ncbi.nlm.nih.gov/books/NBK222848/

The clinical trial info linked above by @cassava7 may only be one dose, but I gather from patient stories of visits to Dr. Systrom that many patients end up on Mestinon as a potential treatment.


I guess what I'm trying to say is that I would like to see ME/CFS clinical trials be more honest on potential mechanisms, possible benefits, and the risks. Just as several folks on the recent Intravenous Cyclophosphamide in ME/CFS thread have educated us that Cyclophosphamide even if somewhat beneficial in the trial it has side effects and long term risks that make it's use in ME/CFS in clinical practice unlikely.
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Interesting, I have a group of neuromuscular complaints (or that's the closest thing I can call them). They are essentially feelings of tightness and points of pressure and pain along the left side of my spine, about an inch out, from my jaw inwards to a major point of pain at the bottom of my thoracic spine. Right side is completely fine. I've mentioned dystonia to a number of doctors but they didn't seem interested in it after a physical exam. Still have never figured it out (I don't even know it's muscles or nerves or neurologic) nor seen another pwme describe something similar. Those conditions don't fit the bill however (and the later one shouldn't be a concern for this study, it seems like aggresive early onset neurolgic type weakness).

Anyway when I tried mestinon for pots/cfs I noticed a worsening of these symptoms. Likewise, my fatigue and other symptoms were unchanged although there was a minor simulant effect at 60mg. I gave it a few weeks. During this time I regularly timed my exercise and found 0 improvement in exercise intolerance and PEM.

I can see the stimulant effect being problematic in the same way trials of stimulants can create better response bias - including the steps walked, a iffy objective measure - without actually improving the condition. That said, I see the occasional person report mild benefit.
 
$150.000? yeah, i think im done with giving my money to the OMF when its used to reinvent the wheel. Imagine using this amount for new, not 100 times tested before treatments like SS31 or suramin.
 
News on the Kynurenine trial from OMF: https://www.omf.ngo/2020/05/26/omf-announces-new-treatment-trial/

The trial will be randomized, double-blind, placebo-controlled, crossover. No healthy control group (not necessary).
Participants will be randomized to either receive Kynurenine or a placebo for a period of three months and then after a “washout” period, patients will switch to an additional three-months of Kynurenine or placebo in a crossover design.

This design does not require healthy controls and instead focuses on whether Kynurenine supplementation has any benefit above placebo in people with ME/CFS.

The main study endpoints will be the effects of supplemental Kynurenine to improve cognitive impairment (“brain fog”), memory and headache. Patients will also be asked to register their activity by using wearable sensors and have biological samples taken for further testing.
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An explanation from Robert Phair on why brain fog is the chosen endpoint
Suppose that some brain cells in a particular brain nucleus are in the IDO metabolic trap. This means that in those cells the concentration of tryptophan is too high, and the concentration of kynurenine is too low.

Supplying an outside source of kynurenine, as Dr. Bergquist proposes, could conceivably solve part of the problem by allowing those brain cells to make the neuroactive metabolites of kynurenine that they cannot make if the metabolic trap has been sprung.

So, the clinical trial might improve symptoms caused by too little kynurenine or too little kynurenic acid, a known neuro-protectant.
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Jaybee00 said:
Hopefully they’ll post it here. https://clinicaltrials.gov/

I want to know if this (kyn) is orally administered or via IV. If oral, maybe it won’t pass the blood brain barrier? If via IV, will it automatically pass the BBB?

If it works, but folks will need daily IV infusions (or injections) then probably not so great.
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Since they've specifically highlighted that brain cells may be trapped "intracellular tryptophan too high - kynurinine pathway not working" then they'll have figured out that kynurinine crosses the blood brain barrier - I guess. If you look at the picture, this is a leading group of scientists/clinicians (Jonas s a medical doctor as well as a PhD) - impressive lineup. Neatly thought out trial --- good luck.
 
Jaybee00 said:
If it works, but folks will need daily IV infusions (or injections) then probably not so great.
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It would still be important to know that it works, though, as it could provide some hard evidence of a metabolic trap. If the trap is real, there may be other, better ways to treat it; at the very least, we would know that it's worth channelling resources into further research.
 
Kitty said:
It would still be important to know that it works, though, as it could provide some hard evidence of a metabolic trap. If the trap is real, there may be other, better ways to treat it; at the very least, we would know that it's worth channelling resources into further research.
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there is no trap...
 
strategist said:
My guess is the decision to conduct a clinical trial of kynurenine means they have some new information.
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I'm pretty sure you guys are way ahead of me here. Kynurenine came up following Robert Phairs work on IDO2 i.e. blockage in the conversion of tryptophan to kynurenine owing to IDO2 not working(?). Anyway Robert's work ran into difficulties, measuring the level of intracellular tryptophan wasn't that easy!
Turned out Jonas's team had already produced medical grade kynurenine (for an un-related project) and was pretty much set up to test whether kynurenine supplementation would help. Sort of trying out Robert's 1DO2 hypothesis by another route.
Haven't heard anything about pilot data @strategist
 
wigglethemouse said:
We should all remember treatments can have positive as well as negative outcomes. Will OMF explain the proposed benefit of increasing kynurenine, and what the risks are? We've yet to see ANY convincing data for the metabolic trap, two years after work first started!!!

There seems to be a lot of articles about the relationship between the kynurenine and Schizophrenia. Anyone have any knowledge in this area? A bit concerning.
https://www.google.com/search?client=firefox-b-1-d&q=kynurenine+schizophrenia
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Not sure what I'm going to say here.

If someone with severe ME was assessed by a psychiatrist, I wonder if Schizophrenia would be a potential diagnosis?

I'd like to see more biomedical research on psychiatric diseases like Schizophrenia e.g. GWAS studies - people with ME, and people with psychiatric diseases, have a lot in common - they could be better served e.g. by increased funding for biomedical research.
 
butter. said:
there is no trap...
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I've no idea whether there is a trap or not. However, Chris Armstrong found low levels of amino acids in blood (low because they were used for cellular energy production?) and glucose was elevated (because it wasn't been used as the "normal" preferred energy source?). Fluge and Mella refined this by identifying that it was a certain class of amino acids which were lower and that there was a factor in the blood causing the switch to utilising these amino acids.

The uptake of amino acids, in the absence of an adequate clearance mechanism (1DO2), might cause problems - amino acids like tryptophan are highly toxic even at relatively low intracellular concentrations.

I'm an interested amateur --- not a professional, so don't assume I'm adding this up correctly!
 
I don't know if this is the right thread to post it or if there is a general OMF Trials thread, but in Cort's blog he mentioned they will also conduct a trial with Abilify. So, I believe that's 4 trials (Abilify, kynurenine, mestinon and Chris Amrstrong's study).
 
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OMF posted an update on the Kynurenine trial at some point:
  • IRB approval has been obtained and trial conducted in healthy volunteers. Paper published. [paper]
  • Analysis of preliminary data for ME/CFS patients did not indicate significant disturbances in the Kynurenine pathway so further trials steps on hold.
For the Mestinon trial, it was published last year, thread here.
 
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