Professor & patients' paper on the solvable biological challenge of ME/CFS: reader-friendly version
Simon McGrath provides a patient-friendly version of a peer-reviewed paper which highlights some of the most promising biomedical research on ME/CFS ...
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Soluble Guanylate Cyclase for use in treatment of CFS with B-cell depletion

Discussion in 'Rituximab: News and Research' started by deleder2k, May 31, 2015.

  1. deleder2k

    deleder2k Senior Member

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    New patent application from Øystein Fluge and Olav Mella:

    ACTIVATORS OR STIMULATORS OF SOLUBLE GUANYLATE CYCLASE

    FOR USE IN TREATING CHRONIC FATIGUE SYNDROME

    Some key points:


    [​IMG]

    Source: http://worldwide.espacenet.com/publ...T=D&ND=3&date=20150507&DB=EPODOC&locale=en_EP


    Looks interesting. And it seems that this is more potent than isosorbide mononitrate (Imdur).

    A major drawback is the price of Riociguat. In Norway a pack of 28 costs $4000. The drug was recently introduced. Trade name is Adempas.
     
    Last edited: May 31, 2015
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  2. Bob

    Bob

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    Thank-you deleder.

    My brain's not working at the moment, and the above text looks rather complicated, with lots of words I've never seen before. Is anyone able to give a brief explanation of what it means?
     
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  3. deleder2k

    deleder2k Senior Member

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    Here is the patent filing for the use of nitric oxide in CFS thread: http://forums.phoenixrising.me/inde...ith-or-without-b-cell-depletion-in-cfs.36592/

    This drug looks even more efficient in restoring endothelial function.


    @Bob, I don't understand much of this. Hopefully someone can explain how the drug works for normal human beings ;). Take a look at the other thread in the meantime.

    This is their hypothesis (at least it was like this a few months ago): [​IMG]
     
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  4. A.B.

    A.B. Senior Member

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    I can't say I fully understand it either but Wikipedia says that soluble guanylate cyclase (sGC in short) is an enzyme in cells that is activated by NO and involved in vasodilation.

    Taking a stimulator of sGC is just another way to achieve vasodilation, and apparently one with fewer side effects.

    A shame the drug is so expensive. Isosorbide mononitrate gives me a nasty headache.

    Edit: I think I finally got it.
     
    Last edited: May 31, 2015
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  5. Marky90

    Marky90 Science breeds knowledge, opinion breeds ignorance

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    Yeah i felt quite lousy on Imdur as well... Only tried one day though. I rather wait for this! :)
     
  6. leokitten

    leokitten Senior Member

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    This is just so compelling thank you @deleder2k. It almost shocks me that before Fluge and Mella no one was looking into this other than the small paper done by Newton et al. (Dundee)

    The reduced endothelial NO vascular dysfunction theory really does explain most if not all the symptoms of ME/CFS, including low NK function which some people might not know.

    Now I keep asking myself what is going on that is causing us to not produce enough endothelial NO? And how is this possibly linked to some b-cell mediated process? Very interesting...
     
    Last edited: May 31, 2015
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  7. Jon_Tradicionali

    Jon_Tradicionali Alone & Wandering

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    Yes this patent was filed recently after Fluge/Mella noticed 'instant remission' as they're now being termed, in some of his patients.
    This came after they noticed NO donors were working in some patients but not all.

    As per cGMP, it is formed from NO stimulation of GC-C receptor. Its thought provoking (or not ) that it is found predominantly in the intestine.

    A proven way (in animal testing) to restore the glutamate-NitricOxide-cGMP pathway:

    • a)
      phosphodiesterase 5 inhibitors (sildenafil, zaprinast), that increase cGMP levels by reducing its degradation

    • b)
      extracellular cGMP

    • c)
      antagonists of type A GABA receptors (bicuculline)

    • d)
      neurosteroids that modulate GABAergic tone (pregnenolone sulfate)

    • e)
      inhibitors of cyclooxygenase (ibuprofen) which reduce neuroinflammation

    • f)
      inhibitors of MAP- kinase p38 (SB239063), that reduce microglial activation and neuroinflammation
    http://www.newhorizonsintranslationalmedicine.com/article/S2307-5023(14)00047-2/abstract

    SGC stimulator is second-line choice. sGC activator Cinaciguat is what we would require as Fluge/Mella also themselves acknowledge.
    However the activator is still in experimental stages.
     
  8. alex3619

    alex3619 Senior Member

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    In my case the headache disappeared after about a week. This is a common finding on isosorbide mononitrate.

    Phosphodiesterase inhibitors include resveratrol, though this targets phosphodiesterase 4 primarily. I will not willingly give this up, its effects are too useful.

    Restoration of the NO pathways may be specific to our problems though. Treatments for other causes might not work. However these create a list of things that can be tried and formally tested.
     
    Last edited: Jun 1, 2015
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  9. leokitten

    leokitten Senior Member

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    From what I read the already available riociguat is actually better than cinaciguat, because riociguat can stimulate sGC independently of NO, from Wikipedia:
     
  10. Navid

    Navid Senior Member

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    Hi:

    Is this a drug that a US Dr. if willing can prescribe to a ME/CFIDS patient off label. Are there tests that would show whether or not this would be an appropriate drug for one to take. Finally, how is this drug delivered (IV, SUBq....etc). Sorry for stupid questions. I am scientifically ignorant....but bedbound w/ME. I have tried almost every treatment out there and nothing has helped.....desperate like so many others out there. Thanks for any and all help. Is there a US ME Doc who is up on this work of Fluge and Mella and the results they have been having with drug.

    Thanks : )
     
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  11. duncan

    duncan Senior Member

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    God. I feel embarrassed posting this, but it may have relevance in some of these endothelial NO ME/CFS cases:

    Borrelia Burgdorferi have been demonstrated in vitro to invade endothelial cells intracellularly. I don't know the significance of that, or whether enteroviruses do the same, or some other pathogen. I think it's clear Fluge and Mella don't think Bb is pertinent.

    I realize, too, there are significant reasons why Bb cannot equate to ME/CFS. For instance, the heavy female portion of the ME/CFS community runs counter to Bb demographics.

    I point out these Lyme data not to undermine a thread or be contentious. I post them because I have questions about how they play into a development, and because others besides me may find the data interesting.

    I also realize how sometimes I can sound like a broken record, and for that, my apologies in advance.
     
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  12. leokitten

    leokitten Senior Member

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    Both CMV and HHV-6 invade vascular endothelial cells as well but...

    We have to not confuse things and remember here that Fluge and Mella are seeing significant symptom remission from Rituximab alone for 2/3rds of patients and if this turns out to be real then it goes against the chronic infection theory of ME/CFS for this subset.

    The reason they are also experimenting with these other other drugs is because they have been seeing vascular dysfunction in patients and believe this is driving symptoms so are trying therapies that can give more immediate relief in conjunction with rituximab therapy.
     
    Last edited: May 31, 2015
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  13. Bob

    Bob

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    I'm not so tired this morning, and managed to read it all. The above quote sums it up in a nutshell. So it looks like Fluge and Mella have now found a fast acting drug (Cinaciguat and/or Riociguat) for improving a range of symptoms in ME patients. The 'example' at the end of deleder's opening post outlines the fast positive response that they've seen in a (mild to moderately affected) CCC ME patient (of ten years) after six days of administering Riociguat. The patient had not previously been prescribed rituximab. Improvements were seen in: energy, fatigue, brain fog, concentration, sore throat, and hyper-sensitivity to sound and light. The improvements were thought to be significant and beyond the range of normal fluctuation.
     
    Last edited: Jun 11, 2015
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  14. Jon_Tradicionali

    Jon_Tradicionali Alone & Wandering

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    Riociguat and all other sGC stimulating compounds are inferior to Cinaciguat and sGC activators.

    If that's quoted from Wiki then it's incorrect as stimulators are NO independent BUT they are haem dependant. This is contrast to activators which are both NO and haem independent which makes them much superior in activating sGC receptors burdened by oxidative stress (which applies to us).

    "The second group comprises the sGC activators (including BAY 58–2667 and HMR-1766), which have been found to require neither NO nor haem, and demonstrate even more pronounced action on the oxidized form of sGC."

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2225477/
     
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  15. Asa

    Asa Senior Member

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    "A major drawback is the price of Riociguat. In Norway a pack of 28 costs $4000. The drug was recently introduced. Trade name is Adempas."

    Is Riociguat something an ME/CFS patient would take for life?
     
  16. deleder2k

    deleder2k Senior Member

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    I don't think so. I think they write that it can be used until b-cell depletion (Rituximab, MTX) gives effect after weeks or months.

    This is just a proof of concept. As far as I am concerned they haven't done any large studies on this. If they have only tested this on one patient we have a long way to go. Hopefully they will do a phase 2 trial soon with either isosorbide mononitrate or this.
     
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  17. cigana

    cigana Senior Member

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    I do not know how similar isosorbide mononitrate is to isosorbide dinitrate in its mechanism of action, but I thought it was worth pointing out other PWMC's have had instant remission from the dinitrate (as discussed here).
     
  18. leokitten

    leokitten Senior Member

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    Does anybody know with what % of PWME are Fluge/Mella finding endothelial/vascular dysfunction? And secondly for this group what % have POTS/OI and what % are like me who got sudden higher blood pressure and blood volume and no POTS/OI?

    Still trying to understand how a person could have vascular/endothelial dysfunction and POTS/OI, because in vascular/endothelial function there is
    reduced NO like they've seen and this results in arteries and capillaries that do not expand, higher blood pressure, and sympathetic nervous activation resulting in further constriction of arteries and higher pressure. With POTS/OI your blood pressure gets very low.
     
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  19. deleder2k

    deleder2k Senior Member

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  20. Hutan

    Hutan Senior Member

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    @leokitten, yes, I'm confused too. I tried to explain this endothelial dysfunction theory to my husband and got tangled up at the part where the vessel walls aren't expanding. My blood pressure has always been low and my body is flexible - so I had the idea that overly-flexible arterial walls might have been part of my POTS problem. I ended up muttering to my husband 'umm, I think I need to read about this theory a bit more'.

    I have self-diagnosed POTS (reliably >30 bpm increase in heart rate from supine to standing, and dizziness). If I stand still, the heart rate and blood pressure increase. I think this started about six months after the ME onset. I'm waiting to see the specialist for confirmation.

    But actually, I am finding now that I am monitoring things more closely, I am having episodes of high blood pressure after exertion. As getting to my doctor involves exertion, my doctor is beginning to think I have hypertension. Dysregulation seems to be a word that applies to much about ME.
     
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