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A1 agonists to treat CFS/ME + OI? (A1 adrenergic autoantibodies / CellTrend)

Discussion in 'Problems Standing: Orthostatic Intolerance; POTS' started by Jesse2233, Aug 10, 2017.

  1. Jesse2233

    Jesse2233 Senior Member

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    TL;DR

    Has anyone tested positive for A1 autoantibodies and successfully reduced symptoms (OI or otherwise) using A1 agonists?


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    I recently tested positive through CellTrend for A1 autoantibodies (and no other ones save for being at risk on M4). This led me to a rabbit hole of research into potential treatments I've not seen widely discussed here.

    The A1 (alpha-1 adrenergic) receptor primarily mediates smooth muscle contraction (vasoconstriction) via the central and peripheral nervous system. Autoantibodies against this receptor have been implicated as a causal factor in one POTS study (1) and identified as a CFS/ME subset in another (2).

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    Readily available A1 agonists
    • Midodrine (antihypotensive) - Oral Rx common in first line POTS treatment
    • Butchers broom (herbal) - Oral OTC supplement derived from the Ruscus aculeatus plant
    • Phenylephrine (decongestant) - Oral OTC as Sudafed PE, have seen good anecdotal results
    • Pseudoephedrine (decongestant) - Oral OTC as Sudafed (old formula)
    • Naphazoline (decongestant) - Eye drops OTC, Rx strength (0.10%) used by Dr Jay Goldstein
    • Oxymetazoline (decongestant) - Nasal spray OTC found in Sudafed OM, Vicks Sinex, and Zicam
    • Tetrahydrozoline (decongestant) - Eye drops OTC, found in Visine and the movie Wedding Crashers
    • Xylometazoline (decongestant) - Nasal spray OTC used to improve symptoms of nasal congestion
    Less available A1 agonists
    • Synephrine (mild vasoconstrictor) - Alkaloid found in citrus fruits and various sups / pharamceduals
    • Etilefrine (antihypotensive) - IV Rx for orthostatic hypotension of multi-system origin
    • Metaraminol (antihypotensive) - IV RX used in the prevention and treatment of hypotension
    Unavailable A1 agonists
    • Cirazoline (vasoconstrictor) - Research compound and full A1 agonist
    • Methoxamine (vasoconstrictor) - Discontinued oral Rx
    Tagging some people who might be interested or could provide additional insight: @Lolinda @halcyon @Hip @Gingergrrl
     
  2. Hip

    Hip Senior Member

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    Probably CellTrend test did not indicate whether your alpha-1 adrenergic autoantibodies have agonist or antagonist effects at the receptor (because this is more difficult to determine). So it is not clear what effect, agonism or antagonism, your autoantibodies might be having.

    This study says activation of the alpha-1 adrenergic receptor likely leads to vasoconstriction in the cerebral blood vessels. Since ME/CFS involves hypoperfusion of the brain anyway, any further vasoconstriction might make things worse. So perhaps you might want to look at alpha-1 antagonists (see also the list here) for vasodilation rather than agonists. Although I would think that such antagonists might make POTS symptoms worse.



    Isn't that beta-2 adrenergic autoantibodies they found in that ME/CFS study you cited, by the way?
     
    Last edited: Aug 10, 2017
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  3. Jesse2233

    Jesse2233 Senior Member

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    Thanks @Hip

    It hadn't occurred to me that the autoantibodies could actually be agonistic and therefore indicate use of an antagonist. Hmm. I suppose I could try Sudafed-PE and (at a separate time) an OTC A1 antagonist and see which one benefits me.

    Regarding POTS and A1, the first study abstract states:
    Edit: And yes B1-2 and M1-5 ABs were found in the ME/CFS study but if you look at the chart they also indicate A1

    Also in certain cases might vasoconstriction also for greater blood flow by allowing a more concentrated flow of blood to reach the brain (like a hose that when tightened pushes the water further?).
     
    Last edited: Aug 11, 2017 at 1:12 AM
  4. Jesse2233

    Jesse2233 Senior Member

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    I have emailed Dr Heidecke at CellTrend to inquire whether the autoantibodies are antagonistic or agonistic
     
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  5. Gingergrrl

    Gingergrrl Senior Member

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    Thanks, Jesse, for starting this thread and Midodrine has been helpful for me in the past and at present. Although Midodrine varied for me, and at times lost effectiveness, but has been much more helpful to me after doing IVIG (although I am not sure why)?

    I tested positive for 7 of the 9 Cell Trend autoantibodies (both times I did the test) and for the one you are focusing on, the anti a-1 adrenergic autoantibody, on my first test it was 22.6, and my second test it went up to 27.3, and the top of the range was 7.0!

    I'll give you all my numbers for the first test in case they provide anything useful:

    1) Anti a-1 adrenergic: 22.6 (top of range 7.0)
    2) Anti a-2 adrenergic: Negative
    3) Anti B-1 adrenergic: 30.4 (top of range 15.0)
    4) Anti B-2 adrenergic: 18.3 (top of range 14.0)

    5) Anti Muscarinic/Cholinergic R1:
    13.0 (top of range 9.0)
    6) Anti Muscarinic/Cholinergic R2: 9.6 (top of range 9.0- so this one very slight)
    7) Anti Muscarinic/Cholinergic R3: 24.1 (top of range 10.0)
    8) Anti Muscarinic/Cholinergic R4: 27.0 (top of range 7.0)
    9) Anti Muscarinic/Cholinergic R5: Negative

    I had several e-mails with Dr. Heidecke when I was trying to arrange the first test and then we ended up scheduling a phone call and he answered all of the questions that I had. He was very generous with his time and very helpful so I will be curious what you learn.
     
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  6. Gingergrrl

    Gingergrrl Senior Member

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    @Strawberry wanted to be tagged into this thread, too, so am tagging her.
     
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  7. Jesse2233

    Jesse2233 Senior Member

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    That's great! What sort of benefits did you notice?

    Wow I'd forgotten you had so many! High numbers too. Can't wait to see how Rituximab affects them

    Welcome @Strawberry !
     
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  8. Gingergrrl

    Gingergrrl Senior Member

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    With Midodrine it helped my breathing when I stood up and the doctors thought it helped to bring more blood to my lungs and heart when standing through "preferential perfusion" (even when it did not raise my BP on a arm cuff).

    My BP though stayed around 80/50 even with Midodrine. When I tried it again after IVIG, it helped to raise my BP, too, which is now around 100/70 on most days.

    I will be very curious to see how my Cell Trend tests change (or do not change) after Rituximab, too! And also my other autoantibodies especially the CA+ Ab.
     
    Last edited: Aug 11, 2017 at 10:18 AM
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  9. Learner1

    Learner1 Professional Patient

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    Jesse,

    I have high A1 and M4 and am happy you brought this topic up.

    Interestingly, my BP has been running high (140/90 to 165/105) over the past few months without meds. I have POTS as well.

    I'd love to fix this as the symptoms affect my ability to function.

    My concern with the list of meds you mentioned is that they might raise my blood pressure further.

    The other concern is the effect any of the meds might have on mitochondria.
     
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  10. Hip

    Hip Senior Member

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    Yes, I believe they can have both agonistic or antagonistic effects at the receptor, but a lot of studies don't seem to investigate which, because that involves more detective work. It is relatively easy I think to determine whether an autoantibody has affinity for a given receptor; but demonstrating that an autoantibody binds to a receptor does not in itself tell you whether that autoantibody blocks or activates the receptor, that requires extra work.

    But that info is useful to know if you are a patient, and want to figure out a way to compensate for the effects of autoantibodies that you know you have: obviously if it blocks the receptor, you might want to try an agonist drug to compensate; and if it activates the receptor, you might want to try an antagonist drug.

    I while ago I went through all the studies I could find on autoantibodies in ME/CFS, POTS and orthostatic hypotension, and created the autoantibody table shown in this post. I have updated it a few times when new studies were published, so I think the table is still up to date.



    Is that fig 1 of the Fluge and Mella paper that you are looking at, where they compare the number of ME/CFS patients found to have various autoantibodies to the healthy controls? I'd only previously read the abstract of this paper.

    I wonder why they did not mention β1 autoantibodies in the abstract, only β2 (as well as M3 and M4)? Looking at fig 1, there are much more β1 and β2 autoantibodies in patients compared to controls.

    Perhaps they omitted to mention β1 because they may have concluded these β1 autoantibodies came from the POTS comorbidity, rather than from ME/CFS itself. Previous studies have shown β1 autoantibodies in POTS.

    Fluge and Mella found 47 out of 268 patients = 18% had β1 autoantibodies, and 18% is roughly the prevalence of POTS in ME/CFS. So POTS could explain those β1 autoantibodies.

    So possibly the β1 autoantibodies Fluge and Mella found came from POTS, and the β2 autoantibodies came from ME/CFS.



    I would not have thought so. Constricting a hose will push the water further because the pressure builds up in the hose; but I think you would find that the flow rate (liters per minute) through a constricted hose will still be less than a free hose.

    Intriguingly though, Dr Goldstein found that as ME/CFS patients improved in response to his drug treatments, this coincided with increased hypoperfusion (= less blood flow) in the brain. See this post:
     
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  11. Gingergrrl

    Gingergrrl Senior Member

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    @Hip If IVIG or Ritux knocked out the autoantibodies, would it matter if they ended up being agonist vs. antagonist?

    I know the info would be useful, and would guide which meds to use, but could treatments that knock out autoantibodies work even without knowing the info?

    I hope this question makes sense!
     
  12. Hip

    Hip Senior Member

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    If there are no more autoantibodies after rituximab treatment, they cannot have any further pathogenic effects, neither agonist nor antagonist.
     
    Last edited: Aug 11, 2017 at 12:35 PM
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  13. Gingergrrl

    Gingergrrl Senior Member

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    Thanks and that is what I assumed but wanted to confirm. (Although I'd still like to know the answer if Jesse reaches Dr. Heidecke)!!
     
  14. Jesse2233

    Jesse2233 Senior Member

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    @Hip

    This study shows that cognitive performance (n-back performance) while standing (HUT) improved in CFS patients who had received phenylephrine due to increased cerebral blood flow velocity (CBFv).
     
    Last edited: Aug 11, 2017 at 2:26 PM
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  15. Jesse2233

    Jesse2233 Senior Member

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    Took 10mg of oral phenylephrine (OTC Sudafed PE) 20 minutes ago, let's see what happens...
     
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  16. Hip

    Hip Senior Member

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    I am interested to hear your report. It might take several days of taking it notice any cognitive benefits, if those benefits are relatively subtle. The half life of phenylephrine is 2.5 to 3 hours, so the benefits will wear off after say 6 hours.
     
  17. Jesse2233

    Jesse2233 Senior Member

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    Interesting, thanks for looking that up. So far I'm sitting upright and my HR is steady at 55 bpm. Brain fog is still present, but there may be improved clarity (or it's my imagination).

    Here's a write up of the phenylephrine study by Cort: https://www.healthrising.org/blog/2...ops-orthostatic-intolerance-mecfs-next-steps/

    Edit: It seems oral dosing of phenylephrine may not be enough:
    That may be the reason midodrine and not phenylephrine is a first line POTS treatment
     
    Last edited: Aug 11, 2017 at 2:42 PM
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  18. Hip

    Hip Senior Member

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    Look like the oral bioavailability is 38%, which is not too bad (this is due to the fact that phenylephrine undergoes extensive first-pass metabolism in the intestinal wall). Ref: 1

    It's possible that better bioavailability might be obtained by crushing the tablets into fine powder, and applying that transdermally on the skin, with a few drops of water. That will help avoid the first-pass metabolism in the intestinal wall.
     
  19. Jesse2233

    Jesse2233 Senior Member

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    What would be the best location to apply it transdermally?
     
  20. Gingergrrl

    Gingergrrl Senior Member

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    @Jesse2233 Does phenylephrine give you tachycardia?
     

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