Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine (Joseph et al, 2022)

Consul

Senior Member
Messages
318
Likes
1,061
Authors

Phillip Joseph,
Rosa Pari,
Sarah Miller,
Arabella Warren,
Mary Catherine Stovall,
Johanna Squires,
Chia-Jung Chang,
Wenzhong Xiao,
Aaron B. Waxman,
David M. Systrom,

Abstract

Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, post-exertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS.
Research Question
Does neurovascular dysregulation contribute to exercise intolerance in ME/CFS and can its treatment improve exercise capacity?

Methods
Forty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60 mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 minutes later. The primary end point was the difference in peak exercise oxygen uptake (VO2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange.

Results
Twenty-three subjects were assigned to pyridostigmine and 22 to placebo. The peak VO2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs. -40.2 ± 21.3 mL/min, P<0.05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak versus rest VO2 (25.9 ± 15.3 mL/min vs. -60.8 ± 25.6 mL/min, P<0.01), cardiac output (-0.2 ± 0.6 L/min vs. -1.9 ± 0.6 L/min, P<0.05), and RAP (1.0 ± 0.5 mm Hg vs. -0.6 ± 0.5 mm Hg, P<0.05) were greater in the pyridostigmine group compared to placebo.

Interpretation
Pyridostigmine improves peak VO2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise VO2, Qc, and RAP after placebo may signal the onset of post-exertional malaise. We suggest treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS.

The study: https://journal.chestnet.org/article/S0012-3692(22)00890-X/pdf
 
Last edited:

Pyrrhus

Senior Member
Messages
4,171
Likes
12,769
Location
U.S., Earth
Thanks for posting this follow up to David Systrom's previous paper:

Exercise Intolerance: Insights from Invasive Cardiopulmonary Exercise Testing of Patients with ME/CFS (Joseph et al., 2021)
https://forums.phoenixrising.me/thr...patients-with-me-cfs-joseph-et-al-2021.82907/

This previous paper concluded that:
Aerobic exercise intolerance in ME is caused by vascular dysautonomia, which the authors refer to as "neurovascular dysregulation".


It's great to see that David Systrom is now using a prospective RCT to test the conclusion of his previous paper, which had used a retrospective analysis based on a convenience sample. The study design of this paper is much more robust than the one used in his previous paper.

But it's still disappointing to see him use a cholinergic drug like pyridostigmine (mestinon) instead of an adrenergic drug like atomoxetine (strattera). Neurovascular junctions use adrenergic receptors, not cholinergic receptors.

Cholinergic receptors are used at the neuromuscular junction, not at the neurovascular junction. This means that this study used a drug that temporarily strengthens muscles, not a drug that temporarily improves vascular circulation.

Therefore the improvement seen in peak VO2 could simply be due to stronger heart muscles and stronger lung muscles, and could have nothing to do with the vascular dysautonomia (neurovascular dysregulation) that his previous paper found.

So, despite a much improved study design, one can not really say that this study confirms the findings of the previous study.
 

Pyrrhus

Senior Member
Messages
4,171
Likes
12,769
Location
U.S., Earth
what about the synapses that appear before the neurovascular junctions, arent most of those dependent on acetylcholine so that this drug will make those synapses fire more reliably? So the neurovascular junctions might not fire more reliably but all the synapses upstream of them will?
Yes, that is exactly right for autonomic nerves.

So, the question is:
Is the effect of pyridostigmine on these upstream autonomic synapses more dominant than the effect of pyridostigmine on the neuromuscular junctions? Can we even untangle these two effects in an exercise study?
 

mitoMAN

Senior Member
Messages
612
Likes
1,177
Location
Germany/Austria
Thanks for posting this follow up to David Systrom's previous paper:

Exercise Intolerance: Insights from Invasive Cardiopulmonary Exercise Testing of Patients with ME/CFS (Joseph et al., 2021)
https://forums.phoenixrising.me/thr...patients-with-me-cfs-joseph-et-al-2021.82907/

This previous paper concluded that:
Aerobic exercise intolerance in ME is caused by vascular dysautonomia, which the authors refer to as "neurovascular dysregulation".


It's great to see that David Systrom is now using a prospective RCT to test the conclusion of his previous paper, which had used a retrospective analysis based on a convenience sample. The study design of this paper is much more robust than the one used in his previous paper.

But it's still disappointing to see him use a cholinergic drug like pyridostigmine (mestinon) instead of an adrenergic drug like atomoxetine (strattera). Neurovascular junctions use adrenergic receptors, not cholinergic receptors.

Cholinergic receptors are used at the neuromuscular junction, not at the neurovascular junction. This means that this study used a drug that temporarily strengthens muscles, not a drug that temporarily improves vascular circulation.

Therefore the improvement seen in peak VO2 could simply be due to stronger heart muscles and stronger lung muscles, and could have nothing to do with the vascular dysautonomia (neurovascular dysregulation) that his previous paper found.

So, despite a much improved study design, one can not really say that this study confirms the findings of the previous study.
I used Atomoxetine ( Strattera ) up to 80mg for ADHD with zero effect on CFS
 

Pyrrhus

Senior Member
Messages
4,171
Likes
12,769
Location
U.S., Earth
I used Atomoxetine ( Strattera ) up to 80mg for ADHD with zero effect on CFS
Please feel free to share your experience in the atomoxetine thread:
https://forums.phoenixrising.me/threads/strattera-atomoxetine.19755/

Note that it is used for vascular dysautonomia (orthostatic intolerance or aerobic exercise intolerance), not for all ME/CFS symptoms. If you don't have vascular dysautonomia (orthostatic intolerance or aerobic exercise intolerance), then there's probably no reason to try it.
 

mitoMAN

Senior Member
Messages
612
Likes
1,177
Location
Germany/Austria
Please feel free to share your experience in the atomoxetine thread:
https://forums.phoenixrising.me/threads/strattera-atomoxetine.19755/

Note that it is used for vascular dysautonomia (orthostatic intolerance or aerobic exercise intolerance), not for all ME/CFS symptoms. If you don't have vascular dysautonomia (orthostatic intolerance or aerobic exercise intolerance), then there's probably no reason to try it.
ah I see I have strong SFN (proven by Biopsy), POTS and very strong OI (I am severe, can hardly sit upright until I started my endothelial protocol)
 

Avena

Senior Member
Messages
136
Likes
183
Sad fact from my CFS neurologist.
40% patients don't tolerate Mestinon at all
10% have significant improvements.
The rest either nothing or minor improvements
Did they mention details on how the 40% react? What symptoms get worse?
 
Messages
79
Likes
315
Location
Spain
I started Mestinon few days ago. First 15mg, then 30mg and now I'm taking 45mg.

It was prescribed by my Neurologist. I was a little bit afraid about taking it. Thus far I tolerated it well. I pretend to reach 60-120mg/day

I did not notice any benefit (nor bad effect) yet.

At least this study give me one more reason for keeping with it.

If I don't see any improvement I will try Abilify and/or Pentoxifiline next, while keeping an eye on what the NIH does..

Guinea pig mode activated... :sluggish: