The Exercise Response to Pharmacologic Cholinergic Stimulation in ME/CFS, 2020/21, Systrom, phase2 trial registration

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Brief Summary:
Myalgic encephalomyelitis/Chronic fatigue syndrome (ME/CFS), otherwise known as Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME), is an under-recognized disorder whose cause is not yet understood. Suggested theories behind the pathophysiology of this condition include autoimmune causes, an inciting viral illness, and a dysfunctional autonomic nervous system caused by a small fiber polyneuropathy. Symptoms include fatigue, cognitive impairments, gastrointestinal changes, exertional dyspnea, and post-exertional malaise. The latter two symptoms are caused in part by abnormal cardiopulmonary hemodynamics during exercise thought to be due to a small fiber polyneuropathy. This manifests as low biventricular filling pressures throughout exercise seen in patients undergoing a level 3 CPET along with small nerve fiber atrophy seen on skin biopsy.

After diagnosis, patients are often treated with pyridostigmine (off-label use of this medication) to enhance cholinergic stimulation of norepinephrine release at the post-ganglionic synapse. This is thought to improve venoconstriction at the site of exercising muscles, leading to improved return of blood to the heart and increasing filling of the heart to more appropriate levels during peak exercise. Retrospective studies have shown that noninvasive measurements of exercise capacity, such as oxygen uptake, end-tidal carbon dioxide, and ventilatory efficiency, improve after treatment with pyridostigmine. To date, there are no studies that assess invasive hemodynamics after pyridostigmine administration.

It is estimated that four million people suffer from ME/CFS worldwide, a number that is thought to be a gross underestimate of disease prevalence. However, despite its potential for debilitating symptoms, loss of productivity, and worldwide burden, the pathophysiology behind ME/CFS remains unknown and its treatment unclear. By evaluating the exercise response to cholinergic stimulation, this study will shed further light on the link between the autonomic nervous system and cardiopulmonary hemodynamics, potentially leading to new therapeutic targets."
Drug: Pyridostigmine Bromide Phase 2

https://clinicaltrials.gov/ct2/show/NCT03674541

 

Pyridostigmine has been a fantastic PEM-busting drug for me, huge improvements in both threshold to PEM and recovery time from PEM.

I was only prescribed it once my autonomic dysfunction had deteriorated to become very clearly abnormal, with SFN suspected - 20 years on from initial ME/CFS diagnosis. Though there were signs of those problems right from the beginning.

It will be interesting to see if it shows the same value in the wider ME/CFS cohort as it has in patients like me (prior Systrom et al studies). After about 12M on 60mg TID i've recently increased to 90mg TID and seen another boost. I hope the proposed single 60mg dose planned in this trial is enough...

 

On our side, Mestinon, has not done anything, and shortly after taking it, side effects emerged which became intolerable, so the drug was stopped.

 

Just looked up Mestinon - it's pyridostigmine.

 

I'm really sorry to hear that @Perrier

I found the side effects annoying but thankfully tolerable and eventually they wore off. I had to start with a very very small dose and titrate up over a period of weeks/months. Increased sweating, eyes and nose running, some stomach gripes. Then they'd come back with every dose bump but thankfully the only persistent thing for me is probably some extra congestion.

I've talked about it before here but the first and most striking thing I noticed was that I could have a late night and not be utterly useless and brain fogged the next day. I then started to realise my achy legs and "blood pooling" symptoms were reduced and I had fewer labile blood pressure issues, particularly on days after activity. Eventually I realised I just had a great deal more cognitive capacity, I could sit at the computer for some hours and not have my brain turn to jelly. When I do go well over my limits my PEM is milder and now limited to 1-2 days max, rather than taking a week to recover.

For me its been no magic cure, it hasn't really reversed the considerable limitations on my physical activity. It seems to help with reducing the negative after-effect of activity though and has been wonderful for cognition. I've heard it referred to as a stimulant, if it is one its nothing like caffeine, there's no "wired" buzz or crash after - it just feels normal.

 

Yes, here this tiny titration method was also implemented, but the side effects were unmanageable. I recall reading on Cort's site when he addressed this issue, that a good number of people found they could not withstand this medication. I am very happy to hear that you at least have had some relief using this. I wonder if Dr Systrom has ever addressed the side effect problem; I have never heard him refer to it.

 

For those mentioning benefits/side effects, can you state which dosages you tried? In Australia, there is 10 mg, 60 mg, and 180 mg slow release, I'd expect experience of side effects may vary as a result.

 

I was advised to start with 30mg TID with a gradual increase to 60mg TID. Experience has taught me to be extra cautious so started with 15mg once a day and very gradually increased to recommended dose over about 3-4 months, side effects were indeed dose dependent. I was prescribed 60mg pills but they were pre-scored for quartering. I am lactose intolerant so switched them out for a lactose-free liquid formulation soon after.

Pyridostigmine was a little out of my cardiologist's comfort zone and he was hesitant to go above 60mg TID. More recently he referred me on to a leading Prof in a tertiary clinic, who was happy to bump it to 180mg TID + freedom to tailor the dose around time of day/need. I'm currently at 90mg TID after 18M or so and still recognise a persistent improvement.