Colchicine is one key for our recovery. Aussy study 2022 Long covid

[pattismith]

CLINICAL IMPROVEMENT IN PATIENTS WITH ME/CFS WITH SYNERGISTIC EFFECT OF COLCHICINE AND SPIRONOLACTONE TARGETING INHIBITION OF INFLAMMASOME ACTIVITY​

https://onlinelibrary.wiley.com/doi/10.1111/imj.23_15766

The starting dose of Spironolactone was 12.5 mg a day increased to 25 mg a day (during years 2019 to 2021). The introduction of Colchicine 0.5 mg/day on treatment plan was during year 2021. Patient follow-up was in the outpatient clinic and GP clinic.

Results: Total 23 Patients 19 were Females age 37.3+28 and 4 were Males age 61+9. Two patients stop colchicine after 4 weeks. Improvement in cognitive skills was the early manifestation of spironolactone benefit. Patients reported to be less brain foggy, more alert, and they found it easier to focus when doing normal everyday activities.

They were also less irritable by noise and light and described themselves to be able to multi-task again. There was an improvement in general condition and everyday activities four weeks after Colchicine started.

I happened to discover accidentally that low dose Colchicine + low dose Piroxicam (non selective cox inhibitor) give me instant relief from my brain fog/fatigue/sleepiness.

After a quick research I found Dr Montoya was using Colchicine in his treatment and also Dr Chia was using the combo Indometacine/Colchicine: it's very close to my Piroxicam/Colchicine combo.

My trial is currently Colchicine 0.25 mg + Piroxicam 5 mg per day.

My husband who suffers with hypersomnia took it as well and felt an instant relief too (he suffers from aging, cancer and post chemotherapy fatigue).

Low dose Colchicine is currently include in the cardiology European Guidelines:

Accordingly, new 2021 European Society of Cardiology (ESC) guidelines recommend low-dose of colchicine (0.5 mg daily) for secondary prevention of cardiovascular diseases, particularly if other risk factors are insufficiently controlled or if recurrent cardiovascular disease events occur under optimal therapy (Class IIb, Level A) 9

https://eso-stroke.org/cytokines-and-stroke-worst-enemies-or-best-friends/

 

[pattismith]

Dr Jo Campo patients include one that worsened after Pfizer covid RNA vaccine

Case Report: A 46-year-old male with a previous history of Sarcoidosis and Haemochromatosis had ME/CFS since 2016. He was followed up at Noosa Hospital clinic related to his ME/CFS. His general symptoms related to this condition were under control and he was able to work and study at the University. After the second dose of his SARS-CoV-2 (Pfizer –BioNTech COVID-19) vaccination in August 2021 his general condition deteriorated. During September—October 2021 his cognitive skills declined and he had to stop his university studies. The patient also stopped driving his car because of lethargy and could not do any sport recreational activity. Because of ME/CFS he was on treatment with multivitamins and low dose Naltrexone and Spironolactone before vaccination. After the ME/CFS clinical deterioration the decision was to start Colchicine 0.5 mg a day (November 2021). After four weeks of Colchicine plus his previous medication, his level of energy and cognitive skills recovered to pre vaccination status.

Discussion: The immunologic cascade after SARS-CoV-2 vaccination triggered by Ab2 ended in activation of pyrin domain containing protein3 (NRLP3 Inflammasome). This is the pattern of activation for interleukin (IL-1beta). This may determine a general increase in the systemic and microglia inflammation as described in ME/CFS. The clinical manifestation in the present case was worsening in the symptoms of the ME/CFS. The patient was already on Spironolactone targeting the increase on number of macrophages ACE2 receptors as immune modulation.

An anti-inflammatory synergy between Colchicine and Spironolactone is currently the focus of research in atherosclerosis. Colchicine has a direct effect on phagocytes leading to inflammasome inhibition and impaired production of IL-1 beta.

https://onlinelibrary.wiley.com/doi...se reported in this,the reason for this paper.

 

[pattismith]

This study may bring some light about the advantage of using Colchicine together with a COX inhibitor:

It's about patients treated either with Colchicine or with a COX-2 inhibitor:

Expression of microRNAs in the plasma of patients with acute gouty arthritis (AGA) and the effects of colchicine and etoricoxib (cox-2 inhibitor) on the differential expression of microRNAs

DOI: https://doi.org/10.5114/aoms.2018.75502
2019 China

Results:
Compared with normal subjects and asymptomatic hyperuricemia (HUA) patients, plasma of acute gouty arthritis (AGA) patients contained 21 differentially expressed miRNAs.

qRT-PCR indicated specific downregulation of miR-223-3p and miR-451a in AGA.

There were no statistically significant differences in the baseline characteristics between colchicine and etoricoxib groups.

Furthermore, no significant difference in joint pain scores after 5- and 10-day treatment were found between groups (p > 0.05).

Comparison of differences between pre- and 5-day post-treatment values confirmed that the upregulation of miR-223-3p and downregulation of IL-1β induced by colchicine were more significant than etoricoxib (p < 0.05).


However, the latter outperformed the former in the upregulation of miR-451a and downregulation of COX-2 (p < 0.05).

After 10-day treatment, the magnitude of miR-223-3p upregulation and IL-1β downregulation in the colchicine group was significantly higher than in the etoricoxib group, while the etoricoxib group had higher expression of miR-451a and lower expression of COX-2 than the colchicine group (p < 0.05).



Conclusions:
In AGA patients, 21 differentially expressed miRNAs were detected in the plasma.

Colchicine could upregulate miR-223-3p and downregulate IL-1β in the plasma, while etoricoxib may treat AGA by upregulating miR-451a and downregulating COX-2.

 

[bob800]

I happened to discover accidentally that low dose Colchicine + low dose Piroxicam (non selective cox inhibitor) give me instant relief from my brain fog/fatigue/sleepiness.

Very glad this is working for you! How long have you been taking it?

Do you notice any gastric upset from this combo?

 

[hmnr asg]

Would celebrex be an option for the COX inhibitor half of this combo ?

 

[pattismith]

Very glad this is working for you! How long have you been taking it?

I take regularly piroxicam for my cervical pain (herniated disc) for years, and I take colchicine from time to time for one or two years, but I realized taking them together is fixing my fatigue/brain fog/sleepiness/drowsiness only since the 14 of july. So I take them together for 1 week now only, but it's still working.

It works for my husband who suffers with fatigue for different reasons than I do, so I guess it may works for lot's of people.

Do you notice any gastric upset from this combo?

This a very interesting question, my stomac is very sensitive to cox-inhibitor NAISD, but while taking it with colchicine seems to protect me.

I found a mouse study that explains that, unfortunately no human clinical study was done...

Colchicine prevents NSAID-induced small intestinal injury by inhibiting activation of the NLRP3 inflammasome​

Indomethacin-induced small intestinal damage was reduced by 77%, as determined by the lesion index in NLRP3−/− mice, and colchicine treatment failed to inhibit small intestinal damage in NLRP3−/− mice. These results demonstrate that colchicine prevents NSAID-induced small intestinal injury by inhibiting activation of the NLRP3 inflammasome.

https://www.nature.com/articles/srep32587

 

[pattismith]

Would celebrex be an option for the COX inhibitor half of this combo ?

It's a cox-2 inhibitor so I can't see why it wouldn't work as well. The problem would be to take a low dose, because you can't cut the 100 mg caps...

 

[pattismith]

In this thread , it is explained how Dr Chia was using Low doses colchicine /indomethacin for pericarditis/myocarditis in ME/CFS patients.

https://forums.phoenixrising.me/thr...estions-should-i-ask.49595/page-6#post-835905

At the same time in 2017, this kind of regimen was recommanded by the European Society of Cardiology for acute pericarditis

https://www.escardio.org/Journals/E...of-acute-pericarditis-treatment-and-follow-up

I don't think I have any pericarditis or any myocarditis nor do my husband, but something wrong we do share is insulin resistance and vascular issue.

 

[pattismith]

After 10-day treatment, the magnitude of miR-223-3p upregulation and IL-1β downregulation in the colchicine group was significantly higher than in the etoricoxib group, while the etoricoxib group had higher expression of miR-451a and lower expression of COX-2 than the colchicine group (p < 0.05).

a new chinese study about miR-451a

Decreased miR-451a in cerebrospinal fluid, a marker for both cognitive impairment and depressive symptoms in Alzheimer's disease​

Theranostics 2023;
doi:10.7150/thno.81826.

Abstract​

Background: Alzheimer's disease (AD) patients are often accompanied by depressive symptoms, but its underlying mechanism remains unclear. The present study aimed to explore the potential role of microRNAs in the comorbidity of AD and depression.

Methods: The miRNAs associated with AD and depression were screened from databases and literature and then confirmed in the cerebrospinal fluid (CSF) of AD patients and different ages of transgenic APP/PS1 mice. AAV9-miR-451a-GFP was injected into the medial prefrontal cortex (mPFC) of APP/PS1 mice at seven months, and four weeks later, a series of behavioral and pathological analyses were performed.

Results:
AD patients had low CSF levels of miR-451a, which was positively correlated with the cognitive assessment score, but negatively with their depression scale.
In the mPFC of APP/PS1 transgenic mice, the miR-451a levels also decreased significantly in the neurons and microglia.
Specific virus vector-induced overexpression of miR-451a in the mPFC of APP/PS1 mice ameliorated AD-related behavior deficits and pathologies, including long-term memory defects, depression-like phenotype, β-amyloid load, and neuroinflammation.

Mechanistically, miR-451a decreased the expression of neuronal β-secretase 1 of neurons through inhibiting Toll-like receptor 4/Inhibitor of kappa B Kinase β/ Nuclear factor kappa-B signaling pathway and microglial activation by inhibiting activation of NOD-like receptor protein 3, respectively.

Conclusion: This finding highlighted miR-451a as a potential target for diagnosing and treating AD, especially for those with coexisting symptoms of depression.

 

[pattismith]

Would celebrex be an option for the COX inhibitor half of this combo ?

I feel sorry, but I have to change my mind... it may be that a selective COX2 inhibitor will not do the same job as Piroxicam will.

I have read several papers that and I have to dig into this to better understand the difference...

Cyclooxygenase I and II inhibitors distinctly enhance hippocampal- and cortex-dependent cognitive functions in mice 2015​

The aim of the present study was to comparatively investigate the effects of piroxicam, a selective COX-I inhibitor, and celecoxib, a selective COX‑II inhibitor, on cognitive functions in an AlCl3‑induced neurotoxicity mouse model to understand the specific role of each COX enzyme in the hippocampus and cortex.

First I wish to point that they say wrongly in this paper that piroxicam is a selective COX1 inhibitor although it is not. See this picture below showing where Piroxicam is situated between COX1 and COX2 selective inhibitors:

Any way, in this study both drugs (Celecoxib and Piroxicam) improve neuroinflammation and neurodegenration, but with some differences that may be important to us.

Piroxicam and NS-398 rescue neurones from hypoxia/reoxygenation damage by a mechanism independent of cyclo-oxygenase inhibition 2001​

We studied whether NS-398, a selective cyclo-oxygenase-2 (COX-2) enzyme inhibitor, and piroxicam, an inhibitor of COX-2 and the constitutively expressed COX-1, protect neurones against hypoxia/reoxygenation injury. Rat spinal cord cultures were exposed to hypoxia for 20 h followed by reoxygenation. Hypoxia/reoxygenation increased lactate dehydrogenase (LDH) release, which was inhibited by piroxicam (180-270 microM) and NS-398 (30 microM). Cell counts confirmed the neuroprotection. Western blotting revealed no COX-1 or COX-2 proteins even after hypoxia/reoxygenation. Production of prostaglandin E2 (PGE2), a marker of COX activity, was barely measurable and piroxicam and NS-398 had no effect on the negligible PGE2 production.

Hypoxia/reoxygenation increased nuclear factor-kappa B (NF-kappaB) binding activity, which was inhibited by piroxicam but not by NS-398.

AP-1 binding activity after hypoxia/reoxygenation was inhibited by piroxicam but strongly enhanced by NS-398.

However, both COX inhibitors induced activation of extracellular signal-regulated kinase (ERK) in neurones and phosphorylation of heavy molecular weight neurofilaments, cytoskeletal substrates of ERK.

It is concluded that piroxicam and NS-398 protect neurones against hypoxia/reperfusion.
The protection is independent of COX activity and not solely explained by modulation of NF-kappaB and AP-1 binding activity. Instead, piroxicam and NS-398-induced phosphorylation through ERK pathway may contribute to the increased neuronal survival.

https://pubmed.ncbi.nlm.nih.gov/11208911/

https://www.spandidos-publications.com/10.3892/mmr.2015.4351

 

[bob800]

I got a script for colchicine, here's what I've noticed so far (taking it by itself, only for a few days so far):

I have the same reaction to it as I have with valacyclovir and ranitidine. That is: the first dose is great, it lifts the drowsiness/mental fatigue dramatically and cleanly within an hour. But then after a few hours to a day, a different kind of deep grogginess/fatigue sets in, and additional doses at that point just intensify that negative effect. With the other drugs I mentioned, it takes at least a week to "reset" my body and get the initial positive reaction from the first dose again.

I'm at the point where I genuinely believe that the "benefit" I get from these drugs is not due to NLRP3 inhibition, nor immune modulation, nor metabolic effect, but rather as direct GABA antagonists. I hear similar things from people that trial antibiotics (many of which are GABA antagonists): they are very stimulating at first, then after some time, the effect goes away or causes problems. (GABA antagonists are also used clinically to treat hypersomnia.)

Colchicine inhibits GABA(A) receptors independently of microtubule depolymerization​

https://linkinghub.elsevier.com/retrieve/pii/S0028390898000203

Enhancing and inhibitory effects of H2-receptor antagonists on the GABA and the GABAA-agonist muscimol responses of the isolated guinea pig ileum: a pharmacodynamic interaction​

https://www.sciencedirect.com/science/article/abs/pii/S1043661803001488

I've also noticed that these drugs (valacyclovir, colchicine, ranitidine) seem to have the most stimulating effect when I take them later in the day, or after a night of poor sleep. If the first dose is large enough, then I'm often stimulated enough that I sleep poorly the first night, which ironically seems to be a positive predictor that the drug continues to work the next day. But once I get a solid night sleep, it's a guarantee that the drug flips its action from stimulating to exhausting.

Why that happens, I am still not sure. Here is my latest hypothesis:

Role of GABA in the regulation of the central circadian clock of the suprachiasmatic nucleus​

https://jps.biomedcentral.com/articles/10.1007/s12576-018-0604-x
"GABA exhibits excitatory and/or inhibitory characteristics depending on the circadian phase or region in the SCN."

I would be very interested to know if anyone else has this kind of reaction. Perhaps the combination with COX inhibitor modulates this effect somehow (I haven't tried that).

 

[MartinK]

What are the best and safe alternatives to Piroxicam? Can anyone advise? Thanks

 

[Katt]

Would celebrex be an option for the COX inhibitor half of this combo ?

I take celebrex as an occasional PEM inhibitor and ti get rid of any brain fog or feelings of neuroinflamation. My doctor originally prescribed it for joint pain but I accidentally discovered that it's great for my cfs symptoms.

 

[SWAlexander]

What are the best and safe alternatives to Piroxicam? Can anyone advise? Thanks

may I suggest reading https://medlineplus.gov/druginfo/meds/a684045.html and making your own decision?