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Cortene Peptide for MECFS? "Curative"?!

Hip

Senior Member
Messages
17,824
I wonder what advantages this new CT38 peptide has over the abortion drug mifepristone (aka RU-486)?

Both CT38 and mifepristone act to temporarily inhibit the actions of the HPA-axis, and in both cases this is thought may lead to a HPA-axis reset. The idea is that the temporary inhibition of the HPA-axis resulting from taking these drugs for a few days or weeks facilities the axis reset.

From Cort's excellent article:
If his hypothesis is correct, he believes CT38 will be able to reset the limbic system almost as quickly as it fell off the tracks in the first place; i.e., a couple of treatments might be enough to return the system to normal and begin the healing process.

The HPA-axis reset achieved by mifepristone works in a similar way, and has been shown effective for major depression, 1 and psychotic major depression. 1

A mifepristone HPA-axis reset was also trialed for Gulf War illness, 1 but did not seem to help the symptoms, except some improvement in verbal learning (but did not improve other cognitive measures).



In terms of how the HPA-axis reset is actioned, the difference between CT38 and mifepristone is where they inhibit the HPA-axis. Here is the HPA-axis (and how it activates as part of the fight-or-flight response):

Stress ➤ Hypothalamus releases CRH ➤ Pituitary releases ACTH ➤ Adrenal glands release cortisol ➤ Activates glucocorticoid receptors

CT38 inhibits the effect of CRH (corticotropin-releasing hormone) by down-regulating the corticotropin-releasing hormone receptor 2 in the pituitary (ref: 1), and this then inhibits the whole HPA-axis.

Whereas mifepristone acts further downstream in the HPA-axis, by blocking the glucocorticoid receptor 2 (a cortisol receptor), preventing cortisol from activating the glucocorticoid receptor.

So this is how both drugs achieve an axis reset in their own ways; presumably CT38 must offer some additional advantages by inhibiting the HPA-axis further up, otherwise why would Cortene be trialing CT38 for ME/CFS.

Or maybe with CT38 they are not aiming to reset the HPA-axis, but rather reset some more local feedback loop just within the limbic system.



I am planning to try a HPA-axis reset using mifepristone in the very near future. I guess from its failure to make any major improvements in Gulf War illness, I should not expect it to help ME/CFS much. Although since the mifepristone HPA-axis reset did prove effective in treating depression, I am keeping my fingers crossed that a mifepristone reset may permanently improve the comorbid depression I often have, and lead to a better mood.

www.ec21.com is a good source of inexpensive mifepristone powder.
 
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junkcrap50

Senior Member
Messages
1,330
I am planning to try a HPA-axis reset using mifepristone in the very near future. I guess from its failure to make any major improvements in Gulf War illness, I should not expect it to help ME/CFS much. Although since the mifepristone HPA-axis reset did prove effective in treating depression, I am keeping my fingers crossed that a mifepristone reset may permanently improve the comorbid depression I often have, and lead to a better mood.

Damn. That sounds ballsy. What are the potential risks? (I'm in no way interested in trying it. Just curious why you're willing to do it.)
 

Hip

Senior Member
Messages
17,824
That sounds ballsy. What are the potential risks? (I'm in no way interested in trying it. Just curious why you're willing to do it.)

A rash can appear after longer term use, but for a HPA-axis reset, you only need to take mifepristone for a few days. Quite a few studies have tested mifepristone as a depression treatment, and I did not see mention of any significant risks.
 

Jesse2233

Senior Member
Messages
1,942
Location
Southern California
This paper from Suzanne Vernon goes in quite some depth on how the HPA axis might be reset

It’s fascinating (albeit purely theoretical)

The inability of the body to return to the healthy steady state is due to the fact that once the body establishes a new equilibrium it inherently seeks to stay near this point. In order to force the body to return to its original equilibrium its state must first be shifted to a point where the only stable condition in proximity is one corresponding to this original healthy state. Once this is done, the internal regulatory mechanisms of the body will ensure that this healthy stable point is achieved and maintained.

image


http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1000273

From the paper, her ideas on how this might be clinically

Unfortunately as in strategies involving the direct inhibition of CRH, a reduction of positive feedback to the hypothalamus also leads to a reduction in ACTH synthesis by the pituitary. Recall that the proposed treatment requires the inhibition of the negative cortisol feedback without the removal of positive stimulation of ACTH production. This could be achieved by temporarily reducing the bioavailability of cortisol itself. Binding proteins and metabolizing enzymes have been identified for cortisol. Corticosteroid-binding globulin (CBG) regulates the concentration of free or active cortisol [32]. Oral oestrogen preparations have been shown to increase CBG levels [33]. In addition to CBG, the enzyme 11-β-hydroxysteroid dehydrogenase rapidly inactivates endogenous glucocorticoid hormones upon entry into the cell [34]. Similarly the multi-drug resistance (MDR) P-glycoprotein (Pgp) has been shown to control access of cortisol and corticosterone to the brain [35]. In all cases a reduction in the bioavailability of cortisol would limit the effect of negative feedback on ACTH synthesis without hampering the positive feedback from pro-inflammatory cytokines. ACTH would conceivably accumulate as a natural consequence of such an imbalance. ACTH could also be administered directly [36] under these conditions of reduced cortisol inhibitory feedback to accelerate the treatment course. Finally the treatment might also be administered at a time of day that corresponds to the natural circadian reduction in cortisol secretion
 
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junkcrap50

Senior Member
Messages
1,330
A rash can appear after longer term use, but for a HPA-axis reset, you only need to take mifepristone for a few days. Quite a few studies have tested mifepristone as a depression treatment, and I did not see mention of any significant risks.
How did you hear about this HPA-axis reset? Can you post (either here or in your own thread) the research you found that led you to this?
 
Messages
19
Could this have something to do with stmts Dr. Chia made to a patient in recent weeks about some important treatment breaththrough occurring soon. There was a post from a Chia patient last week or the week earlier.
I was asking myself the same question, but i don't think so:

Yes. He suggested it involved something that had already been approved in a similar form for something else. So sooner.

As far as i know CT 38 / Cortene has not been approved for other disease.
 

FMMM1

Senior Member
Messages
513
Does anyone know how long it takes for a drug to go through trials before hitting the market? I assume if this drug works for a cohort, the process may be hurried along since we have no approved treatments for our disease?

Not quite the answer your looking for but see below an extract from the companies website. They describe this as "Early phase 2 proof-of-concept". I guess that if this is promising they'd need a larger Phase 2 and then Phase 3. I guess this is why the Cort Johnson article states "years".

Does anyone know if they can they demonstrate the presence/activation of "CRF2" receptor the drug targets?

If they can't identify those who respond i.e. by correlating response with the "CRF2" receptor then that seems like a potential problem i.e. assuming some of those with ME/CFS respond positively.

"Having successfully completed a Phase 1 clinical trial (in healthy human subjects) under FDA oversight, we are planning to test CT38 in ME/CFS patients. We believe that a short course of treatment with CT38 may be curative.
phase-progress-graphic-v31.png
 

dreampop

Senior Member
Messages
296
The raphe nuclei and limbic system shape the stress response (by incorporating assessments of risk, reward, history, etc), but under intense stress they can desensitize the 5HT1A autoreceptors that normally halt the stress response – allowing it to run amok. Pereira/Cortene believe this is what is happening in ME/CFS.

My, undeducated attempt to analyse this.

There are 2 5-ht2a receptor agonist that are effective in the at least the raphe nucleus, vortioxetine and flibanserin. At least in the short term, and only in the short term, you would expect them have some effect on CFS, but I could find no positive stories from them. Then they trigger autoreceptor desensitization. So, these drugs should cause CFS.

The trouble is that SSRIs block the serotonin transporters on all neurons. This means SSRI will eventually reduce serotonin from neurons releasing excess serotonin (via auto-regulation), but it will also increase serotonin release everywhere else (just not to a level that triggers auto-regulation). This is what causes the many side-effects of the SSRIs—and, notably, these are the symptoms of ME/CFS.

This is what I don't get. Wouldn't anti-depressant's be flipping out half the population (maybe they are but not to the extent most people with CFS have)? Also if people's auto-receptors can be permanently fucked up, seeming by innocous triggers or normal things like the flu, having sledgehammer SSRIs working on them would be a recipe for a ton of CFS. Like national crisis thing.
 

JES

Senior Member
Messages
1,320
This is what I don't get. Wouldn't anti-depressant's be flipping out half the population (maybe they are but not to the extent most people with CFS have)? Also if people's auto-receptors can be permanently fucked up, seeming by innocous triggers or normal things like the flu, having sledgehammer SSRIs working on them would be a recipe for a ton of CFS. Like national crisis thing.

I agree. SSRI's might well cause some CFS symptoms, but there is no evidence that they would trigger CFS itself. Considering that millions of people use SSRI's every day, I think it would be obvious by now if they played a role in causing or curing CFS, and neither seems to be happening. This is why I'm skeptical with these kinds of simplified theories, i.e. that screwing with one receptor would be curative.
 

Hopeful1976

Senior Member
Messages
345
I've been reading about seratonin and what it does in the body. As it is implicated in the whole body, it makes sense that an issue with it could cause the multitude of symptoms we all suffer from. I was particularly intrigued by the gut connection as I suffer terribly with stomach symptoms, as I know so many others do also.