CFS_Kristin
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I found this article on Urocortin and Urocortin II....not sure if it relates or not
http://www.jneurosci.org/content/22/2/404
http://www.jneurosci.org/content/22/2/404
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Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of, and finding treatments for, complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia, long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.
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Also, Urocortin II is a 38 amino-acid peptide.
Urocortin II is essentially an anxiolytic (anti-anxiety), an anorexigenic (appetite suppressant) and a hypotensive (blood pressure reducer.)
If CT38 is indeed Urocortin II (or an analog), what are the odds that this is curative for SEID?
I'm a bit troubled as these are not universal symptoms and in fact many of us don't fit this profile very well. While many patients have high levels of norepinephrine (I am the opposite), I think most have low cortisol--at least in the morning. And many of us have low heart rates except in the cases of POTS patients where the HR jumps in response to standing, whether or not it was low while sitting or reclined. They don't indicate "how" urine production is affected but that would be interesting to know as some of us know that our urine production is higher than normal. There has been a lot of discussion as to whether we have diabetes insipidus as part of our profile.The animals’ heart rate increases, their blood pressure, body temperature and gut motility are reduced, their urine production is affected, their movement is dramatically reduced, and their stress hormones are released (norepinephrine and cortisone, the rat equivalent of cortisol).
The implications are important because the fatigue in CFS is central fatigue, in other words, fatigue in the central nervous system (CNS)! According to these researchers, fatigue in the CNS results from fatigue that occurs in a large portion of intercerebral control circuits caused by suppression in the level of voluntary exciting, which are suppressed in the number of motor units to the level of voluntary neuromuscular junction - muscle fibers and the firing frequency. In other words, CFS fatigue is a fatigue different from the fatigue in the motile muscles themselves. Moreover, these researchers have found that this fatigue is different from the so called tiredness feeling caused by physical (muscular) fatigue and, in fact, is generated in a state that is not accompanied by physical fatigue.
BCH is 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid.Cortene posits that elevated levels of serotonin are responsible for many/most ME/CFS symptoms, and their proposed treatment is a 38-amino acid peptide. I'm wondering how, if at all, this would relate to this article: http://www.ncf-net.org/forum/Fword.htm which talks about elevated levels of tryptophan (which is needed to synthesize serotonin) causing something called "central fatigue" and how a remedy for central fatigue is BCAAs. The article also mentions a compound called BCH which is supposed to accomplish the same thing.
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I want to be, but i am equally very scared to be... I dare not allow myself to think too much about - it is my/our finest dream to be well again. Such a gift it would be. But also devastating if i invest too much hope. It's awful how this illness makes cynics of us. Cynics with a secret hope deep inside all of us though.Who is hopeful?
The heart rate situation is complicated - my understanding is that we have higher than normal heart rates during sleep and at rest and lower than normal heart rates during exercise (chronotropic incompetence).Quoting the blog:I'm a bit troubled as these are not universal symptoms and in fact many of us don't fit this profile very well. While many patients have high levels of norepinephrine (I am the opposite), I think most have low cortisol--at least in the morning. And many of us have low heart rates except in the cases of POTS patients where the HR jumps in response to standing, whether or not it was low while sitting or reclined. They don't indicate "how" urine production is affected but that would be interesting to know as some of us know that our urine production is higher than normal. There has been a lot of discussion as to whether we have diabetes insipidus as part of our profile.
I think maybe cautious hope is appropriate. I keep coming back to Ron Davis's comment about how complex the body is. It's dauntingly complex and plenty of time drugs that seem like they should work don't. I think it would take a bit of luck for a new drug based on a hypothesis to works AND it's certainly possible that it will,.I want to be, but i am equally very scared to be... I dare not allow myself to think too much about - it is my/our finest dream to be well again. Such a gift it would be. But also devastating if i invest too much hope. It's awful how this illness makes cynics of us. Cynics with a secret hope deep inside all of us though.
I would love to know what Ron and the omf thinks of it.
I think there are some big differences. Antidepressants can have a very wide mode of action while Cortene is much more targeted. Plus SSRI's attempt to boost serotoniin levels and CT38 seeks to reduce them. Finally the antidpressants are reuptake inhibitors while Cortene is attempting to target one receptor in the brain.The above doesn't sound too different to me than how antidepressants work. Antidepressants modulate the stress response by blocking all kinds of receptors in the brain that are controlling serotonin, glutamate, norepinephrine, dopamine, etc. None of this has ever worked to treat/cure CFS/ME.
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 wonder if Dr. Kaufman and Dr. Chedda (sp?) know anything about this....and yes, what about Dr. Davis and OMF?
I hate when stuff like this is all cloaked in mystery. Why will it take Cort 3 blogs to release the full story?
We've already been waiting 25+ years isn't that enough time to build suspense.
Thanks for the initial info though, very much appreciated that there may be something to look forward to in terms of treatment. Especially a treatment that might actually fix us and not take a million years and treatments to do so.
@Ben H (any info from OMF avail?)
: )
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:
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 blocking the corticotropin-releasing hormone receptor 2 in the pituitary, 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.
If it works well it should be speeded up. That said it will probably take far longer than any of us would want.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?
I really apologize for not communicating during the delay. For some reason I didn't think of just posting something on Facebook and explain what was going on or coming on here (I just discovered this thread). I was just focused on completing the blog. Trying to get caught up...I wouldn’t say that at all. Don’t read too much into the delay, other than we all do the best we can with this illness.
CT38 is a big experiment. It's a very interesting and totally untried hypothesis and drug.
So I guess "CT38 might be curative" is no hype at all, then.
I think there are some big differences. Antidepressants can have a very wide mode of action while Cortene is much more targeted. Plus SSRI's attempt to boost serotoniin levels by blocking and CT38 seeks to reduce them. Finally the antidpressants are reuptake inhibitors while Cortene is attempting to target one receptor in the brain.
This article does propose developing CRF1 antagonists for use in depression but also suggests that they have a different mode of action
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1525061/
An alternative approach to antidepressant drug development targets the CRF receptor."
It's really very exciting - I can't help but think that something will show from this...I think maybe cautious hope is appropriate. I keep coming back to Ron Davis's comment about how complex the body is. It's dauntingly complex and plenty of time drugs that seem like they should work don't. I think it would take a bit of luck for a new drug based on a hypothesis to works AND it's certainly possible that it will,.
These guys do seem to be real sharp! If they think it has a good enough chance to spend a couple of years working on it full time, that's pretty good.
There's some animal data and some human data but it's limited; the drug is not being used in humans - so we don't have data there - and it's certainly never been applied to someone with ME/CFS. I think its experimental in the true sense of the word. Crossing fingers time
The spread among individuals makes it hard to know. I have tracked my HR closely day and night so I know what is happening and I may be an outlier (very long term ME/CFS). My HR is low during the day and about 6 beats lower at night. During exercise? Well that is complicated by the POTS response.The heart rate situation is complicated - my understanding is that we have higher than normal heart rates during sleep and at rest and lower than normal heart rates during exercise (chronotropic incompetence).
Of course we were never tracking our cortisol in the early stages--at least if we have been sick for decades.I believe Cortene believes that higher cortisol earlier in the disease lead to lower cortisol later.
The spread among individuals makes it hard to know. I have tracked my HR closely day and night so I know what is happening and I may be an outlier (very long term ME/CFS). My HR is low during the day and about 6 beats lower at night. During exercise? Well that is complicated by the POTS response.
Of course we were never tracking our cortisol in the early stages--at least if we have been sick for decades.