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mTor Inhibitor Rapamune Helps 5 ME/CFS Patients in Dallas

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516
I tried Now Foods Arginine 500mg and Citrulline 250mg, Capsules for at least a week. Actually, it may have made me more tired, if anything. It's always hard to tell whether something is having an effect, or if it's just regular CFS ups and downs, but I did feel more tired on Citruline and Arginine for what that's worth.
Thanks (I get similar tiredness/slight-stupid feeling from it and I'm not on rap). To be clear I wouldn't expect much out of any of these aminos without at least 4g single doses or more (for a couple weeks maybe), but I don't think you should do it with arginine anyway.
 
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Hip

Senior Member
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17,824
This info comes from @eljefe19:

Apparently rapamycin may be able to reduce T-cell exhaustion:
Long‐term eRapa reduces PD‐1+ and exhausted T cells

T cells become exhausted with age, losing functionality for unclear reasons that could include long‐term antigenic stimulation or chronic inflammation (Lages et al., 2010). PD‐1 is an exhausted T‐cell marker (Barber et al., 2006). Long‐term eRapa significantly reduced PD‐1+CD4+ and PD‐1+CD8+ T‐cell prevalence in aged mice (Fig. 2A), suggesting reduced exhaustion.

Source: Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

@halcyon may be interested in this.
 

XenForo

Senior Member
Messages
107
@halcyon may be interested in this.[/QUOTE]
That's a mouse dose. To convert to a human dose, you need to divide by the mouse-to-human conversion factor of 12.3, giving a human dose of 0.18 mg/kg.
Ah, I see. That's still almost 12mg/day for my weight. I'm only at 1/2mg/day dose right now.
 

Hip

Senior Member
Messages
17,824
A few people have asked me about sources for rapamycin (sirolimus), so I am just posting some pharmacies that sell it here:

I bought rapamycin from Buy Pharma, who are a reliable pharmacy that I have used many times:

http://www.buy-pharma.co/Generic-Rapamune-Sirolimus-p-609.html

Other people on the thread have bought rapamycin from:

http://www.coinrx.is/generic-rapamune/1mg (no online reviews for this)
https://www.allgenericmedicine.com/product/rocas-1mg/601

Rapamycin is also available from these reliable pharmacies:

https://goldpharma.com/search/sirolimus/lang/ENGLISH/
http://www.internationaldrugmart.com/sirolimus.shtml
https://www.riverpharmacy.ca/drug/rapacan

I also found these pharmacies:

http://www.daynighthealthcare247.com/product/sirolimus
https://www.lifesaverpharma.com/anti-cancer/rapacan-1mg-sirolimus.html
https://aipctshop.com/product/rapacan-rapamune1mg/

Though I don't know about the reliability of this last set of pharmacies, as I just found them with a Google search.
 

Hip

Senior Member
Messages
17,824
Is anyone getting the diarrhea side effects of rapamycin (which is listed as one of its common side effects)?

I have taken 3 rapamycin doses so far, taken once every five days. And although I think I may be seeing glimmers of improved mental clarity and improved executive functioning, initially, for a day or two just after taking rapamycin, I suffer some diarrhea, and on those days generally feel worse (a bit more tired, and a bit vague mentally).

But after those one or two bad days, I then feel better for a couple of days, and this is where I seem to be experiencing reduced brain fog and clearer executive functioning. But then this positive effect seems to wear off around about the 4th day after my rapamycin dose (which is what you might expect, given that the rapamycin half-life is around 2.5 days).

At the moment I am just taking 1 mg of rapamycin every five days (but because of the grapefruit juice and itraconazole CYP3A4 inhibitors I am taking, this 1 mg should be equivalent to around 5 mg).

My sense is that the initial worsening of symptoms I experience after taking rapamycin may be due to the diarrhea and temporarily worsened gut health, rather than to the rapamycin itself. I have IBS-D anyway, so my guts are sensitive to being perturbed in this way.


So next time I take rapamycin, I may try taking it transdermally, in the hope of avoiding the diarrhea and the increased fatigue and brain fog that seems to come with it.

Rapamycin is poorly soluble in water, but is soluble in ethanol and DMSO, so I may crush and dissolve a 1 mg rapamycin tablet in a tablespoon of vodka or gin (40% ethanol), and then apply that solution to my skin.



EDIT: I have just realized that transdermal rapamycin will not work: rapamycin has an unusually high molecular weight of 914 grams per mole, and the human skin is generally impermeable to molecules whose molecular weight is higher than around 500 grams per mole (this is the 500 Dalton rule).
 
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XenForo

Senior Member
Messages
107
Is anyone getting the diarrhea side effects of rapamycin (which is listed as one of its common side effects)?.
.
I have IBS-D and if anything, the rapamune helps alleviate the diarrhea, for me. I don't take grapefruit juice with it, and take 1/2 mg per day. (I don't know enough about the drug to know much more than my own experiences on it - and what I read here on PR ;) )
 
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Hip

Senior Member
Messages
17,824
Hey @Hip, wouldn't it be better to take the usual dose without grapefruit juice to establish its effectiveness first, then try alternative administration methods and compare them?

I think taking CYP3A4 inhibitors to increase the effective dose of rapamycin is on pretty solid ground, given the study I mentioned earlier. It saves a lot of money that way.
 

pattismith

Senior Member
Messages
3,932
@Hip ,

I really look forward to see if you improve with this drug.
I wish you will take care and pay attention to the side effects, because the effect of Rapamune on mitochondria is still not fully elucidated, and I read some good and some bad about it.

Thanks for elaborating. It's great that rapamycin has allowed such an increase in what you can do.

Mitochondrial disease is a genetic defect that causes key metabolic enzymes to underperform. It usually shows up early in childhood and has extremely severe symptoms

Well if they're consistent symptoms, then that's not what I have, but I'll ask the doc anyway. I used to be pretty good at sports, except of course when I wasn't.


Primary Mitochondrial disorders arising at a young age are the best known because they are the more severe and the easier to diagnose....

But primary mitochondrial disorders can arise much later in life, and this kind of MitoD starts to be more and more recognized.
According to my readings, about 5% of fibromyalgia cases and 5% of CFS cases may be Mitochondrial disorders.

Secondary mitochondrial disorders can be also a result of environmental or drug toxicity, so I think it is important to talk about these possibilities on PR, even though they are not representative of the general picture of ME/CFS.
 
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Hip

Senior Member
Messages
17,824
the effect of Rapamune on mitochondria is still not fully elucidated, and I read some good and some bad about it

I don't know if this paper I just found has been discussed previously in this thread, but if says that rapamycin increases mitochondrial respiration and succinate dehydrogenase (complex II) activity, and decreases H2O2 production.

Furthermore, rapamycin appears to act on the mtDNA, and it's this action on the mtDNA that may mediating the mitochondrial effects of this drug.
 

XenForo

Senior Member
Messages
107
I don't know if this paper I just found has been discussed previously in this thread, but if says that rapamycin increases mitochondrial respiration...
What I notice is that when I take it I don't breathe as many times per minute when I meditate, and when I go biking it doesn't feel like I'm breathing as much either. Not sure why that would be, it just really seems to be the case, and when I meditate, I count breaths so it really is the case for sure.

Maybe that's a way to measure if it's "working."
EDIT: Gosh I really should have shared this as soon as I noticed it, I mean, in case it's helpful for people.
 

pattismith

Senior Member
Messages
3,932
I don't know if this paper I just found has been discussed previously in this thread, but if says that rapamycin increases mitochondrial respiration and succinate dehydrogenase (complex II) activity, and decreases H2O2 production.

Furthermore, rapamycin appears to act on the mtDNA, and it's this action on the mtDNA that may mediating the mitochondrial effects of this drug.

I found exactly the opposite statement in this 2013 paper that reviews the effects of Rapamycin on mTOR1 (paragraph 4.2, but you have to read the entire article, because I'm not sure to fully understand it!):

"They found that rapamycin lowers mitochondrial respiration and induces a shift from OXPHOS towards glycolysis as measured by metabolic profiling."

http://rsob.royalsocietypublishing.org/content/3/12/130185

This paper from 2006 says "Disruption of this complex following treatment with the mTOR pharmacological inhibitor rapamycin lowered mitochondrial membrane potential, oxygen consumption, and ATP synthetic capacity."


http://www.jbc.org/content/281/37/27643.full

On the other hand we can find several papers about the anti-aging effect of rapamycin by decreasing dysfunctionning mitochondria and increasing good ones...(this means longer term effect)


https://www.ncbi.nlm.nih.gov/pubmed/26872208
http://www.aging-us.com/article/100576/text
https://www.ncbi.nlm.nih.gov/pubmed/24101601

so the picture is certainly complexe, and needs to be clarifyed.
 
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Hip

Senior Member
Messages
17,824
"They found that rapamycin lowers mitochondrial respiration and induces a shift from OXPHOS towards glycolysis as measured by metabolic profiling."

http://rsob.royalsocietypublishing.org/content/3/12/130185

That's very interesting. But the paper does say just before the sentence you quoted that:
Ramanathan & Schreiber [64] used a shorter rapamycin treatment to exclude transcriptional effects.

The "transcriptional effects" refers to rapamycin's alteration mitochondrial gene expression, and I think what they are saying is that in a study using a short rapamycin treatment, you can measure the initial effects of rapamycin on the mitochondria before this drug later starts altering mitochondrial gene expression.

It appears from the paper you quoted that the initial effect of rapamycin is to reduce mitochondrial respiration (mitochondrial aerobic energy output), and this effect is caused by rapamycin's down-regulation of mTORC1. The paper explains it:
Blocking mTORC1 by a 12-h rapamycin treatment lowers Δψm and maximal oxidative capacity

Δψm is the voltage across the mitochondrial membrane, analogous to the voltage of a battery. So the initial short term effect (in the first 12 hours) of rapamycin's inhibition of mTORC1 is a reduction in mitochondrial aerobic energy output, which would likley be undesirable in ME/CFS.


However, in the longer term (judging by the results of the paper I mentioned earlier), as rapamycin starts altering mitochondrial gene transcriptional, this drug would appear to provide a net increase in mitochondrial aerobic energy output, in spite of the fact that rapamycin's mTORC1 inhibition reduces the energy output.

So my guess is that rapamycin may have two opposing effects on mitochondrial respiration: an initial reduction in aerobic energy output caused by mTORC1 inhibition, and a later increase in aerobic energy output due to alterations in mitochondrial gene expression. And I think it is the latter effect that dominates in the long term, providing an overall increase in aerobic energy output.

This echos @nandixon's comment earlier in the thread:
So either rapamycin must be doing something else that beneficially offsets that seeming disaster, or diversion of pyruvate away from the mitochondria is actually beneficial in ME/CFS.



Anyway, that's my interpretation, but I could be wrong, because it's hard to understand these papers. It could explain, though, why I felt more tired and brain fogged the for two days after taking rapamycin, before some glimmers of benefits kicked in at around day three.
 
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Messages
516
@Hip increased complex II activity one way or another is probably inevitable. Decreasing mTorC1 switches from lipogenic pathways to lipolytic (e.g. https://www.ncbi.nlm.nih.gov/pubmed/17142137 ) which depends on complex ii. It's reminiscent of muscle fiber reprogramming (ppar).

Both the studies you guys posted show a tiny (in vitro) part of the picture. mTorC1 triggers heavily energy-demanding growth programs which is why it has to increase oxphos in the first place. You can't know the net effect on the organism unless you factor in both production and demand, the net effect is entirely relative.