Discussion in 'Antivirals, Antibiotics and Immune Modulators' started by Jesse2233, Apr 6, 2017.
@nandixon Awesome explanation, thanks for clarifying!
Nandixon beat me to some parts. But there are a lot of nuances. To say anything right now, I have to put aside the fact it's cancer cells, sub-cellular localization of mTor, and relative concentration of the mTor enzyme (cause it's rarely all or nothing). Already a lot of variables, not all of which I grasp, but anyway...
The confusing factor is that mTorC1 itself does in fact increase oxidative phosphorylation in mitos. That comes off counter to the Akt-producer/mTorC1-consumer bastardization from other articles. But in reality a lot of the oxphos from mTorC1 is just there to fuel protein synthesis and proliferation. So it's not free energy, it gets used up simultaneously, and depending how measured it gives different net effect (I was still trying to wrap my head around some of that, so I'll get back to you someday...).
In the case of CFS/ME, since PDH is already ruined, I'd think lowering mTorC1 in those cells might simply make no significant difference to oxphos from glycolysis. But meanwhile knocking down mTorC1 still lowers the energy-consuming processes. Such that relative to disease, keeping your fuel intake the same, Akt+/mTorC1- still increases net ATP [and through glycolysis].
[You can stick to simpler explanation along what nandixon wrote and say mTorC1 was simply too low such that lowering it makes no difference, while increase in Akt is pure positive... anything along these lines will work out]
I think the story probably doesn't end there, even for healthy people, but that gives another picture.
On related topic, for what it's worth, I was coming to the conclusion that the Akt might not have enough direct effects on PDH/PDK to explain all the relief, it's depending on what is keeping PDK high, and there are other complications. So, while I'm personally convinced the Akt/mTor direct energy partitioning modulation is significant to maintaining energy high while on rapamycin and alternatives, the specific disease-modifying aspect - or multiple aspects - might likely be something else, immune suppression or other.
About alcohol, I've been coming across so many different possible explanations that it practically fits every theory. I'm not putting stock in it anymore.
Or the symptoms of this disease aren't at all caused by metabolic issues.
Maybe Rapamune's effect on B cells outweighs any metabolic impairment. In other words perhaps it's diminishing problems upstream and encouraging systemic improvement
He's your doctor, but that's seems alarmist to me. Do you have known infections or whatever? In your scihub paper for SLE they were taking 2mg rap/day nonstop for up to 2 years plus varying prednisone.
I haven't heard a good reason (except price) why you couldn't cycle Rap on weeks you need it, if nothing else (can't really say "days" because half-life covers a couple). I'm not taking Rap, but if it was cheap that's what I'd be trying, and just until someone figures out if it has exclusive disease-modifying effects or not.
That theory doesnt fit well with the delayed response times in rtx-trials imo.. If rapamune has an effect i would assume its due to something else. I`m gonna mail Haukeland and ask them if they would be interested in looking into it on some pilot-patients
Pretty notable risk of Lymphoma seems a legitimate concern: 1.1%(24months) to 3.2%(36months) on 5mg and .7%(24months) to 1.8%(36months) on 2mg with .8% (36month) placebo.
Those numbers are high and seem to increase significantly with time. That's a big black mark over this drug as long term treatment. Still, even if it works THAT alone would be a big finding. The good news is lower dosage is less risk, so maybe 1mg would be doable. But if the risk increased over time like 5mg and 2mg it would still be sketchy past a few years.
That is very high indeed. At least considering we dont know the potential effect rate
Can't spot where you got those figures, but for it to be relevant we need to know the frequency of administration. If this is 24-36 month continuous daily dosing, that was never on the table.
"Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system" [and cancer, I'll wager]
I imagine a person would stop taking it if it wasn't working after say 6 months, so at least you could mitigate the longterm risk of a non-effective treatment
I found it in the prescribing info - https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021083s058,021110s075lbl.pdf page 17, 6.1. Haven't looked at the studies themselves. I don't think anybody can say what dosing would be necessary. AFAI the people that took it this far took it daily.
what else did they suggest?
Next time my boyfriend is in Dallas I will ask him to as to find the doctor. He's very good at uncovering details (but not everything). I will also ask my pa about this drug "rapamycin". He is a GP and will know all about it and how it works
So I texted my pa (who we in the family call Dr Dad ) bc he's awake in the UK and he said that "rapamycin" is good for moving kidneys about as it calms down the immune system and helps the body to accept the kidney as one of its own. He's not sure if it can help the Epstein Barr but said it couldn't hurt. I'd advise you to talk to your doctor before trying it just to be safe. You never know about drugs these days
So is the present consensus that it doesn't really matter whether a compound activates or inhibits mTOR, as long as Akt is activated?
Increasing mTorC1 is still central to everything I do, so unqualified that statement doesn't sit well with me. I haven't justified well (and there are parts of the story missing in my estimate), but Akt+/mTorC1+ and I believe Akt+/mTorC1- each have different valuable uses, but the former more. I'm speaking about normal skeletal/brain cells, and from this perspective the immune system is more a wildcard.
Surefire way to see this is rather that Akt+/mTorC1- is always going to be relatively better than Akt-/mTorC1-. No matter what else rapamycin is doing and despite the half-life, if it maintains Akt, then metabolically, it's a relatively much more appropriate treatment than other things that lower Akt that get suggested or that people don't have a choice to take. (Actually Akt contributes to cancer, but I'm not nearly as worried about the cancer as much as the prolonged mTorC1 inhibition in normal skeletal/brain cells)
Hey @Tunguska what's one Akt activator you wanna try???
This is my question too!!
So Akt+/mTOR+ > Akt+/mTOR- > Akt-/mTOR-.
You can also try a Google Site Search
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