mTor Inhibitor Rapamune Helps 5 ME/CFS Patients in Dallas

[Tunguska]

So Akt+/mTOR+ > Akt+/mTOR- > Akt-/mTOR-.

Generally, but it's context and timing.

Hey @Tunguska what's one Akt activator you wanna try???

ALA works for me and is enough for short windows.

What I'd press at this point (I said in other thread) is that Akt should work best in combination with a known PDK inhibitor: high-dose thiamine, DCA, ??? (in turn this will increase ROS, but ALA should help already) To promote best glucose oxidation. I thought Akt would do enough on its own, but now I'm guessing, not quite there. Problem is I don't respond to thiamine, and DCA is not risk free.

 

[adreno]

Problem is I don't respond to thiamine

I don't do well with thiamine at all. So much for that theory.

 

[Tunguska]

I don't do well with thiamine at all. So much for that theory.

Yeah a lot of mixed experiences, I get negatives. But B1 has its own side effects. There has to be something else. (Or there might sadly not be, and the only way to unblock PDH is upstream: immune etc.)

 

[Jesse2233]

Any thoughts on ultra lose dose Rapamune? Like say 0.25 mg?

 

[Emily L]

I have been on here reading about these new pills that can help called "rapamycin" so I thought I would ask my pa who is a doctor if I could try them.

He said "Couldn't hurt"

So my next move was having him call my GP who prescribed and called Banny (my boyfriend and he's a pharmacist) and I stopped by the CVS a couple days ago to get them.

To be clear: My doctor prescribed, and Banny fulfilled the prescription. These are serious pills, do not take them unless your doctor says ok!

Banny (not his real name btw) gave me 5 pills. But so far I only took 1 because I like to be careful with new things

Day 1 :: felt wretched
Day 2 :: felt a little better

Cured? No but then again it will probably take awhile if it does anything

Will let you know as this plays

Was taking Valtrex but I may stop it because I hate it

Hoping

 

[adreno]

@Emily L

How convenient to have both a doctor and a pharmacist in the family

 

[dreampop]

I have been on here reading about these new pills that can help called "rapamycin" so I thought I would ask my pa who is a doctor if I could try them.

He said "Couldn't hurt"

So my next move was having him call my GP who prescribed and called Banny (my boyfriend and he's a pharmacist) and I stopped by the CVS a couple days ago to get them.

To be clear: My doctor prescribed, and Banny fulfilled the prescription. These are serious pills, do not take them unless your doctor says ok!

Banny (not his real name btw) gave me 5 pills. But so far I only took 1 because I like to be careful with new things

Day 1 :: felt wretched
Day 2 :: felt a little better

Cured? No but then again it will probably take awhile if it does anything

Will let you know as this plays

Was taking Valtrex but I may stop it because I hate it

Hoping

Nice, another sample point always helps. 2 questions: what's your dose and are you taking them daily?

Hope it works out for you.

 

[Tunguska]

Any thoughts on ultra lose dose Rapamune? Like say 0.25 mg?

Not a bad thought, but I doubt there's a point, you might as well do 1mg 1-2x a week or something, it's just easier. Half life ~60+ hours. Unless constant blood levels are critical for some reason. I would maybe contact that doctor someone linked to see what he's doing nowadays, because he probably figured out all the alternative dosing already more than me.

 

[Tunguska]

If you were trying to compare for the same dosing schedule, I think tiny dose will just be less effective, and there's a cutoff point where it will have no effect. I don't know what that point is, maybe can derive from http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135256 [beware the animal/human conversion] and https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021083s058,021110s075lbl.pdf

I doubt there's any harm in just trying it, it shouldn't have the risks of antibiotics.

 

[Tunguska]

Hmm here's something you might have to keep in mind: https://en.wikipedia.org/wiki/Sirolimus

Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump.[4] It has an elimination half-life of 57–63 hours.[2]

The absorption of sirolimus into the blood stream from the intestine varies widely between patients, with some patients having up to eight times more exposure than others for the same dose. Drug levels are, therefore, taken to make sure patients get the right dose for their condition.[12] This is determined by taking a blood sample before the next dose, which gives the trough level.

I hadn't seen this, I thought the variance was from liver elimination, I guess gut is significant.

 

[Jesse2233]

Hmm here's something you might have to keep in mind: https://en.wikipedia.org/wiki/Sirolimus

I hadn't seen this, I thought the variance was from liver elimination, I guess gut is significant.

Interesting, the specific blood monitoring points to the need to have a knowledgeable doctor assessing whether or not you're getting adequate levels of the drug

 

[Emily L]

Nice, another sample point always helps. 2 questions: what's your dose and are you taking them daily?

Hope it works out for you.

Took "1 milligram" for a few days

Felt some bounce in my step on day 3 (?) but have stopped taking for the time being because it is that time of the month for me

 

[Steve4Andrea]

This might be the silver bullet we're looking for... or not.

We have an initial 30 pills ordered for about $190 from India, if it shows up and everything seems right ( I ordered the brand name Wyeth drug as opposed to an Indian generic) I'll post the pharmacy information.

Rapamune is not your garden variety immune suppressor, it started life as an anti-fungal, became an anti rejection drug and is now being investigated for it's anti cancer properties. Immune suppressors are not known to be big anti anythings much less fungus or cancers. Several studies also indicate that Rapamune may inhibit viral infection.

So far the side effect studies that I've seen are all on patients who had received a transplant and who were also being treated with corticosteroids and/or other immune suppressant drugs, I'm not sure this represents our situation. The biggest problems I found reported by actual patients were swelling of the hands and feet, mouth sores, slow wound healing and elevated lipids and all were reported by people who'd had a transplant. I have not been able to find any studies of side effects from it's anti fungal days.

In our case we have a proven Coxsackie B4 infection in the wall of the small intestine which matches the absorption route of Rapamune so I'm more optimistic about it's potential effectiveness. It is involved in the CYP3A4 pathway so no grapefruit juice but otherwise it does not seem to interact poorly with other drugs.

We will start with a dose of 1mg daily but we'll try to reduce that if it is effective, I haven't seen any prohibitions on splitting pills or we can dissolve it in ethanol, dilute with water and take smaller doses of the liquid. Most reports of the side effects indicate that they are dose sensitive so less is better, for anti rejection a loading dose of up to 15 g. was used and daily doses of 2 to 5 g. were used. I'm guessing that the level of immune suppression required to prevent rejection of a transplant has got to be greater than suppressing reaction to infection. The variability of absorption is a problem but since we don't know what plasma levels we want it does no good to check blood samples, this is an N=1 test so we will adjust until we get results.

Our plan is to use the Rapamune in conjunction with the anti-viral Arbidol, I'm hoping that the suppression of the immune symptoms by the Rapamune will allow us to use a full dose of the Arbidol against the Coxsackie B4.

I'll post updates as we go along.

 

[halcyon]

Our plan is to use the Rapamune in conjunction with the anti-viral Arbidol, I'm hoping that the suppression of the immune symptoms by the Rapamune will allow us to use a full dose of the Arbidol against the Coxsackie B4.

I'd worry that you'd be working slightly at cross purposes with these two drugs. I know that Arbidol has direct antiviral effects on enterovirus, but I'm not sure by what mechanism this occurs. The other important effect it seems to have is that it stimulates immune response, and as that recent paper showed, it suppresses IL-10 release. This is important because IL-10 is an immunosuppressive cytokine that suppresses T cell proliferation. Rapamycin also blocks T cell proliferation by cell cycle arrest. While blocking viral replication is probably important, I believe you also need the T cell response to actually eliminate the virally infected cells and clear the infection. In ME, as in other chronic viral diseases, we are in a state of T cell exhaustion due to the persistent exposure of T cells to viral antigen. I believe this needs to be reversed before the infection can be cleared and antiviral therapy alone might not be enough because the antivirals available today are not strong enough at limiting enterovirus replication/translation. I also worry because rapamycin causes cell cycle arrest at G1, and enteroviruses replicate quite well at this phase (ref).

My current idea for what a combined therapy for enteroviral ME would look like would be 1) antiviral compounds that can sufficiently inhibit viral replication and translation, 2) compounds that can reverse T cell exhaustion by blocking suppressive cytokines (IL-10, TGF beta, etc) and/or immune regulatory molecules (PD-1, TIM-3, LAG-3, etc), and 3) compounds which help reverse the metabolic changes. I'm still a bit dubious about #3, though I believe there is evidence from HIV and hep B/C research that shows this might be helpful. A potential #4 might be something that stimulates innate immunity such as type I interferon, though this is a bit of a double edged sword as interferon can also facilitate T cell exhaustion.

If rapamycin is indeed helping people, my guess is that it's doing so by blocking inflammatory cytokine release. So really it's just blocking symptoms as steroids would do, but doesn't address the root cause and might have similar consequences as steroid treatment does.

 

[Keela Too]

I haven't read this whole thread - it now seems so long and daunting - but today I was reading about fasting and autophagy.

Then I came across mTOR being mentioned and I thought "wait up, that looks familiar".... obviously my subconscious was paying attention because when I looked in recent threads here... Yeah there it is, mTOR!

Anyway... thought perhaps some of this page might be of interest:
https://intensivedietarymanagement.com/fasting-and-autophagy-fasting-25/

 

[ScottTriGuy]

and 3) compounds which help reverse the metabolic changes. I'm still a bit dubious about #3, though I believe there is evidence from HIV and hep B/C research that shows this might be helpful.

Do you have any reference links for the compounds, especially the HIV research?

Thanks much.

 

[halcyon]

Do you have any reference links for the compounds, especially the HIV research?

http://sci-hub.cc/10.2217/17469600.2.4.327
http://sci-hub.cc/10.1038/nm.4275

One of the compounds that's been used in vitro for reversing hep B T cell exhaustion is MitoQ, which has been discussed a bit around here.

 

[XenForo]

..Rapamune ... started life as an anti-fungal, became an anti rejection drug and is now being investigated for it's anti cancer properties. Immune suppressors are not known to be big anti anythings much less fungus or cancers. Several studies also indicate that Rapamune may inhibit viral infection.

@Steve4Andrea Can you point to the studies about Rapamune as antiviral, and anti-fungal, anti-cancer? I'd like to show my docs. I'm especially interested in the anti-viral properties. If you can get me the names of the studies, I can find them.

 

[XenForo]

Well it's been a week since I went off Rapamune and I still feel great. I mean really great, not just a temporary respite from ME/CFS, but like I can push myself and not suffer for it (so far.) I didn't expect to continue feeling great after the Rapamune. Maybe these supplements from my GP are having a good effect on me. It's just hard to tell, hard to interpret what's going on. ME/CFS just seems to have a mind of its own sometimes. It can be so frustrating. I'm just happy for now, and for as long as I continue feeling great.

 

[Steve4Andrea]

Xenforo- here are some of the viral studies I've run across, there are numerous citations out there if you search under "Sirolimus viral" (that is the generic name of Rapamune).

http://articles.latimes.com/2014/ap...o-eliminate-lingering-hiv-infections-20140403

http://www.catie.ca/en/treatmentupd...irolimus-potential-applications-hiv-infection

https://www.ncbi.nlm.nih.gov/pubmed/24128134

There is also a sentence in the package insert (https://www.fda.gov/ohrms/dockets/ac/02/briefing/3832b1_03_FDA-RapamuneLabel.htm ) under the paragraph CLINICAL PHARMACOLOGY -Mechanism of Action -

" In some studies, the immunosuppressive effect of sirolimus lasted up to 6 months after discontinuation of therapy."

So we don't know how long the benefits may last after discontinuing the drug- keep us informed as to how you feel. I'm hoping this will give us the option of pulsing the Rapamune to lower the chance of side effects. We are still waiting for our shipment to arrive.

Halcyon,

My micro-biology is not good enough to discuss the specific pathways you mention but my general biology is good enough to have two concerns about the treatment of CFS/ME patients-

I am concerned at the effort to treat them as a homogeneous population- while most people here share some common symptoms most seem to have their own unique subset which makes me believe that there may be either a common reaction to different pathogens or diseases or different reactions to the same pathogen or disease or some combination of both. Either way the value of N=1 evaluation of treatment becomes very important, we try and see what happens while trying to minimize risk to the patient.

I am also concerned at the possibility of confusing causation with correlation- without baseline testing prior to becoming sick with CFS/ME we can not definitely know whether the abnormalities discovered are caused by the illness, caused the illness to manifest or are unrelated to the illness. I know for us, as is probably the case for most people, we do not have the depth of testing from my wife prior to becoming sick to make that determination, again we come back to N=1.

Ultimately we are left with an all too common situation - we know what we know, we know what we don't know but it is what we don't know that we don't know that is most important.