mTor Inhibitor Rapamune Helps 5 ME/CFS Patients in Dallas

JaimeS

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P.S. just an addendum to say that my appetite has increased, dont know if it has anything to do with rapamycin, but my stomach has been s@#t, so happy with any improvement, coincidental or not.

It could! Rapamycin increased appetite in one rat study, though more in rats of the lady persuasion.

Food consumption was higher for rapamycin-fed females, but not for males, during the first 8 weeks of treatment (by an average of 1.25±0.12 g/mouse/week, P<0.0001; two-way ANOVA). This may be a result of the inhibition of the mTOR pathway, which is expected to mimic the unfed state.

From here:
Halloran, J., Hussong, S., Burbank, R., Podlutskaya, N., Fischer, K., Sloane, L., … Galvan, V. (2012). Chronic inhibition of mTOR by rapamycin modulates cognitive and non-cognitive components of behavior throughout lifespan in mice. Neuroscience, 223, 102–113. http://doi.org/10.1016/j.neuroscience.2012.06.054
 

XenForo

Senior Member
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107
I was just thinking today that it seems like I'm more tolerant of the cold; I was diagnosed with Raynaud's.

I'm curious if I'd also respond to the macrolide azthromycin; I wonder if other macrolides also help some of us - the ones who respond to sirolimus / rapamycin.
I've been on Rapamune for 7 weeks and have had improvement:
...
- better toleration of the cold
I also previously responded to azithromycin during my second bout of ME.
 

nanonug

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This is counterintuitive to the latest research. Perhaps Rapamune's immune suppressing effect outweighs its mTor inhibition.

Suppressing the immune system leads to reduced creation of reactive oxygen/nitrogen species, such as superoxide and peroxynitrite. This, in turn, leads to a reduction in the expression of pyruvate dehydrogenase kinase, leading to the reactivation of the pyruvate dehydrogenase complex that feeds the electron transport chain responsible for the creation of the majority of ATP by the mitochondria.

Makes sense to me. At least until one gets a serious infection or cancer due to a suppressed immune system.
 

nanonug

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Myself and a few others here on PR use dichloroacetate (because of Naviaux et al.)

Today I decided to do a Pubmed search on DCA (dichloroacetate) and mTOR. I found the following which qualifies as very interesting from my perspective.

Overexpression of pyruvate dehydrogenase kinase supports dichloroacetate as a candidate for cutaneous melanoma therapy.

Abstract
OBJECTIVE:
We aimed to verify if there is evidence to consider dichloroacetate (DCA), which inhibits the pyruvate dehydrogenase kinase (PDK) and reverts the metabolic shift of cancer cells from glycolysis to oxidative phosphorylation, as a promising drug for therapy of cutaneous melanoma (CM) patients.
RESEARCH DESIGN AND METHODS:
We assessed the expression profile of PDK 1, 2 and 3 in a series of melanoma samples, to verify if melanoma tumors express the DCA targets, if this expression correlates with the activation of important signaling cascades for melanomagenesis and also with the prognosis of melanoma patients. We also established the sensitivity of melanoma cell lines to DCA treatment, by assessing their metabolic alterations, proliferation and survival.
RESULTS:
We observed that both PDK 1 and 2 isoforms are overexpressed in CM compared to nevi, this expression being associated with the expression of the mTOR pathway effectors and independent of the BRAF mutational status. Melanoma cell lines treated with DCA showed a shift in metabolism, that is, a decrease in glucose consumption and lactate production, downregulation of proliferation, an increase of apoptosis and a decrease in mTOR pathway activation.
CONCLUSION:
Our results suggest that PDK expression may play a role in melanoma development and that DCA can be useful for CM therapy, alone or in combination with mTOR inhibitors.


Dichloroacetate induces protective autophagy in esophageal squamous carcinoma cells

Abstract
Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase, which promotes the flux of carbohydrates into mitochondria and enhances the aerobic oxidation of glucose. DCA has previously been demonstrated to exhibit antitumor properties. The present study revealed that treatment with DCA induced increased levels of autophagy-associated proteins in esophageal squamous carcinoma cells while minimally affecting apoptosis. The present study examined the localization of light chain (LC)-3 by adenovirus infection with a green fluorescent protein (FP)-red FP-LC3 reporter construction and confirmed that DCA treatment induced significant autophagy. Furthermore, the inhibition of DCA-induced autophagy facilitated cell apoptosis and improved the drug sensitivity of esophageal squamous carcinoma cells to DCA and 5-FU (5-fluorouracil). The proliferation of TE-1 cells was markedly inhibited at low concentrations of DCA and 5-FU treatment when subjected to Atg5 mRNA interference, indicating that autophagy performed a protective role in cell survival upon DCA treatment. To determine the underlying mechanism of DCA-induced autophagy, the present study measured alterations in autophagy-associated signaling pathways. Notably, the protein kinase B (Akt)-mechanistic target of rapamycin (mTOR) signaling pathway, an important negative regulator of autophagy, was demonstrated to be suppressed by DCA treatment. These results may direct the development of novel strategies for the treatment of esophageal squamous carcinoma based on the combined use of DCA and autophagy inhibitors.


Dichloroacetate induces autophagy in colorectal cancer cells and tumours

Abstract
BACKGROUND:
Dichloroacetate (DCA) has been found to have antitumour properties.
METHODS:
We investigated the cellular and metabolic responses to DCA treatment and recovery in human colorectal (HT29, HCT116 WT and HCT116 Bax-ko), prostate carcinoma cells (PC3) and HT29 xenografts by flow cytometry, western blotting, electron microscopy, (1)H and hyperpolarised (13)C-magnetic resonance spectroscopy.
RESULTS:
Increased expression of the autophagy markers LC3B II was observed following DCA treatment both in vitro and in vivo. We observed increased production of reactive oxygen species (ROS) and mTOR inhibition (decreased pS6 ribosomal protein and p4E-BP1 expression) as well as increased expression of MCT1 following DCA treatment. Steady-state lactate excretion and the apparent hyperpolarised [1-(13)C] pyruvate-to-lactate exchange rate (k(PL)) were decreased in DCA-treated cells, along with increased NAD(+)/NADH ratios and NAD(+). Steady-state lactate excretion and k(PL) returned to, or exceeded, control levels in cells recovered from DCA treatment, accompanied by increased NAD(+) and NADH. Reduced k(PL) with DCA treatment was found in HT29 tumour xenografts in vivo.
CONCLUSIONS:
DCA induces autophagy in cancer cells accompanied by ROS production and mTOR inhibition, reduced lactate excretion, reduced k(PL) and increased NAD(+)/NADH ratio. The observed cellular and metabolic changes recover on cessation of treatment.


Dichloroacetate induces protective autophagy in LoVo cells: involvement of cathepsin D/thioredoxin-like protein 1 and Akt-mTOR-mediated signaling

Abstract
Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase (PDK), and recently it has been shown as a promising nontoxic antineoplastic agent. In this study, we demonstrated that DCA could induce autophagy in LoVo cells, which were confirmed by the formation of autophagosomes, appearance of punctate patterns of LC3 immunoreactivity and activation of autophagy associated proteins. Moreover, autophagy inhibition by 3-methyladenine (3-MA) or Atg7 siRNA treatment can significantly enhance DCA-induced apoptosis. To determine the underlying mechanism of DCA-induced autophagy, target identification using drug affinity responsive target stability (DARTS) coupled with ESI-Q-TOF MS/MS analysis were utilized to profile differentially expressed proteins between control and DCA-treated LoVo cells. As a result, Cathepsin D (CTSD) and thioredoxin-like protein 1 (TXNL1) were identified with significant alterations compared with control. Further study indicated that DCA treatment significantly promoted abnormal reactive oxygen species (ROS) production. On the other hand, DCA-triggered autophagy could be attenuated by N-acetyl cysteine (NAC), a ROS inhibitor. Finally, we demonstrated that the Akt-mTOR signaling pathway, a major negative regulator of autophagy, was suppressed by DCA treatment. To our knowledge, it was the first study to show that DCA induced protective autophagy in LoVo cells, and the potential mechanisms were involved in ROS imbalance and Akt-mTOR signaling pathway suppression.


My observations:
  • dichloroacetate is a good candidate drug to deal with Naviaux's hypometabolic state
  • it appears that dichloroacetate also inhibits mTOR
  • if mTOR inhibition is desirable as a treatment for SEID, then dichloroacetate would be truly a magic drug!
 

XenForo

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107
The Center for Complex Diseases in Mountain View, CA diagnosed me with MCAS (Mast Cell Activation Syndrome) and my doc there thinks the Rapamune might have been helping to alleviate my MCAS. I've been doing much better on the MCAS drugs and have gone off Rapamune for now.
 
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XenForo

Senior Member
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107
Wow, I'm doing MUCH, MUCH better on lots of meds for MCAS. I do wonder if Rapamune helps with MCAS symptoms. Any other Rapamune responders find out you have MCAS?
 
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Marky90

Science breeds knowledge, opinion breeds ignorance
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Wow, I'm doing MUCH, MUCH better on lots of meds for MCAS. I do wonder if Rapamune helps with MCAS symptoms. Any other Rapamune responders find out you have MCAS?

Grats!! What kind of drugs is that?
 

ScottTriGuy

Stop the harm. Start the research and treatment.
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Wow, I'm doing MUCH, MUCH better on lots of meds for MCAS. I do wonder if Rapamune helps with MCAS symptoms. Any other Rapamune responders find out you have MCAS?

I've been taking Rapamune since Nov.

What MCAS testing was done and, if you don't mind, what tests were you positive? My doc is very open so would pursue this line of inquiry.
 

XenForo

Senior Member
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107
Grats!! What kind of drugs is that?
It is so nice to have a skilled doctor I trust to help direct my care. It is so much better than desperately ordering drugs online without a doctor's direction. Anyway, here's what my doc is prescribing for my MCAS:
Zantac 1 tab 2x day
Zyrtec 1 tab pm
Claritan 1 tab in am
Hydroxizyne tabs, titrated up to 50 mg 2 or 3 times a day
Xanax .25mg 2x day
Chromolyn Sodium 15 to 30 minutes before eating, titrating up to maybe 3 or 4 ampules. I'm still at 2 ampules
Phosphatidyl choline 1 gelcap 3x day
Low dose naltrexone 6mg at night
Ketotifen titrating up to 3mg 2 times a day
and a bunch of supplements like vit. D, B12, methylfolate, magnesium threonate (sp?) etc.
I'm still doing really really well. Scheduled to go back to work Wednesday next week. I'm going to start at 4 hours and see how it goes. I'm not sure I'm ready for that, but I'm going to try and see how it goes. I'm really looking forward to it.
 
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XenForo

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107
What MCAS testing was done and, if you don't mind, what tests were you positive? My doc is very open so would pursue this line of inquiry.
I'll mention a couple things that I'm guessing are big clues to MCAS: I had allergy testing in the past (before going to Mountain View CCD) and I reacted to everything (or almost everything, I can't remember) except the control. I had lots and lots of vomiting between the ages of 1 and 2 or whenever that is when you first start walking to about age 2, 2 1/2 or so. And I've had lots of diarrhea and digestion issues throughout my life. No doctor has ever been able to address the root causes except CCD. One other clue is I've always had seasonal asthma (sp?). And of course, the PEM, but I guess that one is not specific. Specific tests and results pm'd.
 

XenForo

Senior Member
Messages
107
If no one else in this thread has MCAS maybe the MCAS stuff should be split into it's own thread? Any other Rapamune responders have an opinion about a possible relationship between MCAS and Sirolimus or other mTOR inhibitors?
 

XenForo

Senior Member
Messages
107
Just a super quick update: I'm working well over 10 hours a day, at a very very stressful place that I hope to get away from in the next year. I'm also going through a divorce and also unrelated litigation. Stress is usually one of the triggers that brings me down very very fast. I do have down days, especially after very hard physical work over 3 hours at a stretch. But, overall, I am doing orders of magnitude better. Once in a while I do still reach for the rapamune, but it's rare nowadays. Mast Cell Activation Syndrome is what I have been diagnosed with and my doc says that Sirolimus helps fight mast cell activation as one of it's many activities. I'm still following this forum, because I'm curious if anyone else who is a rapamune responder has been diagnosed with MCAS as well.
 
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