#96

@RapAdmin @MAC @rivasp12

Great discussion Thread!! it almost feels like you guys are cracking the code.

@RapAdmin I believe you posted something on the Rapa scientist that used 1mg / day to stave off his stage 4 colon cancer. He must of had his reasons for a daily low dose.

@MAC Your arguments for higher doses creating more cancer / tumor inhibition should be seen with renal transplant patients? You may have run across that comparison in your extensive reading.

Thanks guys! I learn something everyday.

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#97

The most beneficial results for rapamycin in mouse studies has been high doses. Full stop. Unless something has changed since June 2022. I don’t think there’s any support for daily dosing absent unusual circumstances.

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#98

There are mtorc2i studies for cancer in transplant pt, mentioned it before

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#99

@David, these are long, but if you haven’t seen either of these webinars, you will get a lot of helpful information from 3 of the best in this field, Dr. Green being one of them.

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#100

Generally yes, higher daily doses results in higher trough/AUC, and better cancer and renal rejection outcomes, but more side effects.

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#101

@Terri56 - Thank You! I will try to check them out this weekend. Kind of you to pass this on!

#102

Could someone summarize the key points of those presentations for those of us with time constraints? :slight_smile:

I will definitely try to watch them though! They go right to the top of my to watch list.

#103

@EnrQay summarized the second one - the first you’d have to listen to.

Second Webinar Here: Rapamycin Update - Summary of Recent Matt Kaeberlein, Dr. Green, Blagosklonny Conference Call (June, 2022)

#104

Yes I agree that there is much to recommend low dosing. That is what I intend to do. 6 mg once per week is low dosing. Where things begin to become much more controversial is when low dosing means 1 mg per day.

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#105

I agree and that’s particularly true with a long half life drug like rapamycin. If you wanted to do multiple dosing per week but still be low dosed, everolimus is the better choice.
My dose continues to be 6 mg’s per week of rapamycin and I’m not swayed by very high metabolism mice , with probable high mTOR activity, to go high on the dose.

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#106

@rivasp12

Using the lower half life of everolimus does make sense for more frequent dosing.

I have been using 6mg weekly for the last several months and more than happy with quality of life changes, I try not to work out a few days after due to a drop off in recovery.

In an attempt to have a smoother mTOR modulation more similar to our youth than an up and down effect as the pulsed dosing, the every other day everolimus may be worth a try.

I believe Dr. G was trying 10mg x 2 days biweekly. It would be nice to understand his thoughts on why change what has been working - improved outcome or safety?

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#107

Another study demonstrating rapamycin as a Modulator. In the presence of obesity and a high fat diet, rapamycin lowers visceral fat content and corrects metabolic markers at a relatively low dose.

Rapamycin seems to modulate both immune function and metabolic functioning at relatively low dosing. The dosing in this study was continuous.

Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat

https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/EP087207#.W3mUbIUJNeU.twitter

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#108

@rivasp12 - Thats an interesting study! I am not sure how to convert the 2.4mg/ Kg dose the mice got to our human dosing, but it seems to suggest more to learn on the mTOR1 and mTOR2 regulation / modulation based on dosing and downstream lipid, visceral fat and glucose affect.

Thank You!

#109

HED is 2.4/12.3 x 70kg = 14mg.

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#110

Thanks @MAC !

That does not seem to be a very low dose. I may have the numbers wrong, but if not, interesting they did not get mTOR 2 inhibition.

#111

A very high HED.

Brief read through the paper, there is NO measurement of mTOR2, only mTOR1. They “speculated” about mTOR2.

The study is pretty dsyfunctional for human translation. It is a FACT that humans taking rapamycin at mTOR inhibition doses WILL get lipid dysregulation, most especially elevated hepatic TG, and even glucose dysregulation, both higher fasting and hbA1c.

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#112

It may be more nuanced than that. Not everyone on rapamycin will get lipid dysregulation, and certainly not elevated A1C, and the effects may be transient. So the study addressed a very specific question , what does rapamycin do in the presence of an obesity induced diet high in fat and sugar.
In this case rapamycin reduces fat and corrects metabolic dysfunction. That’s precisely what you’d expect from a modulator.

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#113

Show me a HUMAN study where trough sirolimus is tested at mTOR inhibition doses where this is the case? That is, no dsyregulation.

I will argue most everyone on this site is NOT doing much mTOTR inhibition.

Dr Mark Ratain, the Rapamycin/cancer oncologist told me “no dysregulation, no mTOR inhibition”

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#114

Given the abundance of supporting evidence for the efficacy of sirolimus and everolimus in treating the same TSC manifestations, which medication should be favored when initiating treatment? In preclinical studies, the 2 agents are often used interchangeably, but direct side-by-side comparisons are rarely made in the same study design. Sirolimus demonstrates slightly higher binding affinity to FKBP12 than everolimus (half-maximal inhibitory concentration of 0.4–0.9 nM vs 1.8–2.6 nM, respectively),86 although this difference is not likely to be relevant clinically because human serum levels range between 5 and 15 ng/mL (5.5–16.4 nM). When compared, both agents similarly inhibit cell proliferation and T-cell immunologic activity, and both are efficacious in preventing organ rejection.86

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#115

From Mannick study…
In the intent-to-treat population, the low-dose RAD001 (0.5 mg daily or
5 mg weekly) cohorts, but not the higher-dose (20 mg weekly) cohort, met
the primary endpoint of the study (Fig. 1A). Modeling and simulation
based on mTOR-mediated phosphorylation of its downstream target S6
kinase (S6K) predicted that the 20 mg weekly dosing regimen inhibited
mTOR-mediated S6K phosphorylation almost completely, the 5 mg weekly
dosing regimen inhibited S6K phosphorylation by more than 50%, and the
0.5 mg daily dosing regimen inhibited S6K phosphorylation by about 38%
over the dosing interval (12). Thus, partial inhibition of mTOR-mediated
S6K phosphorylation achieved with a relatively low dose of RAD001 may
be as effective as nearly complete inhibition associated with high-dose
RAD001 at enhancing the immune response of the elderly volunteers.

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