One hypothetical possibility I can think of for such silent pathology with high single dosing may be insidious onset hearing loss occurring gradually over a multi-year period. Hearing loss is already listed as a possible side effect in patients. So there must be rare reports of it in sensitive individuals taking higher doses for immune suppression.
A primary reason for taking periodic high doses is to get better penetration across the BBB. However, there’s also something called the blood-labyrinth barrier which protects the sensory epithelia of the inner ear. And it likewise can be overcome. When researchers injected mice at 10 mg/kg, they experienced severe, rapid hearing loss within two weeks as these hair cells died. Unknown is the threshold at which more mild and gradual damage may start in mice other than that 2 mg/kg injections didn’t evidence ototoxicity. The dose makes the poison with medications. And as you ramp up the dose with rapamycin, these delicate cells of the inner ear are among the first to start showing severe toxicity. And that’s actually pretty common in pharmacology particularly with antibiotic drugs.
A silent and progressive adverse effect needn’t be common to become a significant factor in a risk/benefit analysis. For example, in the above hypothetical, what if the spike from very high single doses of the drug elevated the chance of hearing loss or some other rare adverse effect from less than 1/1000 to say, 4% chance?
Edit: I’m not suggesting that I believe this will be an emerging concern at repeated 36 mg single dose. I don’t know, actually. I’m just envisioning a plausible scenario for an unknown emerging silent pathology.
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Reference study:
Fu X, Li P, Zhang L, et al. Activation of Rictor/mTORC2 signaling acts as a pivotal strategy to protect against sensorineural hearing loss [published correction appears in Proc Natl Acad Sci U S A. 2022 May 17;119(20):e2204956119]. Proc Natl Acad Sci U S A . 2022;119(10):e2107357119. doi:10.1073/pnas.2107357119
This is interesting… I wonder if the oral administration studies of rapamycin (high dose) to mice would have shown any of this…
High Concentration of Sirolimus Led to Severe Hearing Loss in C57BL/6J Mice.
As an FDA-approved drug, the most effective dose with minimal side effects of sirolimus to the auditory system was determined, following which, we evaluated the efficacy of different concentrations of sirolimus on the hearing of C57BL/6J mice. Notably, consistent with our previous reports, low doses of sirolimus (i.p. to 6-mo-old C57BL/6J mice every other day at 1 mg/kg to 2 mg/kg) had no obvious effect on the hearing sensitivity of mice compared with the untreated WT mice (Fig. 1 A and D). In contrast, unexpectedly, high doses of sirolimus (10 mg/kg to 20 mg/kg) injection for 2 wk led to severe hearing loss in C57BL/6J mice (Fig. 1A). ABR thresholds to tune bursts between 4 and 32 kHz and click stimulation were significantly elevated by about 30 dB to 50 dB sound pressure level (SPL) in mice injected with high concentrations of sirolimus (Fig. 1A).
Interestingly… I was searching on mTORC2 activators (because higher mTORC2 countered the negative impact on hearing from the very high doses of rapamycin)… and found this:
We found that a diverse array of AMPK activators increased mTOR complex 2 (mTORC2) signaling in an AMPK-dependent manner in cultured cells. Activation of AMPK with the type 2 diabetes drug metformin (GlucoPhage) also increased mTORC2 signaling in liver in vivo and in primary hepatocytes in an AMPK-dependent manner.
Valsko writes:
A primary reason for taking periodic high doses is to get better penetration across the BBB. However, there’s also something called the blood-labyrinth barrier which protects the sensory epithelia of the inner ear.
Matt, in his latest interview on the Drive with Attia and Sabatini - says getting across the BBB may be easier for older adults as the immune defense weakens… he also says peripherally and on the outer area of the brain, the benefits may be enough without crossing completely through or in.
On the one hand, thats good value for the money, in this one tablet or batch of tablets.
On the other hand, a quality control system that allows that wide a variance from the mean (.i.e. +/- .69 of a mg, or in other words about +/- 70% of target dose), suggests that some significant part of the time you may be getting something like .3mg or .4mg instead of 1mg. I find that disconcerting and problematic as you would never really know what dose you’re taking.
And, if they have that wide a standard deviation in the dosing, how much can you trust them on the possible contaminants?
Has anyone tested blood levels to see if they correspond to the dose they think they are taking of Siroboon tablets? I’m curious both as to the accuracy of the tablet amount but also if their are any differences in absorption (per brand) due to different enteric coatings.
There were results posted. But one problem is that people were possibly having their blood drawn too soon, trying to catch a peak that only applies to rapamycin liquid preparations on an empty stomach.
yes, probably would need a direct comparison of 1mg zydus brand and 1 mg Siroboon brand. I guess another reason that it is worthwhile to test your own blood level on the dose you are taking to determine if your in your own personal target range.
I’ve been taking the Biocon Rapacan 1mg pills for almost six months. I take 8mg every Friday morning. Three times I’ve tested my rapamycin blood level, all of them two hours post consumption. Test 1 result was 17.1 ng/ml, Test 2 was 12.9 and test 3 was 31.9 (with GFJ). And, I’m getting good results (check out my hair picture on the Anti-Aging Benefits thread).
Two months ago I tried the Siroboon 2mg pills (fewer pills seemed easier and cheaper). I took four 2mg pills and my blood test came back at a paltry 3.1 (also after two hours and posted results on this thread). Quite disappointing.
Yesterday (Friday), I tried the Siroboon again, taking four 2mg pills (maybe the first time it was something with my digestive system or a bad test?). I then had my blood tested twice- once after two hours post consumption and again after six hours.
Two hours: 3.8 ng/ml
Six hours: 3.2 ng/ml
My take: Siroboon = SiroCrap
I’ve bought everything from Maulik at Vallabh Enterprise/Shreeji Impex and I’m certain that he is sending me unadalterated Siroboon. I’ve bought a bunch of stuff from him and all of my tests show that they have worked as advertised. Maybe I just got a bad batch? I couldn’t excuse that either.
I bought my Siroboon directly from Kachhela and got similar results (posted up-thread) where two 10mg Rapacan tests showed values of 40+ and Siroboon came in at 8.9. (I weigh 120lbs.) All at nearly the same time, and with same food intake. I never tried the rest of my Siroboon after this, stuck with Rapacan.
Yes - I think that there is likely a significant difference in quality control in these companies. I would stick with leaders in the market in India. In this case, we’re talking Zydus and Biocon for sirolimus.
QC or there are differences in the enteric coatings between the different manufacturers. I wonder has anyone compared Biocon to Zydus in their blood levels post ingestion?
