A bit more than rapamycin but not a lot.
adssx
#22
2 to 3x more than rapamycin. But that doesn’t compensate the big difference in mTOR inhibition.
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adssx
#23
Some recent content published on Neurizon’s website (the pharma behind NUZ-001, which is the pill version of monepantel investigated for use in humans):
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AnUser
#24
It’s interesting, I just don’t know enough to judge a drug in the preclinical or early clinical phase.
@adssx meclizine crossed the BBB. What’s wrong with using that instead? Dramamine
“Meclizine extends male mouse lifespan by ~8%.
Astaxanthin prolongs the lifespan of male mice by ~12%.
Interestingly, fisetin, a compound known for eliminating aging-related dysfunctional cells (senescent cells), confers no effects on either mouse lifespan or tissue senescence.”
The effect on mTORC1 is mild even at relatively high doses.
In addition, meclizine inhibits mitochondrial respiration, which is not a good thing.
Meclizine is also an anticholinergic, which is also not a good thing, especially for the elderly. But maybe this could be mitigated by a choline supplement.
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Didn’t know re: anticholinergic bit. Makes sense.
adssx
#29
I don’t think there’s data on this.
Meclizine => anticholinergic => bad?
“Meclizine is a first-generation antihistamine.”
"Meclizine is an anticholinergic.
“First-generation antihistamines also tend to have notable anticholinergic properties (blocking acetylcholine receptors)”
I was wrong in suggesting that choline supplements might mitigate the effects of anticholinergic medications because the medications block the receptors and do not diminish the amount of choline in your system.
“According to the American Geriatrics Society (AGS Beers Criteria 2023), the long-term use of anticholinergic medications such as meclizine is associated with an elevated risk of delirium, falls, delirium, and dementia among older adults.”
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adssx
#31
That’s why the quest for a safe BBB-crossing mTOR inhibitor is still on. Hopefully, monepantel will be the one.
@CronosTempi after discussing with Ora Biomedical, a C. Elegans test is probably useless as monepantel is a dewormer even at low dose, but we might try on C. Elegans with the target gene acr-23, knocked out. Alternatively, we might try on zebrafish and Drosophila? I can ask WuXi for a quote. But which doses should we test?
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Well, fish and flies are too far from mammals, so there probably is no sense in trying to extrapolate dosing in humans per body weight to these little creatures. The usual procedure in labs is to do a series of doses to see which one gives effects. Probably not practical in this scenario, so it’s just going to be a guessing game. Maybe the dose can be derived from gene targets:
Phylogenomics of Ligand-Gated Ion Channels Predicts Monepantel Effect
“The nematode species in the Caenorhabditis genus, equipped with ACR-23/MPTL-1-like receptor subunits, are sensitive to monepantel (EC50<1.25 µM), whereas the related nematodes Pristionchus pacificus and Strongyloides ratti , which lack an ACR-23/MPTL-1 homolog, are insensitive (EC50>43 µM). Genome sequence information has long been used to identify putative targets for therapeutic intervention. We show how comparative genomics can be applied to predict drug sensitivity when molecular targets of a compound are known or suspected.”
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adssx
#33
Yes we need to do a dose response but I just don’t know which 3 doses to start from. Then we can ask a Chinese lab such as WuXi to run the study.
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