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of Mice and Men and Resveratrol


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#31 niner

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Posted 01 September 2009 - 03:44 AM

I used the BSA equivalent calc based on http://www.fasebj.or...fasebj;22/3/659 . I think the lifegen/weindruch paper that is discussed previously in the thread using mice @ 4.9 mg/kg, mentions that a low dose turns on a certain set of longevity genes (it discusses overlap of gene expression between CR and resveratrol, etc.).

But I *think* there is a comment in that paper mentioning that a low dose turns on a high % of these genes expressed in CR, and that a higher dose may not be ideal because it would change the expression profile or increase expression in genes not desired (if i recall properly, dont have the paper atm i am on the road).

why wouldn't you want to equate a low dose strategy to the BSA-HED used in this paper? i realize what you are trying to do in terms of plasma level, but what is the differential between human/mice such that the HED-BSA calc is invalid for resv.

The BSA method is used for determining the dose for the first use in humans, where there is no human PK data. It is really focused on toxicology, not pharmacodynamics. Many of the examples in that paper, whose authors included a cancer researcher and a toxicologist, concerned toxic chemotherapy drugs. They even go as far as to say:

BSA normalization of doses must be used to determine safe starting doses of new drugs because initial studies conducted in humans, by definition, lack formal allometric comparison of the pharmacokinetics of absorption, distribution, and elimination parameters.

It's the ADME where the BSA calculation really falls apart. It's basically designed to err on the safe side. There are undoubtedly some compounds where it works well, but from what we know about resveratrol, now well studied in humans and other species, resveratrol isn't one of them. That's why Sirtris was using such large doses in their trials.

#32 tunt01

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Posted 01 September 2009 - 07:03 AM

ty niner/max. appreciate it much.

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#33 maxwatt

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Posted 17 January 2012 - 05:17 AM

A footnote to this topic, but the paper I cited to start this thread has been reported to contain fabricated and falsified data by the University of Connecticut's investigation report.


This paper found negative effects from resveratrol in high doses in rats:

Resveratrol, a unique phytoalexin present in red wine, delivers either
survival signal or death signal to the ischemic myocardium
depending on dose
Jocelyn Dudley, Samarjit Das, Subhendu Mukherjee, Dipak K. Das⁎
PMID: 18789672

Das found that 5 mg/kg administered by gavage exerts a survival signal by up-regulating anti-apoptotic and redox proteins Akt and Bcl-2, while at higher doses (>25 mg/kg), it potentiates a death signal by down-regulating redox proteins and up-regulating pro-apoptotic proteins. (After 14 days, isolated working hearts were prepared from both experimental and control animals, and the hearts were subjected to 30-min global ischemia followed by 2 h of reperfusion.)

I found this curious, as Lagouge administered 400mg/kg to mice with only positive effect. (Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Lagouge M, Argmann C, et al. Cell. 2006; 127(6): 1109-22). 400 mg is the dose that made athletes out of couch potato rats.

The metabolic difference between mice and rats is such that 400 mg/day resulted in a plasma level of 120 ng/ml (Lagouge) albeit in chow, vs by gavage in the rats. I had to search for serum levels in rats, but found that administering 2mg/kg resulted in a peak plasma level of 550 ng.ml (Planas, Food Research International,Volume 35, Issues 2-3, 2002, Pages 195-199, Plasmatic levels of trans-resveratrol in rats.). This is a huge difference in levels for a given dose. It may reflect metabolic differences between rats and mice, or may be due to the difference between an acute dose, and a dowse mixed in food.

We have data for humans from Boocock's paper, where he found peak blood serum levels in humans of 117 ng/ml at a dose of 1 g (14 mg/kg for a 70 kg human) effectively the same as a mouse gets from a dose 400mg/kg. ( Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Boocock DJ, Faust GE, Patel KR, Schinas AM, Brown VA, Ducharme MP, Booth TD, Crowell JA, Perloff M, Gescher AJ, Steward WP, Brenner DE., Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1246-52.)

I concluded that Das' rats were receiving the equivalent of at least 10 times Lagouge's mouse dose, even though the mice were receiving the equivalent of 16 times as much resveratrol as Das' rats. Boocock's paper(*) found peak blood serum levels in humans of 117 ng/ml at a dose of 1 g (14 mg/kg for a 70 kg human) effectively the same as a mouse gets from a dose 400mg/kg when mixed in food. Rats appear to have much higher serum levels than mice from a given dose, though the difference may be at least partially due to the method of administration. J

Judging by peak plasma levels, it does seem that humans can achieve sufficiently high blood serum levels that resulted in mitochondrial and other metabolic improvements in mice. It also appears the human serum levels even with gram doses are below that which produced adverse effects in rats.



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#34 Mind

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Posted 17 January 2012 - 09:06 PM

Thanks for following up and making a note of this Maxwatt!




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