42 replies to this topic

[maxwatt]

I took Anthony's t-res 99% pure about a tablespoon worth and still get bad diarrhea -- any idea why?  Supposed to be no emodin. 

Is there something else in pure t-res that causes this?  It's consistent with anthony's -- but I don't get it at all with Longivenix's res which I also take -- but at smaller dosages admitedly.

I can't take large doses if this keeps up unless the res is low quality.

I have a theory why some people have a sensitivity to high-purity resveritrol; unless it is dispersed, the powder, even in capsule form, forms an undisolved bolus that irritates the small intestine. I am awaiting feedback from one person who has had this proble, but you can try using a dispersant such as lecithin to mix your resveratrol in lecithinated water, or you can try mixing it with a fat-containing food such as yogurt; mix thoroughly so there are no clumps of powder.

If you try this, kindly let us know if it helps.

[sUper GeNius]

I took Anthony's t-res 99% pure about a tablespoon worth and still get bad diarrhea -- any idea why? [...]

I have a theory why some people have a sensitivity to high-purity resveritrol; unless it is dispersed, the powder, even in capsule form, forms an undisolved bolus [...]

You just might be correct. I had a problem until I started dissolving in lecithin.

Edited by Michael, 24 July 2009 - 03:28 PM.
Trim quotes

[niner]

Maxwatt and/or tobar8, is lecithin better than Miralax? (with resveratrol, that is...) What are the advantages of it? What brand of lecithin do you like?

[maxwatt]

Maxwatt and/or tobar8, is lecithin better than Miralax?  (with resveratrol, that is...) What are the advantages of it?  What brand of lecithin do you like?

I found Miralax to function as a laxative when taken cumulatively, as have others. Lecithin does not have this problem.

PS any powdered or granulated lecithin should work; I use Vitamin Shoppe only because the store was around the corner and the price was low. All other surfactants are excreted unchanged, in the urine. Lecithin has some nutritive value (choline et al.

Edited by maxwatt, 26 September 2007 - 01:29 PM.

[dannov]

Miralax so far at 2-2.5g a day hasn't been bothering me...slight lax effect, but nothing cumulative that I've been noticing or that is too unusual for bowel movements.

[neogenic]

Well I took heat for my proposal to figure the calculations according to FDA supported techniques...

I thought this unpublished study may add something of interest to this thread.

FASEB J. 2007 Oct 17; [Epub ahead of print]

Dose translation from animal to human studies revisited.
Reagan-Shaw S, Nihal M, Ahmad N.

*Department of Dermatology,Paul P. Carbone Comprehensive Cancer Center;Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin, USA.

As new drugs are developed, it is essential to appropriately translate the drug dosage from one animal species to another. A misunderstanding appears to exist regarding the appropriate method for allometric dose translations, especially when starting new animal or clinical studies. The need for education regarding appropriate translation is evident from the media response regarding some recent studies where authors have shown that resveratrol, a compound found in grapes and red wine, improves the health and life span of mice. Immediately after the online publication of these papers, the scientific community and popular press voiced concerns regarding the relevance of the dose of resveratrol used by the authors. The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight, as was reported. For the more appropriate conversion of drug doses from animal studies to human studies, we suggest using the body surface area (BSA) normalization method. BSA correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. We advocate the use of BSA as a factor when converting a dose for translation from animals to humans, especially for phase I and phase II clinical trials.-Reagan-Shaw, S., Nihal, M., Ahmad, N. Dose translation from animal to human studies revisited.

[xansolo]

Hi! If to stir resveratrol in kefir or yoghurt the diarrhea is not present. But is also such data ...

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 Biomakers and Prevention Group, Department of Cancer Studies and Molecular Medicine, Leicester Royal Infirmary, Leicester University, Leicester LE2 7LX, United Kingdom.

The red grape constituent resveratrol possesses cancer chemopreventive properties in rodents. The hypothesis was tested that, in healthy humans, p.o. administration of resveratrol is safe and results in measurable plasma levels of resveratrol. A phase I study of oral resveratrol (single doses of 0.5, 1, 2.5, or 5 g) was conducted in 10 healthy volunteers per dose level. Resveratrol and its metabolites were identified in plasma and urine by high-performance liquid chromatography-tandem mass spectrometry and quantitated by high-performance liquid chromatography-UV. Consumption of resveratrol did not cause serious adverse events. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol at the highest dose were 539 +/- 384 ng/mL (2.4 micromol/L, mean +/- SD; n = 10), which occurred 1.5 h post-dose. Peak levels of two monoglucuronides and resveratrol-3-sulfate were 3- to 8-fold higher. The area under the plasma concentration curve (AUC) values for resveratrol-3-sulfate and resveratrol monoglucuronides were up to 23 times greater than those of resveratrol. Urinary excretion of resveratrol and its metabolites was rapid, with 77% of all urinary agent-derived species excreted within 4 h after the lowest dose. Cancer chemopreventive effects of resveratrol in cells in vitro require levels of at least 5 micromol/L. The results presented here intimate that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with cancer chemopreventive efficacy. However, the high systemic levels of resveratrol conjugate metabolites suggest that their cancer chemopreventive properties warrant investigation.

PMID: 17548692 [PubMed - indexed for MEDLINE]

[Anthony_Loera]

Wonder why Sirtris is using high doses.... instead of using HED for the phase 1 & 2 studies...

[goku]

do u need to dose the 7 grams all at once, or is it better to break up the dose into several times per day -- also how does all this relate when things that enhance absorbtion are used like lecithin, etc

[maxwatt]

do u need to dose the 7 grams all at once, or is it better to break up the dose into several times per day -- also how does all this relate when things that enhance absorbtion are used like lecithin, etc

The consensus here seems to be that peak serum level is what is critical, rather than area-under-the-curve, so it's best to take it in a single large dose per day.

[Anthony_Loera]

I believe we can use these numbers to roughly calculate an intravenous dosage if needed.
Niner did a great job with his post below.

(high abosption but low bioavailability of oral resveratrol in humans, 2004)
(using 25mg per 70kg)Humans -Serum Peak <22 nM

metabolism and disposition of Resveratrol in Rats, extent of absorption, glucoronidation, and enterophatic circulation, 2002)
(using 50mg/kg of bodyweight) Rats -Serum Peak <6.6 µM

(Pharmacokinetics in mice and growth inhibitory properties of putative cancer chemopreventative agent resveratrol and synthetic analogue trans, 2004)
(using 240mg/kg of bodyweight) Mouse -Serum Peak <32 µM

Using these numbers, plus the study below, where humans given 71mg/kg (assuming 70kg body wt. with 5gm oral resv) had a serum peak of 2.4 µM, we can look at the serum levels obtained per 1mg/kg dose.

6.6uM/50mg kg(-1) = 0.132 (rat)
32 uM/240mg kg(-1) = 0.133 (mouse)
0.022 uM/0.357 mg kg(-1) = 0.0616 (human low dose)
2.4 uM/71mg kg(-1) = 0.0338 (human high dose)

I consider the human high dose number to be more reliable due to the larger values involved, Boocock's involvement in development of resveratrol quantitation methodology, and the fact that the 22 nM value (from Walle et al., Drug Metab Dispos. 2004 Dec;32(12):1377-82.) was given as an upper limit. I wish that I had the full paper from Boocock et al., because then I'd feel comfortable comparing the high and low dose numbers to see if there is a "swamping" effect. Rat and mouse are certainly consistent here, though they are both at high dose levels. For the time being I'll just compare the rat and human high dose numbers:

0.132/0.0338 = 3.9

So it looks like the factor of six that is sometimes used to compare doses between mice and men works in reverse in the case of resveratrol. We don't need one sixth of the dose, but rather something on the order of two to four times as much, if we wish to reach plasma levels comparable to the mice.

Cancer Epidemiol Biomarkers Prev. 2007 Jun;16(6):1246-52.
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.
The red grape constituent resveratrol possesses cancer chemopreventive properties in rodents. The hypothesis was tested that, in healthy humans, p.o. administration of resveratrol is safe and results in measurable plasma levels of resveratrol. A phase I study of oral resveratrol (single doses of 0.5, 1, 2.5, or 5 g) was conducted in 10 healthy volunteers per dose level. Resveratrol and its metabolites were identified in plasma and urine by high-performance liquid chromatography-tandem mass spectrometry and quantitated by high-performance liquid chromatography-UV. Consumption of resveratrol did not cause serious adverse events. Resveratrol and six metabolites were recovered from plasma and urine. Peak plasma levels of resveratrol at the highest dose were 539 +/- 384 ng/mL (2.4 mumol/L, mean +/- SD; n = 10), which occurred 1.5 h post-dose. Peak levels of two monoglucuronides and resveratrol-3-sulfate were 3- to 8-fold higher. The area under the plasma concentration curve (AUC) values for resveratrol-3-sulfate and resveratrol monoglucuronides were up to 23 times greater than those of resveratrol. Urinary excretion of resveratrol and its metabolites was rapid, with 77% of all urinary agent-derived species excreted within 4 h after the lowest dose. Cancer chemopreventive effects of resveratrol in cells in vitro require levels of at least 5 mumol/L. The results presented here intimate that consumption of high-dose resveratrol might be insufficient to elicit systemic levels commensurate with cancer chemopreventive efficacy. However, the high systemic levels of resveratrol conjugate metabolites suggest that their cancer chemopreventive properties warrant investigation. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1246-52).

PMID: 17548692

[Anthony_Loera]

Should this post be updated?

What is the consensus for the Sinclair dosage?

A

[Anthony_Loera]

Just to clear this up, dosage is in the food for both Auwrex and Sinclair.
So the excel sheet on post 1 is incorrect. But the interesting part is the plasma data:


http://www.sciencedi...7de078e6#sec2.4

Metabolic Consequence of RSV in Diet-Induced Obesity

The metabolic effect of RSV was initially evaluated in a cohort of male C57Bl/6J mice that were given a dose of 200 or 400 mg/kg/day (mpk) of RSV administered in either a chow diet or high fat (HF) diet for 15 weeks. With this protocol, the plasma level of RSV was dose-related and ranged from 10–120 ng/ml.

Experimental Procedures
In Vivo Analysis

Four to eight week male C57Bl/6J mice from Charles River (L'Arbresle, France) and 8 week male KKAy mice from Clea (Tokyo, Japan) were housed in specific pathogen-free conditions with a 12 hr light-dark cycle and had free access to water and food. RSV (Orchid, Chennai, India) was mixed with either powdered chow (DO4, UAR, France) or HF diet (D12327, Research diet, New Brunswick, USA) at a concentration of 4 g/kg of food to provide a 400 mpk dose, and pellets were then reconstituted. Control groups received pellets without drug. Body weight and caloric intake were monitored throughout the experiments.