36 replies to this topic

[malbecman]

A group in France has come up with a patented lipid formulation that they claim shows a ~9 fold improvement in the AUC in humans. From the Methods section "The lipid formulation consists of natural t-Res powder (40 mg) dissolved in a complex mixture notably containing polysorbate 20 and polyglyceryl-3-dioleate. This solution is embedded in a caplet as described in patent WO YVERY N° 2010/007252. Other chemicals were purchased from Sigma–Aldrich (France)." It's an interesting read.



Biochimie. 2013 Jan 31. pii: S0300-9084(13)00011-4. doi: 10.1016/j.biochi.2013.01.008. [Epub ahead of print]
Optimization of trans-Resveratrol bioavailability for human therapy.

Amiot MJ, Romier B, Anh Dao TM, Fanciullino R, Ciccolini J, Burcelin R, Pechere L, Emond C, Savouret JF, Seree E.

Source

University Aix Marseille, INRA UMR 1260, 13385 Marseille, France; University Aix Marseille, INSERM UMR 1062, 13385 Marseille, France; University Aix Marseille, Faculte de Medecine La Timone, Marseille F-13385, France.

Abstract


We have developed an innovative soluble galenic form to overcome the low absorption of trans-Resveratrol (t-Res) as a dry powder. We present here data on pharmacokinetics, bioavailability, and toxicity of t-Res in human volunteers treated with this soluble form, plus additional data on biological effects in rodents. Fifteen healthy volunteers of both sexes received 40 mg of t-Res in two forms, the soluble formulation (caplets) and the original powder (capsules), in a crossover design. Blood samples were collected at 15 min, 30 min, and every hour for 5 h. Plasma concentrations of t-Res and its metabolites were analyzed by liquid chromatography and mass spectrometry. The single dose (40 mg) of the soluble t-Res was well absorbed and elicited biologically efficient blood levels (0.1-6 μM) for several hours, despite metabolization into glucuronide and sulfate conjugates coupled to renal elimination. In contrast, t-Res administered as a dry powder barely elicited efficient blood levels for a short duration. The new formulation led to 8.8-fold higher t-Res levels in plasma versus the powder. t-Res metabolism was not modified and neither intolerance nor toxicity were observed during the study and the following week. The soluble formulation elicited a robust anti-inflammatory effect in various tissues of mice fed a high-fat diet, while dry powder t-Res was almost inactive. Our data suggest that significant improvements in t-Res bioavailability and efficiency can be obtained by this soluble galenic form, also allowing lower doses. The use of t-Res in human therapy is thus greatly facilitated and the toxicity risk is reduced.
Copyright © 2013 Elsevier Masson SAS. All rights reserved.

PMID: 23376875


edit for typos...

Edited by malbecman, 11 February 2013 - 05:38 PM.

[niner]

Pretty impressive blood levels for 40mg. I wonder how this formulation compares to micronized resveratrol in Tween? My recollection is about a factor of 7 or 8 (-ish) there. At least for Cmax. I'm not sure how that translated into AUC- not as much, according to my dim memory. So if these guys are really getting a factor of 9 in AUC, that sounds like something. It's proprietary and patented, though, so who knows when it would see the light of day?

[malbecman]

Or who knows how much it will cost???

[xEva]

Sigma lists solubility of resveratrol in EtOH at 50 mg/mL. Ethanol is well absorbed. What prevents people from using resveratrol 'tinctures'?

[niner]

People use ethanolic solutions buccally. One slight hitch is that as soon as you start adding water to the ethanol, the resveratrol solubility drops precipitously. Still, with something like 80 proof vodka, if you can handle swishing that in your mouth for a couple minutes, you can get a pretty high blood level, at least transiently. Some people get psychotropic effects at those levels. It sounds like a stimulant effect, from what people have reported here.

[Wilmore Labs]

We're working on our buccal, with good results. So far we've gotten the same as 3g peak actual unmodified resveratrol with 140mg.

I'm looking at the figures, which are not pay-walled. The parent compound (free resveratrol) only reached .375uM vs our 1.4uM.

http://www.sciencedi...300908413000114

http://ars.els-cdn.c...3000114-gr2.jpg

[niner]

We're working on our buccal, with good results. So far we've gotten the same as 3g peak actual unmodified resveratrol with 140mg.

I'm looking at the figures, which are not pay-walled. The parent compound (free resveratrol) only reached .375uM vs our 1.4uM.

Thanks for pointing that out, Wilmore. In this paper, they kind of scammed us by quoting the numbers for Total Resveratrol, which includes all the inactive metabolites. We only care about free resveratrol. In that case (Fig D), they didn't really do so hot, particularly if you consider AUC. At 180 min, the unformulated powder is significantly better than the formulation. As I recall, similar results were seen with micronized resveratrol in tween. Maybe the two forms should be mixed.

[malbecman]

Yes, that is a good point about the levels of free resveratrol vs. total metabolites. I missed that on my initial skim-through. Thanks.

[Wilmore Labs]

Well, the authors buried the data on the metabolites/ free resveratrol. It drove me a little nuts, and I went by the university to get the paper from their library. Each dose was in two capsules, with the solubolizer's. "containing poly sorbate 20 (aka tween 20) and polyglyceryl-3-dioleate". The patent # is WO YVERY N 2010/007252.

First glance, they used 2x 20mg tRes capsules. It begs the size of the capsules for limitations? Good improvement, but is it limited to the same as a dry 500mg dose?

[maxwatt]

Going from the top of my head from pharmokinetic studies I've seen, yes. 500 mg dry powder can achieve the same levels. But people prefer taking pills. But if the dry powder is held in the mouth while swished with some water for a minute, the levels should be comparable your bucal levels.

[Wilmore Labs]

Max, we had zero from that. Nil. Unpublished on the poster.

We have the approval to test it in the university lab if you want to come down and repeat it at Highpoint. You'll just have to pay for it.

Do you think we took two years pushing this through without discounting "just put it in water?" How many years have you been a biochemist? You should call these guys and tell them you solved the problem by "just using water".

http://www.ncbi.nlm....cal resveratrol

Edited by Wilmore Labs, 20 February 2013 - 11:22 PM.

[maxwatt]

When one mg of resveratrol in 50 mL solution was retained in the mouth for one min before swallowing, 37 ng/ml of free resveratrol were measured in plasma two minutes later.

- ^

Asensi M, Medina I, Ortega A, et al. (August 2002). "Inhibition of cancer growth by resveratrol is related to its low bioavailability". Free Radic. Biol. Med.33 (3): 387–98. doi:10.1016/S0891-5849(02)00911-5. PMID 12126761.

Probably an EtOH solution though.. Still, the solubility of resveratrol in water is 3 mg/100 mL, according to Sigma's data sheet. A misprint? Other sources have the same data. That's about a quarter cup, a big but manageable mouthful. I am surprised you found no detectable amount in blood plasma.

[niner]

When one mg of resveratrol in 50 mL solution was retained in the mouth for one min before swallowing, 37 ng/ml of free resveratrol were measured in plasma two minutes later.

- ^

Asensi M, Medina I, Ortega A, et al. (August 2002). "Inhibition of cancer growth by resveratrol is related to its low bioavailability". Free Radic. Biol. Med.33 (3): 387–98. doi:10.1016/S0891-5849(02)00911-5. PMID 12126761.

Probably an EtOH solution though.. Still, the solubility of resveratrol in water is 3 mg/100 mL, according to Sigma's data sheet. A misprint? Other sources have the same data. That's about a quarter cup, a big but manageable mouthful. I am surprised you found no detectable amount in blood plasma.

Yes, my recollection is that that was an ethanolic solution. I poked around on the Sigma Aldrich site, and managed to find only this:

It is practically insoluble in water.

30mg/L sounds too high. These guys say 5e-5M = 11mg/L, which is pretty close.

Edited by niner, 21 February 2013 - 02:01 AM.

[Wilmore Labs]

When one mg of resveratrol in 50 mL solution was retained in the mouth for one min before swallowing, 37 ng/ml of free resveratrol were measured in plasma two minutes later.

- ^

Asensi M, Medina I, Ortega A, et al. (August 2002). "Inhibition of cancer growth by resveratrol is related to its low bioavailability". Free Radic. Biol. Med.33 (3): 387–98. doi:10.1016/S0891-5849(02)00911-5. PMID 12126761.

Probably an EtOH solution though.. Still, the solubility of resveratrol in water is 3 mg/100 mL, according to Sigma's data sheet. A misprint? Other sources have the same data. That's about a quarter cup, a big but manageable mouthful. I am surprised you found no detectable amount in blood plasma.

Yes, my recollection is that that was an ethanolic solution. I poked around on the Sigma Aldrich site, and managed to find only this:

It is practically insoluble in water.

30mg/L sounds too high. These guys say 5e-5M = 11mg/L, which is pretty close.

It was ethanol as a solubolizer. I've been going on water as 30mg/L but we're putting together a paper and will be testing it again.

Sorry about being rude. Day started at 4:55am, I work a job i'm grossly overqualified for to pay to work at my second job, and I get overly defensive (which I need to watch) even when I'm well rested.

I learned about solubility when working on lectin arrays, which are a blend between microarrays and elisa assays. We weren't able to fix them for clinical applications, but we were working on a early blood test for breast and ovarian cancer identifying the sugar side chains attached to surface proteins. I wasn't able to fix it where it didn't take two days to work get test results (without getting into detail, they're still working on it) This is where I learned about solubility in grad school.

Attached Files

•  25. Oral Mucosal Drug Delivery Clinical Pharmacokinetics and Therapeutic Applications.pdf   383.11KB   4 downloads
•  33. The Nature of the Cosolvent Effects of Sugars on the Aqueous Solubilities of Hydrocarbons.pdf   742.86KB   3 downloads
•  35. Semipermeable lipid bilayers exhibit diastereoselectivity favoring ribose.pdf   292.21KB   2 downloads

[hav]

Max, we had zero from that. Nil. Unpublished on the poster.

We have the approval to test it in the university lab if you want to come down and repeat it at Highpoint. You'll just have to pay for it.

Do you think we took two years pushing this through without discounting "just put it in water?" How many years have you been a biochemist? You should call these guys and tell them you solved the problem by "just using water".

http://www.ncbi.nlm....cal resveratrol

I'm kind of interested in beta cyclodextrin myself. It takes the approach of increasing water solubility of things it carries. Its easy enough to get but I'm not sure if the FDA has approved anyone using it as a supplement or food additive yet.

I think I'm more interested in what I consider the opposite approach of forming lipid soluble analogs as in the French patent. I think that approach may be better if the compounds can cross the BBB and get into more places than water soluble compounds. But the problem, as I see it, is that the lipid soluble analogs are different compounds and may not have the same effects as lets say ordinary resveratrol... no one has studied their effects yet. And the toxicity comments mentioned in the French study sounds a little light.

Anyway, I found the French patent here. Here's what google translate makes of what they used:

A formulation according to the invention preferably comprise between 50 and 93% polyethylene glycol, or a functional equivalent thereof such as a polysorbate, between 3 and 46% glycol ether, or a functional equivalent thereof such as the glycerol or polyglyceryl-3 dioleate (polyglycerol fatty acid ester or an equivalent thereof), and a sufficient amount of water to 100%.

According to one embodiment of the invention, the formulation may further comprise at least one emulsifier. Advantageously according to the invention the emulsifier can be a polysorbate, still more preferably a polysorbate selected from polysorbate 20 (Tween 20 or polyoxyethylene (20) sorbitan monolaurate), Polysorbate 40 (Tween 40 or polyoxyethylene (20) monopalmitate sorbitan), Polysorbate 60 (Tween 60 or polyoxyethylene (20) sorbitan monostearate), or Polysorbate 80 (Tween 80 or polyoxyethylene (20) sorbitan monooleate). The formulation according to the invention is particularly adapted to be used to improve absorption, preferably the intestinal absorption, polyphenols, particularly hydroxystilbenes as for example those of formula (I),

Which makes an interesting contrast to the art employed in an Italian paper published back in 2009 involving piceanatol.

Howard

[Jean-François Savouret]

Hi,

I originated the Resv paper you are talking about. It is the current state of our reflexion on Resv that started with the discovery by myself and RF Casper (Toronto) that Resv inhibitis the Ah (dioxin) receptor. As such, Resv is effective in protecting rats from dioxin or BaP-induced lung and testis procarcinogenesis, bone-protecting, analgesic and anti-inflammatory. it also inhibits transcription from the AhR-dependent HIV genome. Just Pubmed "Savouret, J.F." for details.

To answer some of your questions:

1) resv and the sirtuin/longevity story is a gross misconception. Please read my comment to R. Tennen's review in Cell (Feb 2012) about this. Resv only expands life (30%) of inveertebrates and does nothing on mice unless they're previously made diabetic with a high-fat diet.

2) What about Yvery Pharm resveratrol caplets? they've been on the market thru Internet for almost 4 years, at a a price I consider quite reasonable although I am a scientist and therefore not business oriented: 21€ for 60 caplets which a dose for the first month (2 20 mg caps a day) and then can be extended to 2 months (one 20 mg cap a day).

3) some of the posters in this thread suggested we cheated about the data by confusing free and total resv. This is simply not true. We did not focussed on free resv as free molecules a just a "view of the mind". Therapeutic agents are always bound to carriers or conjugates in some way. Once taken up by cells, they are subject to constant exchange between conjugated, bound and free pools, driven by the classic laws of pharmacology. So th point is to get the best amount available to cells in the first place. Resv conjugates are particularly prone to reabsorption and reactivation by deconjugation as shown by several papers in the litterature.
To make it short, the rodent inflammation data we added in the paper to the human bioavailability data are quite self-explanatory.

4) To date, the most interesting effect of Resv, besides protection against smokers cancer is its ability to suppress pain in join diseases and allow for a drastic diminution of NSAIDS doses. We are currently gathering clinical data on this topic.

5) the origin of the discovery is interesting and I'd be happy to tell more about it to persons interested in epistemology and history of science, but may be later.

Regards,

JF Savouret

Edited by Jean-François Savouret, 10 March 2013 - 12:23 PM.

[Wilmore Labs]

We have a science disagreement on our hands, but we have the science to eventually settle it. We do agree that Resveratrol doesn't extend life in the way it does in c. elgans or yeast in vertebrates:

http://www.ncbi.nlm....pubmed/20974732

We disagree on pharmacokinetics, which is the science. There are two camps forming, and that'll probably expand this year depending on funding.

Edited by Wilmore Labs, 10 March 2013 - 05:07 PM.

[Jean-François Savouret]

An enlightened and open discussion is the best way to accompany experimental data.
BTW, I do concur on the great interest of cyclodextrins in steroid and steroid-like molecule biodisponibility.

JFS

Edited by Jean-François Savouret, 10 March 2013 - 04:59 PM.

[Wilmore Labs]

I will say nothing was dishonest in the paper. It was disappointing to rush to get access to the paper, and find the parent molecule and metabolites were presented pooled in the abstract. You know the amount of work needed for a human trial, no matter how small, in the USA. Also, I'm very competitive which gets people into a discussion on Sunday morning on their work instead of relaxing.

[Jean-François Savouret]

Don't worry, I was aleady working on a thesis and a review.
Being retired means I can relax or work any day I wish, or feel inspired. Saturday was racecar day, and sunday turned out to be resveratrol day.
I know quite well the cost of a FDA trial or an "AMM" in France. We are a small company (three friends and two employees) and turn all our sales into supplies and re-investment. This is why we did the human test in Nam, as we have historical university ties with the Vietnamese through PhD students. I did not look for a dioxin antagonist just for fun.

I hope we get a mutually rewarding discussion. I am not bluntly against sirtuins, I just did not like the fluorochrome story and the disturbing pressure to force Resv into the field without the usual scientific care and double check, especially on secondary pathways (i.e. estrogens), as I am a nuclear receptor man.

Re- immortality, I have a dual approach to it: I already mentionned the pagan/christian controversy on life and I alo consider that the actual conception of a gebnetically-based human life-span of 120 years largely sufficient, provided your mental and physical ability does not fold at 85. I'm for quality more than quantity.

You mentionned the abstract. Does this mean you don't have the full text? I can't post links yet on this forum but I'll send you the pdf by email.

JFS

Edited by Jean-François Savouret, 10 March 2013 - 05:37 PM.

[maxwatt]

,
....
1) resv and the sirtuin/longevity story is a gross misconception. Please read my comment to R. Tennen's review in Cell (Feb 2012) about this. Resv only expands life (30%) of inveertebrates and does nothing on mice unless they're previously made diabetic with a high-fat diet.

Agreed re lifespan in rodents. However, resveratrol does activate Sirt1 by different assays than the fluorophore, which while this is not apparently life extending in mammals, PPAR-delta agonists require Sirt1 to induce mitochondrial biogenesis. I suspect the positive effects we have noted here for increased exercise tolerance are due to PPAR-Sirtuin interaction. Resveratrol also appears to agonize PPAR-alpha and PPAR-delta, though I do not know to what degree or in what concentration.

2) What about Yvery Pharm resveratrol caplets? they've been on the market thru Internet for almost 4 years, at a a price I consider quite reasonable although I am a scientist and therefore not business oriented: 21€ for 60 caplets which a dose for the first month (2 20 mg caps a day) and then can be extended to 2 months (one 20 mg cap a day).

The dose is considered low by the consensus this group reached, based I think on observed exercise tolerance and alleviation of osteoarthritic pain. Perhaps the benefits of the lower dose are different, or may be reversed by a dose of >250mg? Then too these caplets are more bio-available a form of resveratrol, and may be equivalent to the higher doses of powder that have been used here?

3) some of the posters in this thread suggested we cheated about the data by confusing free and total resv. This is simply not true. We did not focussed on free resv as free molecules a just a "view of the mind". Therapeutic agents are always bound to carriers or conjugates in some way. Once taken up by cells, they are subject to constant exchange between conjugated, bound and free pools, driven by the classic laws of pharmacology. So th point is to get the best amount available to cells in the first place. Resv conjugates are particularly prone to reabsorption and reactivation by deconjugation as shown by several papers in the litterature.
To make it short, the rodent inflammation data we added in the paper to the human bioavailability data are quite self-explanatory.

4) To date, the most interesting effect of Resv, besides protection against smokers cancer is its ability to suppress pain in join diseases and allow for a drastic diminution of NSAIDS doses. We are currently gathering clinical data on this topic.

Pain suppresion in joint disease I personally find a good reason to continue taking resveratrol. Protection agains smokers cancer, I cannot say. I do know that it does not apparently cure small cell lung cancer, but prevention? I would like to see data. One would think prevention would imply prevention of metastasis, but this does not seem to be the case.

5) the origin of the discovery is interesting and I'd be happy to tell more about it to persons interested in epistemology and history of science, but may be later.

Regards,

JF Savouret

And welcome to the forums. You will have the ability to post links in the course of time. If you send me the link, I can post it for you.

Edited by maxwatt, 10 March 2013 - 06:48 PM.

[Jean-François Savouret]

Maxwatt,

Thanks for the welcome. We'll have the opprtunity to discuss these points but I would right away draw your attention to the work of B. Stockinger's lab about AhR being a developmental regulator of immunity, whether under the influence of AhR unknown endogenous ligands or Resv. A very interesting line of work.

I personally attach a lot of interest on Resv in cartilage diseases as well as smokers cancers with a caveat: Resv interest seems preventive rather than curative. Once OA or PR or lung cancer is established, I don' think resv will be very useful.
Finally, if you have a hygienic life style (non smoker, mediterranean diet, exercise), Resv action may not be that obvious, nor necessary. Conversely, Resv appears to me as very valuable as a preventive drug in the pre-aging period or menopausal period in women (bone protection) or a protective agent for workers in the pesticides or hydrocarbon industry.

JFS

[ClarkSims]

I bet resveritol dissolves well in limonene. Limonene dissolves so many organic things. I tried adding 10 ml of limonene, to some c60 olive oil, and the limonene, dissolved the rubber and plastic in they syringe. http://en.wikipedia.org/wiki/Limonene

I bet piperine also dissolves well in limonene, and that would slow down the liver from metabolizing the resveritol. Maybe the answer to making bioavailable resveritol is to disolve it with piperine in limonene.

Unfortunately, I haven't been able to find the solubility of resveritol in limonene anywhere. Does anyone have any thoughts on how I could narrow this down?

[niner]

3) some of the posters in this thread suggested we cheated about the data by confusing free and total resv. This is simply not true. We did not focussed on free resv as free molecules a just a "view of the mind". Therapeutic agents are always bound to carriers or conjugates in some way. Once taken up by cells, they are subject to constant exchange between conjugated, bound and free pools, driven by the classic laws of pharmacology. So th point is to get the best amount available to cells in the first place. Resv conjugates are particularly prone to reabsorption and reactivation by deconjugation as shown by several papers in the litterature.

Welcome to Longecity, Jean-François. "Cheated" is really too strong of a word, and isn't what I meant. The normal way that resveratrol pharmacokinetics is described is to quantify the free compound, because that's the active substance. I'm not aware of any evidence that the conjugates (glucuronide and sulfate) are active. Many compounds, resveratrol included, are bound to proteins like albumin. This is a noncovalent interaction, and the compounds come off easily. Resveratrol is very heavily conjugated, which is the primary limitation on its bioavailability. Once a glucuronide conjugate is formed, it doesn't come apart easily. It would require a glucuronidase to perform the hydrolysis. Glucuronidases do exist in humans, but they aren't widely expressed, with cancer cells and some lysosomes being exceptions. I don't think that anyone has shown that resveratrol glucuronide is hydrolyzed to a sufficient extent to provide a useful pool of free resveratrol. There are some glucuronidases in the gut, and probably in enterobacteria as well, and enterohepatic recycling does occur, as you point out. However, enterohepatic recycling does not raise the blood level of resveratrol very much. While the phenomenon exists, it doesn't look like a very major player in resveratrol PK plots that I've seen. The resveratrol conjugates have a high renal clearance, as we'd expect, since conjugation is the body's way of getting rid of xenobiotics.

[Jean-François Savouret]

Hi Niner,

Thanks for the welcome.
I admit i used the wrong word with "cheating". I am usually quite proficient in english but I do make the odd mistake once in a while. No problemo.

As I said to another member of the forum, I am primarily interested in Resv mechanism, as hormone action has been my trade ever since I entered university.
We have solved the bioavailability problem of resv as you may have read in the Biochimie paper. I consider it a done thing. It could alaways be improved but would that be really a valuable expense of effort?

In terms of metabolism (not my expertise really), note that most of the conjugation is sulfated resv, not glucuronide. I think that the sulfated molecule is active per se, not to mention the relatively wide occurence of sulfatases involved in the biosynthesis of many structural cell proteins.
Many of the synthetic derivatives I have made and patented with my friend Marc Poirot are small substitutions akin in size, function and structure to sulfate (alkoxy, chloride, mostly electron donors ... ) and are as active or even more active than resv itself (de Medina et al., J Med Chem, 2005). It would not be a great deal of work to demonstrate it but I'm not really excited by that. I'd rather jump ahead to therapeutic activities since we have the demonstration of the biological effect at micromolar doses in many models in vitro and in vivo (check me in pubmed).

As I said previously, I'm not an opponent to the sirtuin story, i'm just concerned with the bizarre behaviour of its most adamant advocates. Why so many mistakes and overstretching of conclusions if it is so good?

Conversely, I am opposed to the concept of longevity through cellular boost. Comes from my vintage race engine expertise. When i'm relaxing from science, I tweak pre-war and classic motors. Engines are an excellent metaphor for living beings. Any concept that will throw a rod will kill a cell. The basic idea for longevity is not turning mitochondria into top fuel dragsters, but into these new "eco-boost" engines with high power ratio and very low consumption. In a nutshell:
1) Work yourself to the energy baseline with a clean life and restricted food intake.
2) Once there, use moderate amounts of dietary supplement to stabilize this baseline and lower your energy use without lowering your activity.
3) Discard any dietary suppelement that does not produce a clear reproducible effect.
4) Do not expect a miracle, bet on prevention.

JFS

Edited by Jean-François Savouret, 11 March 2013 - 08:47 AM.

[ClarkSims]

Hi Niner,

We have solved the bioavailability problem of resv as you may have read in the Biochimie paper. I consider it a done thing.

Could you post a link to the paper, or fully cite the reference, so I could look it up?
Thanks,
Clark

[hav]

Could you post a link to the paper, or fully cite the reference, so I could look it up?
Thanks,
Clark

Hi, Clark. The link to the abstract and pasted text is in the OP's post #1 above. The galenic formulation appears to address resveratrol absorption which is this paper indicates is normally around 25%.

We have solved the bioavailability problem of resv as you may have read in the Biochimie paper. I consider it a done thing.

I'm not clear on whether you believe the galenic formulation might address low bioavailability due to rapid elimination.

Howard

[hav]

Hi Niner,
...
In terms of metabolism (not my expertise really), note that most of the conjugation is sulfated resv, not glucuronide. I think that the sulfated molecule is active per se, not to mention the relatively wide occurence of sulfatases involved in the biosynthesis of many structural cell proteins.
Many of the synthetic derivatives I have made and patented with my friend Marc Poirot are small substitutions akin in size, function and structure to sulfate (alkoxy, chloride, mostly electron donors ... ) and are as active or even more active than resv itself (de Medina et al., J Med Chem, 2005). It would not be a great deal of work to demonstrate it but I'm not really excited by that. I'd rather jump ahead to therapeutic activities since we have the demonstration of the biological effect at micromolar doses in many models in vitro and in vivo (check me in pubmed).
...

I got the impression from the abstract of the 2005 Wenzel & Somoza paper that they believe nearly all of the reveratrol glucuronide and sulfate metabolites get excreted pretty quickly which I think would be logically necessary for them to conclude almost zero resveratrol bioavailability:

Summarizing the data, resveratrol is absorbed and metabolized. Around 75% of this polyphenol are excreted via feces and urine. The oral bioavailability of resveratrol is almost zero due to rapid and extensive metabolism and the consequent formation of various metabolites as resveratrol glucuronides and resveratrol sulfates.

But I haven't read the full paper, just the abstract. I was wondering what your belief on sulfated resveratrol being bioactive is based on. I've only found your reference to synthetic stilbenes.

I do note however that this more recent 2009 study describes Piceatannol as a human metabolite of resveratrol. A resveratrol metabolite not accounted for in the above studies. And claimed by this paper to be the main resveratrol metabolite suggesting that it might also be the main active metabolite. Any thoughts on that?

Howard

[ClarkSims]

People use ethanolic solutions buccally. One slight hitch is that as soon as you start adding water to the ethanol, the resveratrol solubility drops precipitously. Still, with something like 80 proof vodka, if you can handle swishing that in your mouth for a couple minutes, you can get a pretty high blood level, at least transiently. Some people get psychotropic effects at those levels. It sounds like a stimulant effect, from what people have reported here.

I have been looking everywhere for the solubility of resveratol in limonene, and I can't find it. I did find that limonene and ethanol are soluble in all portions, www.sciencelab.com/msds.php?msdsId=9924496

This implies to me, that it should have about the same solubility in limonene.

Where do people by the resveratol to put in their ethanol solutions? Almost all of the resveratol I have found is in pill form, mixed with many other ingredients. I did find some from Sigma Aldrich. At $1 / mg, it seems overpriced.

http://www.sigmaaldr...ng=en&region=US

I am looking for another source. I can measure the solubility in limonene myself, if I can just find some pure resveratol somewhere.

[ClarkSims]

I consider it a done thing.

I skimmed the paper, and all the associated post, and it is still unclear to me how I can take resveratol and have it absorbed readily. The formulations mentioned in the paper aren't on the market yet are they?

I could crush pills and put the crushed pills in vodka. I could perhaps do the same thing with limonene.

I dislike the idea of drinking vodka. I am OK with the limonene, but am unsure that it would actually dissolve in the limonene. I am only guessing it would dissolve.