1084 replies to this topic

[missminni]

Does anyone else here using DMSO regularly have the odor problem or the rash?

No odor problems though for the first week my face would burn slightly but that effect has gone away. I now add about 1/4 gram to my belly button smear some of the paste on my right knee and face. I take about another 2 grams to milk.

why on your face? any visible effects from that?

I'm applying some to my right cheek to see I can tell any difference in skin tone over time. It's a long shot. No change yet.

Hi Missminni,

Just Curious, I read this thread and wonder out loud:
Has anyone tried Resveratrol Mustard Plasters?
Maybe a way to transport RSV directly into the skin.
Looks like no one has tried MP yet.
Anyone out there know if this is feasible?


Happy New Year!

Bixbyte

I'm not sure what a mustard plaster is but I have used those camphor based chinese adhesive pads and had resveratrol/dmso on the skin that they covered. I had some sort of contact dermatitis on a spot on my back (I think brought on by a reaction to latex in a sport bra)
and I was experimenting. However I didn't do it consistently and I didn't notice any change. BTW, those adhesives (called External Analgesic) are great for sprains & bruises. They go by many different names i.e. Bao Zhen Gao and are very inexpensive. I was thinking perhaps they could be converted into a resveratrol patch.
As they come, they are made with Methyl Salicylate 13% and Menthol 7% and Camphor 7% and Chinese Wild Ginger and Chinese Sweet Gum Resin. I've used them for years. Maybe somebody who imports Chinese resveratrol could get them made with res and dmso instead. Maxwatt, is that a possibility?

ETA~Anecdotal stuff:
My friend started giving Resveratrol (98% pure powder) to her infirmed father. He has so much wrong with him and is on so many medications, I cannot even begin to relate them. He is in his 70's very overweight, and can barely walk a few feet. She started giving it to him about a week ago dissolved in milk, 1g 3x. He didn't mention feeling better or anything, but she kept it up. Yesterday, she rubbed his swollen ankles with res in dmso and almost immediately he felt such relief as he was able to get up and walk across the house, not something he normally can do, and called up to her to come down and do it some more. She had only rubbed it on his ankles and she said you could actually see an indent around his ankles where the swelling had gone down, whereas the feet and calves, where it had not been rubbed were still swollen.
Additionally, she rubbed it on a wrist injury her 70 yr old mother had for a period of time that had remained chronic, swollen and painful. Again, the res reduced the swelling to normal and relieved the discomfort and it's remained so, so far.

Edited by missminni, 26 December 2007 - 07:27 PM.

[niner]

In this post: http://www.imminst.o...&...st&p=215446 I posted an abstract (PMID: 17054386) about resveratrol binding to albumin in human serum. Albumin is a soluble protein that is a major component of serum. (concentration ca. 0.6 mM) It is well known for binding drugs. If they are bound too tightly, delivery can be a problem. The strength of resveratrol's binding to albumin has been measured, so we can calculate the amount of the drug that albumin will soak up. It soaks up quite a lot. To obtain a concentration of 0.5 uM in serum, you will need sufficient resveratrol that 98.5% of it is albumin-bound, effectively 68 uM of resveratrol. To obtain a higher free resveratrol concentration of 5 uM, you will need enough so that about 97% is albumin-bound, or an effective 337 uM.

If you could manage to completely inhibit your gut and liver sulfating and glucuronidating enzymes, how much resveratrol would it take to hit 168uM in serum? This exercise will also assume that ALL of the resveratrol gets into your serum, i.e. you figured out a way to solubilize it in something injectable, and injected it.

5 litres blood * (337e-6m/litre) * (228gm/m) = 0.386gm

So, 386mg resveratrol should be enough to get you a 5 uM blood level, if you can get your conjugating enzymes 100% inhibited, and you shoot it up. Unfortunately, we can't inhibit our conjugating enzymes that well, and injecting this much of a poorly soluble drug is a big problem.

This does not bode well for transdermal systemic dosing of resveratrol. Instead of the very small quantities of resveratrol that many of us thought we needed in a transdermal scheme, it appears that within the blood itself is a resveratrol sponge. Of course, the flux from skin surface to blood that can be achieved transdermally, even with a permeation enhancer such as DMSO, is too small to provide a "first pass effect" (have a pharmacological impact prior to hitting the liver and getting metabolized) anyway, but albumin binding is yet another nail in the coffin for transdermal systemic delivery.

Lest we throw the baby out with the bath water, I do think there may be a role for transdermal delivery of resveratrol, and that is for local application to a joint or some other thing that is relatively near the surface. Meanwhile, if you want to see a systemic 5 uM level, according to Boocock et al., you should be taking 10 grams orally. With the right formulation (micronization/surfactant; micelles; milk?) you might get by with a gram or three. It seems to me that Quercetin and Piperine, as sulfation and glucuronidation inhibitors, respectively, would have to help.

Calculations: Let me know if I missed something...

R + A -> RA
Ka = [RA]/[R][A] = 2.56e5 M(-1)

At = total albumin conc. = [A] + [RA] = 0.6e-3 M

[RA] = Ka At / (1/[R] + Ka)


Some other thoughts on albumin binding: It should be possible to saturate the albumin in blood; in theory this would only require about 700mg resveratrol. Albumin binding is not necessarily a bad thing; it solubilizes resveratrol in blood and could act as a ferry, picking up resveratrol in areas of high concentration and dropping it off in the periphery. It may also protect resveratrol from metabolic enzymes. Resveratrol is not an extremely tight binder to albumin, so it exists in an equilibrium between bound and unbound states. There are probably other biomacromolecules that bind resveratrol, so all the amounts of resveratrol given here should be thought of as lower bounds, with the exception of the 10g oral dose, which is extrapolated from measured Cmax of a 5g oral dose.

[sUper GeNius]

Niner,

Your are saying that this albumin binding may or may not be a bad thing. Question. How is a mouse's blood different than a human's in respect to albumin binding? You probably see what I am thinking.

[maxwatt]

In this post: http://www.imminst.o...&...st&p=215446 I posted an abstract (PMID: 17054386) about resveratrol binding to albumin in human serum. Albumin is a soluble protein that is a major component of serum. (concentration ca. 0.6 mM) It is well known for binding drugs. If they are bound too tightly, delivery can be a problem. The strength of resveratrol's binding to albumin has been measured, so we can calculate the amount of the drug that albumin will soak up. It soaks up quite a lot. To obtain a concentration of 0.5 uM in serum, you will need sufficient resveratrol that 98.5% of it is albumin-bound, effectively 68 uM of resveratrol. To obtain a higher free resveratrol concentration of 5 uM, you will need enough so that about 97% is albumin-bound, or an effective 337 uM.

If you could manage to completely inhibit your gut and liver sulfating and glucuronidating enzymes, how much resveratrol would it take to hit 168uM in serum? This exercise will also assume that ALL of the resveratrol gets into your serum, i.e. you figured out a way to solubilize it in something injectable, and injected it.

5 litres blood * (337e-6m/litre) * (228gm/m) = 0.386gm

So, 386mg resveratrol should be enough to get you a 5 uM blood level, if you can get your conjugating enzymes 100% inhibited, and you shoot it up. Unfortunately, we can't inhibit our conjugating enzymes that well, and injecting this much of a poorly soluble drug is a big problem.

This does not bode well for transdermal systemic dosing of resveratrol. Instead of the very small quantities of resveratrol that many of us thought we needed in a transdermal scheme, it appears that within the blood itself is a resveratrol sponge. Of course, the flux from skin surface to blood that can be achieved transdermally, even with a permeation enhancer such as DMSO, is too small to provide a "first pass effect" (have a pharmacological impact prior to hitting the liver and getting metabolized) anyway, but albumin binding is yet another nail in the coffin for transdermal systemic delivery.

Lest we throw the baby out with the bath water, I do think there may be a role for transdermal delivery of resveratrol, and that is for local application to a joint or some other thing that is relatively near the surface. Meanwhile, if you want to see a systemic 5 uM level, according to Boocock et al., you should be taking 10 grams orally. With the right formulation (micronization/surfactant; micelles; milk?) you might get by with a gram or three. It seems to me that Quercetin and Piperine, as sulfation and glucuronidation inhibitors, respectively, would have to help.

Calculations: Let me know if I missed something...

R + A -> RA
Ka = [RA]/[R][A] = 2.56e5 M(-1)

At = total albumin conc. = [A] + [RA] = 0.6e-3 M

[RA] = Ka At / (1/[R] + Ka)


Some other thoughts on albumin binding: It should be possible to saturate the albumin in blood; in theory this would only require about 700mg resveratrol. Albumin binding is not necessarily a bad thing; it solubilizes resveratrol in blood and could act as a ferry, picking up resveratrol in areas of high concentration and dropping it off in the periphery. It may also protect resveratrol from metabolic enzymes. Resveratrol is not an extremely tight binder to albumin, so it exists in an equilibrium between bound and unbound states. There are probably other biomacromolecules that bind resveratrol, so all the amounts of resveratrol given here should be thought of as lower bounds, with the exception of the 10g oral dose, which is extrapolated from measured Cmax of a 5g oral dose.

Thank you fr this enlightening pst. Some thoughts on sulfation and glucoronadition: Simply increasing the resveratrol dose would swamp the sulfonation and glucoronation mechanisms, so unless one were seeking to achieve effects with low doses, it would be unnecessary. Further, quercetin metabolites are known inhibit Sirt!. My experience using quercetin indicates this is not a weak effect; I find the arthritic inflammation relief obtained by inhibition of nf-KappaB via action of SirT1 to vanish when I take quercetin with resveratrol. Furthermore, luteolin, for which I had high hopes as a sulfonation inhibitor and possible sirtuin activator, also seems to block this form of pain relief, indication it may well be blocking Sirt1activation. Luteolin's structure is very similar to quercetin's, so it is likely it's metabolites also inhibit Sirt1.

The question in my mnd is how much resveratrol is needed to swamp the body's hepatic sulfonation mechanism. So far I don't have an answer, but this paper may have a hint:

Xenobiotica. 2005 Dec;35(12):1101-19. Links
Sulfation of resveratrol in human liver: evidence of a major role for the sulfotransferases SULT1A1 and SULT1E1.Miksits M, Maier-Salamon A, Aust S, Thalhammer T, Reznicek G, Kunert O, Haslinger E, Szekeres T, Jaeger W.
Department of Clinical Pharmacy and Diagnostics, University of Vienna, Austria.

Sulfation of resveratrol, a polyphenolic compound present in grapes and wine with anticancer and cardioprotective activities, was studied in human liver cytosol. In the presence of 3'-phosphoadenosine-5'-phosphosulfate, three metabolites (M1-3) whose structures were identified by mass spectrometry and NMR as trans-resveratrol-3-O-sulfate, trans-resveratrol-4'-O-sulfate, and trans-resveratrol-3-O-4'-O-disulfate, respectively. The kinetics of M1 formation in human liver cytosol exhibited an pattern of substrate inhibition with a K(i) of 21.3 +/- 8.73 microM and a V(max)/K(m) of 1.63 +/- 0.41 microLmin(-1)mg(-1) protein. Formation of M2 and M3 showed sigmoidal kinetics with about 56-fold higher V(max)/K(m) values for M3 than for M2 (2.23 +/- 0.14 and 0.04 +/- 0.01 microLmin(-1)mg(-1)). Incubation in the presence of human recombinant sulfotransferases (SULTs) demonstrated that M1 is almost exclusively catalysed by SULT1A1 and only to a minor extent by SULT 1A2, 1A3 and 1E1, whereas M2 is selectively formed by SULT1A2. M3 is mainly catalysed by SULT1A2 and 1A3. In conclusion, the results elucidate the enzymatic pathways of resveratrol in human liver, which must be considered in humans following oral uptake of dietary resveratrol.

PMID: 164180

[edward]

Interesting straightforward article on sulfonation and glucuronidation the end of the article mentions some things that inhibit or enhance these processes. In reading this I begin to wonder how much inhibition of these detoxification pathways is healthy since most of us are taking so many different compounds daily.

note: scroll down 1/2 to 3/4ths of the way down the article to see info with regards to sulfonation and glucuronidation, the first part of the article is fairly elementary

http://tuberose.com/...xification.html

Edited by edward, 28 December 2007 - 05:11 AM.

[niner]

Niner,

Your are saying that this albumin binding may or may not be a bad thing. Question. How is a mouse's blood different than a human's in respect to albumin binding? You probably see what I am thinking.

I don't know what the normal level for albumin is in the mouse. Offhand, I would guess that it's not wildly different than in humans. The human and mouse albumins are different to some extent, though I don't know how those differences would affect, say, resveratrol binding. It's pretty clear that mice differ from humans a lot in their resveratrol metabolism. Humans are apparently better at sulfation and glucuronidation than mice are, for one thing. For a given mg/kg dose, mice and rats obtain a much higher plasma level of free resveratrol than we do. I don't know if albumin is a factor in this difference, but it might be.

[sUper GeNius]

Niner,

Your are saying that this albumin binding may or may not be a bad thing. Question. How is a mouse's blood different than a human's in respect to albumin binding? You probably see what I am thinking.

I don't know what the normal level for albumin is in the mouse. Offhand, I would guess that it's not wildly different than in humans. The human and mouse albumins are different to some extent, though I don't know how those differences would affect, say, resveratrol binding. It's pretty clear that mice differ from humans a lot in their resveratrol metabolism. Humans are apparently better at sulfation and glucuronidation than mice are, for one thing. For a given mg/kg dose, mice and rats obtain a much higher plasma level of free resveratrol than we do. I don't know if albumin is a factor in this difference, but it might be.

Well, I was thinking that, since it's been shown that t-res is bioavailable in mice, then it stands to reason that albumin binding is not affecting this in a negative way. If we knew that the albumin binding was similar in humans, then we might infer that such binding would not affect the bioavailabilty of t-res in humans. Take care of the sulfation and glucuronidation, then perhaps we would be home free.

[geo12the]

Some other thoughts on albumin binding: It should be possible to saturate the albumin in blood; in theory this would only require about 700mg resveratrol. Albumin binding is not necessarily a bad thing; it solubilizes resveratrol in blood and could act as a ferry, picking up resveratrol in areas of high concentration and dropping it off in the periphery. It may also protect resveratrol from metabolic enzymes. Resveratrol is not an extremely tight binder to albumin, so it exists in an equilibrium between bound and unbound states. There are probably other biomacromolecules that bind resveratrol, so all the amounts of resveratrol given here should be thought of as lower bounds, with the exception of the 10g oral dose, which is extrapolated from measured Cmax of a 5g oral dose.

Not sure if it’s relevant, but I thought I would mention that last year I had bloodwork done for my physical and my albumin/globulin ratio was very slightly off. I had it repeated and the result was the same. My doctor said that it was nothing to be concerned about because the numbers were not off by very much. I wonder if this could be an effect of taking resveratrol? Maybe albumin bound to resveratrol is not measured in the blood test? My significant other is taking the same dosage (1gram/day) and has a normal albumin/globulin ratio.

[missminni]

I've moved the comment to the Resveratrol Effects thread.

Edited by missminni, 07 January 2008 - 04:14 PM.

[maxwatt]

My father (92 years) ran out of the 99% resveratrol powder
for a week and used the R300 until the powder arrived.
He said the R300 didn't relieve his back pain and he suffered with it until
he received the powder the day before yesterday. He said when he took the powder
(about 500 mg orally in sour cream - he hates milk)
he experienced complete relief from his arthritic back pain -
within a very short time.

ETA~I just thought of another subtle improvement since taking restreverol. Before, I would
get "sitting too long backaches" where I could barely stand and straighten up.
I could usually stretch it out but it would ache for a while, and if
I was under any kind of stress at the time, I could be debilitated by it.
The past couple of months....no more sitting too long backaches.

I'm not sure if this post was off topic...
Is there a more appropriate thread for it?

We had a thread on resveratrol effects HERE but it has been inactive for months. Perhaps it is time to revive it. (FWIW., the varicose vein on my leg has disappeared. )

[rhc124]

In this post: http://www.imminst.o...&...st&p=215446 I posted an abstract (PMID: 17054386) about resveratrol binding to albumin in human serum. Albumin is a soluble protein that is a major component of serum. (concentration ca. 0.6 mM) It is well known for binding drugs. If they are bound too tightly, delivery can be a problem. The strength of resveratrol's binding to albumin has been measured, so we can calculate the amount of the drug that albumin will soak up. It soaks up quite a lot. To obtain a concentration of 0.5 uM in serum, you will need sufficient resveratrol that 98.5% of it is albumin-bound, effectively 68 uM of resveratrol. To obtain a higher free resveratrol concentration of 5 uM, you will need enough so that about 97% is albumin-bound, or an effective 337 uM.

If you could manage to completely inhibit your gut and liver sulfating and glucuronidating enzymes, how much resveratrol would it take to hit 168uM in serum? This exercise will also assume that ALL of the resveratrol gets into your serum, i.e. you figured out a way to solubilize it in something injectable, and injected it.

5 litres blood * (337e-6m/litre) * (228gm/m) = 0.386gm

So, 386mg resveratrol should be enough to get you a 5 uM blood level, if you can get your conjugating enzymes 100% inhibited, and you shoot it up. Unfortunately, we can't inhibit our conjugating enzymes that well, and injecting this much of a poorly soluble drug is a big problem.

This does not bode well for transdermal systemic dosing of resveratrol. Instead of the very small quantities of resveratrol that many of us thought we needed in a transdermal scheme, it appears that within the blood itself is a resveratrol sponge. Of course, the flux from skin surface to blood that can be achieved transdermally, even with a permeation enhancer such as DMSO, is too small to provide a "first pass effect" (have a pharmacological impact prior to hitting the liver and getting metabolized) anyway, but albumin binding is yet another nail in the coffin for transdermal systemic delivery.

Lest we throw the baby out with the bath water, I do think there may be a role for transdermal delivery of resveratrol, and that is for local application to a joint or some other thing that is relatively near the surface. Meanwhile, if you want to see a systemic 5 uM level, according to Boocock et al., you should be taking 10 grams orally. With the right formulation (micronization/surfactant; micelles; milk?) you might get by with a gram or three. It seems to me that Quercetin and Piperine, as sulfation and glucuronidation inhibitors, respectively, would have to help.

Calculations: Let me know if I missed something...

R + A -> RA
Ka = [RA]/[R][A] = 2.56e5 M(-1)

At = total albumin conc. = [A] + [RA] = 0.6e-3 M

[RA] = Ka At / (1/[R] + Ka)


Some other thoughts on albumin binding: It should be possible to saturate the albumin in blood; in theory this would only require about 700mg resveratrol. Albumin binding is not necessarily a bad thing; it solubilizes resveratrol in blood and could act as a ferry, picking up resveratrol in areas of high concentration and dropping it off in the periphery. It may also protect resveratrol from metabolic enzymes. Resveratrol is not an extremely tight binder to albumin, so it exists in an equilibrium between bound and unbound states. There are probably other biomacromolecules that bind resveratrol, so all the amounts of resveratrol given here should be thought of as lower bounds, with the exception of the 10g oral dose, which is extrapolated from measured Cmax of a 5g oral dose.

Thank you fr this enlightening pst. Some thoughts on sulfation and glucoronadition: Simply increasing the resveratrol dose would swamp the sulfonation and glucoronation mechanisms, so unless one were seeking to achieve effects with low doses, it would be unnecessary. Further, quercetin metabolites are known inhibit Sirt!. My experience using quercetin indicates this is not a weak effect; I find the arthritic inflammation relief obtained by inhibition of nf-KappaB via action of SirT1 to vanish when I take quercetin with resveratrol. Furthermore, luteolin, for which I had high hopes as a sulfonation inhibitor and possible sirtuin activator, also seems to block this form of pain relief, indication it may well be blocking Sirt1activation. Luteolin's structure is very similar to quercetin's, so it is likely it's metabolites also inhibit Sirt1.

The question in my mnd is how much resveratrol is needed to swamp the body's hepatic sulfonation mechanism. So far I don't have an answer, but this paper may have a hint:

Xenobiotica. 2005 Dec;35(12):1101-19. Links
Sulfation of resveratrol in human liver: evidence of a major role for the sulfotransferases SULT1A1 and SULT1E1.Miksits M, Maier-Salamon A, Aust S, Thalhammer T, Reznicek G, Kunert O, Haslinger E, Szekeres T, Jaeger W.
Department of Clinical Pharmacy and Diagnostics, University of Vienna, Austria.

Sulfation of resveratrol, a polyphenolic compound present in grapes and wine with anticancer and cardioprotective activities, was studied in human liver cytosol. In the presence of 3'-phosphoadenosine-5'-phosphosulfate, three metabolites (M1-3) whose structures were identified by mass spectrometry and NMR as trans-resveratrol-3-O-sulfate, trans-resveratrol-4'-O-sulfate, and trans-resveratrol-3-O-4'-O-disulfate, respectively. The kinetics of M1 formation in human liver cytosol exhibited an pattern of substrate inhibition with a K(i) of 21.3 +/- 8.73 microM and a V(max)/K(m) of 1.63 +/- 0.41 microLmin(-1)mg(-1) protein. Formation of M2 and M3 showed sigmoidal kinetics with about 56-fold higher V(max)/K(m) values for M3 than for M2 (2.23 +/- 0.14 and 0.04 +/- 0.01 microLmin(-1)mg(-1)). Incubation in the presence of human recombinant sulfotransferases (SULTs) demonstrated that M1 is almost exclusively catalysed by SULT1A1 and only to a minor extent by SULT 1A2, 1A3 and 1E1, whereas M2 is selectively formed by SULT1A2. M3 is mainly catalysed by SULT1A2 and 1A3. In conclusion, the results elucidate the enzymatic pathways of resveratrol in human liver, which must be considered in humans following oral uptake of dietary resveratrol.

PMID: 164180

Question for those more knowlegeable than I. Does this mean that we should not take Resv with Milk Thistle?

[maxwatt]

In this post: http://www.imminst.o...&...st&p=215446 I posted an abstract (PMID: 17054386) about resveratrol binding to albumin in human serum. Albumin is a soluble protein that is a major component of serum. (concentration ca. 0.6 mM) It is well known for binding drugs. If they are bound too tightly, delivery can be a problem. The strength of resveratrol's binding to albumin has been measured, so we can calculate the amount of the drug that albumin will soak up. It soaks up quite a lot. To obtain a concentration of 0.5 uM in serum, you will need sufficient resveratrol that 98.5% of it is albumin-bound, effectively 68 uM of resveratrol. To obtain a higher free resveratrol concentration of 5 uM, you will need enough so that about 97% is albumin-bound, or an effective 337 uM.

If you could manage to completely inhibit your gut and liver sulfating and glucuronidating enzymes, how much resveratrol would it take to hit 168uM in serum? This exercise will also assume that ALL of the resveratrol gets into your serum, i.e. you figured out a way to solubilize it in something injectable, and injected it.

5 litres blood * (337e-6m/litre) * (228gm/m) = 0.386gm

So, 386mg resveratrol should be enough to get you a 5 uM blood level, if you can get your conjugating enzymes 100% inhibited, and you shoot it up. Unfortunately, we can't inhibit our conjugating enzymes that well, and injecting this much of a poorly soluble drug is a big problem.

This does not bode well for transdermal systemic dosing of resveratrol. Instead of the very small quantities of resveratrol that many of us thought we needed in a transdermal scheme, it appears that within the blood itself is a resveratrol sponge. Of course, the flux from skin surface to blood that can be achieved transdermally, even with a permeation enhancer such as DMSO, is too small to provide a "first pass effect" (have a pharmacological impact prior to hitting the liver and getting metabolized) anyway, but albumin binding is yet another nail in the coffin for transdermal systemic delivery.

Lest we throw the baby out with the bath water, I do think there may be a role for transdermal delivery of resveratrol, and that is for local application to a joint or some other thing that is relatively near the surface. Meanwhile, if you want to see a systemic 5 uM level, according to Boocock et al., you should be taking 10 grams orally. With the right formulation (micronization/surfactant; micelles; milk?) you might get by with a gram or three. It seems to me that Quercetin and Piperine, as sulfation and glucuronidation inhibitors, respectively, would have to help.

Calculations: Let me know if I missed something...

R + A -> RA
Ka = [RA]/[R][A] = 2.56e5 M(-1)

At = total albumin conc. = [A] + [RA] = 0.6e-3 M

[RA] = Ka At / (1/[R] + Ka)


Some other thoughts on albumin binding: It should be possible to saturate the albumin in blood; in theory this would only require about 700mg resveratrol. Albumin binding is not necessarily a bad thing; it solubilizes resveratrol in blood and could act as a ferry, picking up resveratrol in areas of high concentration and dropping it off in the periphery. It may also protect resveratrol from metabolic enzymes. Resveratrol is not an extremely tight binder to albumin, so it exists in an equilibrium between bound and unbound states. There are probably other biomacromolecules that bind resveratrol, so all the amounts of resveratrol given here should be thought of as lower bounds, with the exception of the 10g oral dose, which is extrapolated from measured Cmax of a 5g oral dose.

Thank you fr this enlightening pst. Some thoughts on sulfation and glucoronadition: Simply increasing the resveratrol dose would swamp the sulfonation and glucoronation mechanisms, so unless one were seeking to achieve effects with low doses, it would be unnecessary. Further, quercetin metabolites are known inhibit Sirt!. My experience using quercetin indicates this is not a weak effect; I find the arthritic inflammation relief obtained by inhibition of nf-KappaB via action of SirT1 to vanish when I take quercetin with resveratrol. Furthermore, luteolin, for which I had high hopes as a sulfonation inhibitor and possible sirtuin activator, also seems to block this form of pain relief, indication it may well be blocking Sirt1activation. Luteolin's structure is very similar to quercetin's, so it is likely it's metabolites also inhibit Sirt1.

The question in my mnd is how much resveratrol is needed to swamp the body's hepatic sulfonation mechanism. So far I don't have an answer, but this paper may have a hint:

Xenobiotica. 2005 Dec;35(12):1101-19. Links
Sulfation of resveratrol in human liver: evidence of a major role for the sulfotransferases SULT1A1 and SULT1E1.Miksits M, Maier-Salamon A, Aust S, Thalhammer T, Reznicek G, Kunert O, Haslinger E, Szekeres T, Jaeger W.
Department of Clinical Pharmacy and Diagnostics, University of Vienna, Austria.

Sulfation of resveratrol, a polyphenolic compound present in grapes and wine with anticancer and cardioprotective activities, was studied in human liver cytosol. In the presence of 3'-phosphoadenosine-5'-phosphosulfate, three metabolites (M1-3) whose structures were identified by mass spectrometry and NMR as trans-resveratrol-3-O-sulfate, trans-resveratrol-4'-O-sulfate, and trans-resveratrol-3-O-4'-O-disulfate, respectively. The kinetics of M1 formation in human liver cytosol exhibited an pattern of substrate inhibition with a K(i) of 21.3 +/- 8.73 microM and a V(max)/K(m) of 1.63 +/- 0.41 microLmin(-1)mg(-1) protein. Formation of M2 and M3 showed sigmoidal kinetics with about 56-fold higher V(max)/K(m) values for M3 than for M2 (2.23 +/- 0.14 and 0.04 +/- 0.01 microLmin(-1)mg(-1)). Incubation in the presence of human recombinant sulfotransferases (SULTs) demonstrated that M1 is almost exclusively catalysed by SULT1A1 and only to a minor extent by SULT 1A2, 1A3 and 1E1, whereas M2 is selectively formed by SULT1A2. M3 is mainly catalysed by SULT1A2 and 1A3. In conclusion, the results elucidate the enzymatic pathways of resveratrol in human liver, which must be considered in humans following oral uptake of dietary resveratrol.

PMID: 164180

Question for those more knowlegeable than I. Does this mean that we should not take Resv with Milk Thistle?

No. Silymarin activates Sirt1 in vivo, as evidenced by increased P53 phosphorylation, unlike quercetin and apparently luteolin, metabolites of which block Sirt1.

[edward]

In my book Silymarin is a definite winner. Increased glutathione, increased SOD, liver/kidney protection, Sirtuin activation... If we could only get more of it to be absorbed without resorting to creating micelles, silymarin PEG milk, or buying expensive phospholipid bound formulas etc etc... Until then I just take lots... Its cheap

edit: yeah yeah I should fix spelling and grammer before I finish my post.

Edited by edward, 07 January 2008 - 08:22 PM.

[rhc124]

Sorry, I did not make my question very clear. Since Silymarin has been shown to increase the level of glutathione of the liver by up to 35%, is it ok to take it at the same time that one takes Resv. I am taking 10mg of Bioperine 30 minutes before I take Resv in the morning. Would it be better then to take my silymarin in the afternoon or night?

[krillin]

Sorry, I did not make my question very clear. Since Silymarin has been shown to increase the level of glutathione of the liver by up to 35%, is it ok to take it at the same time that one takes Resv. I am taking 10mg of Bioperine 30 minutes before I take Resv in the morning. Would it be better then to take my silymarin in the afternoon or night?

My understanding is that resveratrol is primarily conjugated with sulfate and glucuronide. Have you seen a paper showing glutathione conjugation too?

[rhc124]

Sorry, I did not make my question very clear. Since Silymarin has been shown to increase the level of glutathione of the liver by up to 35%, is it ok to take it at the same time that one takes Resv. I am taking 10mg of Bioperine 30 minutes before I take Resv in the morning. Would it be better then to take my silymarin in the afternoon or night?

My understanding is that resveratrol is primarily conjugated with sulfate and glucuronide. Have you seen a paper showing glutathione conjugation too?

No, and I am really speaking from a point of almost total ignorance here. I just saw that sliymarin increases glutathione from the above link and was wondering if it could affect Resv's conjugation. Sorry, that may have been a totally stupid question. I guess I should do some more reading on this because I am getting into an area that I am totally clueless.

[krillin]

No, and I am really speaking from a point of almost total ignorance here. I just saw that sliymarin increases glutathione from the above link and was wondering if it could affect Resv's conjugation. Sorry, that may have been a totally stupid question. I guess I should do some more reading on this because I am getting into an area that I am totally clueless.

It was a good question. Glutathione is used to conjugate many things, the most prominent one being Tylenol.

[luminous]

http://www.cureself....amp;ProdID=4551

Okay, this says:
"Resveratrol has been shown to be very poorly bioavailable, readily undergoing metabolism via glucuronidation and sulphation. In order to increase resveratrol's bioavailability, one has to inhibit these enzyme systems by using specific substrates for these enzymes. It is possible to achieve this by using quercetin, piperine and luteolin, particularly the latter which has been shown to be the most potent inhibitor of sulphation."

I've read so much discussion back and forth about various substances that may or may not increase resveratrol's bioavailability in humans. Is there any concensus at all about whether quercetin, piperine and/or luteolin enhance the effects of resveratrol, as this article/ad suggests? If so, does anyone have any idea about a sensible ratio of each of these supplements vis-à-vis a given amount of resveratrol?

It might be nice to come up with a definitive list of those things that truly enhance resveratrol's performance. I've gathered (loosely) that milk, buttermilk, whey, alcohol, miralax/peg, and DMSO all might be beneficial. Perhaps the above three substances should also go on that list. Would it make sense to not only create a list, but also try to rank the substances, best products first? I realize that a lot of this might be subjective and based on opinion, but without extensive human studies at this point, it might be the best we can do.

[Hedgehog]

http://www.cureself....amp;ProdID=4551

Okay, this says:
"Resveratrol has been shown to be very poorly bioavailable, readily undergoing metabolism via glucuronidation and sulphation. In order to increase resveratrol's bioavailability, one has to inhibit these enzyme systems by using specific substrates for these enzymes. It is possible to achieve this by using quercetin, piperine and luteolin, particularly the latter which has been shown to be the most potent inhibitor of sulphation."

I've read so much discussion back and forth about various substances that may or may not increase resveratrol's bioavailability in humans. Is there any concensus at all about whether quercetin, piperine and/or luteolin enhance the effects of resveratrol, as this article/ad suggests? If so, does anyone have any idea about a sensible ratio of each of these supplements vis-à-vis a given amount of resveratrol?

It might be nice to come up with a definitive list of those things that truly enhance resveratrol's performance. I've gathered (loosely) that milk, buttermilk, whey, alcohol, miralax/peg, and DMSO all might be beneficial. Perhaps the above three substances should also go on that list. Would it make sense to not only create a list, but also try to rank the substances, best products first? I realize that a lot of this might be subjective and based on opinion, but without extensive human studies at this point, it might be the best we can do.

I would say 10mg of piperine and 10mg of quercetin per 200-400mg of resveratrol. This weekend I will be trying piperine + another compound and do some blood testing to see if it has any effect on blood plasma levels of resveratrol.

I think Maxwatt said that 10mg of quercetin can be achieved by drinking grapefruit juice so maybe drink some of that while taking your resveratrol. Please correct me if I'm wrong. There are also ideas if you take to much it could potentially inhibit SIRT1 activation and might actually inhibit it. So if you take quercetin use in a limited amount.

[edward]

Speaking of quercetin, does anyone know how much quercetin is in Maca Root. Someone mentioned that it has a lot in it but they were never able to give me a reference, amount or anything.

I have searched but I can't find any info. I take 3-5 grams of raw Maca powder daily (not standardized just the raw powder)

[bentl]

At pH below 11, trans-resveratrol does not convert to cis-resveratrol. In an ethanolic solution, under fluorescent laboratory lighting, there was about a 50% conversion to cis-resveratrol.

Thanks for the info maxwatt. Do you have any references for the info on "ethanolic solution, under fluorescent laboratory" conversion? I have been using 95% ethanol and would like to get some idea about how long that 50% conversion takes.

[luminous]

http://www.cureself....amp;ProdID=4551

Okay, this says:
"Resveratrol has been shown to be very poorly bioavailable, readily undergoing metabolism via glucuronidation and sulphation. In order to increase resveratrol's bioavailability, one has to inhibit these enzyme systems by using specific substrates for these enzymes. It is possible to achieve this by using quercetin, piperine and luteolin, particularly the latter which has been shown to be the most potent inhibitor of sulphation."

I've read so much discussion back and forth about various substances that may or may not increase resveratrol's bioavailability in humans. Is there any concensus at all about whether quercetin, piperine and/or luteolin enhance the effects of resveratrol, as this article/ad suggests? If so, does anyone have any idea about a sensible ratio of each of these supplements vis-à-vis a given amount of resveratrol?

It might be nice to come up with a definitive list of those things that truly enhance resveratrol's performance. I've gathered (loosely) that milk, buttermilk, whey, alcohol, miralax/peg, and DMSO all might be beneficial. Perhaps the above three substances should also go on that list. Would it make sense to not only create a list, but also try to rank the substances, best products first? I realize that a lot of this might be subjective and based on opinion, but without extensive human studies at this point, it might be the best we can do.

I would say 10mg of piperine and 10mg of quercetin per 200-400mg of resveratrol. This weekend I will be trying piperine + another compound and do some blood testing to see if it has any effect on blood plasma levels of resveratrol.

I think Maxwatt said that 10mg of quercetin can be achieved by drinking grapefruit juice so maybe drink some of that while taking your resveratrol. Please correct me if I'm wrong. There are also ideas if you take to much it could potentially inhibit SIRT1 activation and might actually inhibit it. So if you take quercetin use in a limited amount.

Thanks for the info_hedgehog. ;-) Now, I'm on a quest for luteolin and piperine. Sounds like the quercitin is easy.

[maxwatt]

.....

I think Maxwatt said that 10mg of quercetin can be achieved by drinking grapefruit juice so maybe drink some of that while taking your resveratrol. Please correct me if I'm wrong. There are also ideas if you take to much it could potentially inhibit SIRT1 activation and might actually inhibit it. So if you take quercetin use in a limited amount.

Thanks for the info_hedgehog. ;-) Now, I'm on a quest for luteolin and piperine. Sounds like the quercitin is easy.

I wouldn't bother with the luteolin, I think it's interchangeable with the quercitin. It too inhibits Sirt1 as does quercetin in large amounts according to my "Toe-meter". You have to weight the amount of sirt1 inhibition vs the sulfonation inhibition. I like a ration of 50 prts resveratrol to 1 part quercetin or luteolin: some sulfonation inhibition without inhbiting too much of the sirtuins.

I rather like this recipe:

-Dissolve 3 grams of resveratrol in 30 ml of 80 proof vodka, set aside. (or use 90% ethanol, adjust proportions)
-take a heaping tsp of lecithin and add to one cup of water; mix until dissolved. Use of a blender speeds the process. I use a Braun mini-primer with mixing jar and blade. Any mini-blender should be good.
-Strain the lecithinated water to remove any lumps of lecithin.
-Add the resveratrol-vodka mix to the water and stir.

The mixture kept in the dark, sealed and refrigerated should be stable for several days. Adding a little vinegar to adjust the pH will prevent conversion to the Cis isomer.

*fixed speling, grammer

Edited by maxwatt, 19 January 2008 - 03:10 PM.

[rhc124]

Great info Maxwatt! Along the same lines, any idea how long Trans Resv would last when mixed in some DMSO 50% cream or pure DMSO solution?

[luminous]

.....

I think Maxwatt said that 10mg of quercetin can be achieved by drinking grapefruit juice so maybe drink some of that while taking your resveratrol. Please correct me if I'm wrong. There are also ideas if you take to much it could potentially inhibit SIRT1 activation and might actually inhibit it. So if you take quercetin use in a limited amount.

Thanks for the info_hedgehog. ;-) Now, I'm on a quest for luteolin and piperine. Sounds like the quercitin is easy.

I wouldn't bother with the luteolin, I think it's interchangeable with the quercitin. It too inhibits Sirt1 as does quercetin in large amounts according to my "Toe-meter". You have to weight the amount of sirt1 inhibition vs the sulfonation inhibition. I like a ration of 50 prts resveratrol to 1 part quercetin or luteolin: some sulfonation inhibition without inhbiting too much of the sirtuins.

I rather like this recipe:

-Dissolve 3 grams of resveratrol in 30 ml of 80 proof vodka, set aside. (or use 90% ethanol, adjust proportions)
-take a heaping tsp of lecithin and add to one cup of water; mix until dissolved. Use of a blender speeds the process. I use a Braun mini-primer with mixing jar and blade. Any mini-blender should be good.
-Strain the lecithinated water to remove any lumps of lecithin.
-Add the resveratrol-vodka mix to the water and stir.

The mixture kept in the dark, sealed and refrigerated should be stable for several days. Adding a little vinegar to adjust the pH will prevent conversion to the Cis isomer.

*fixed speling, grammer<---cute

maxwatt--Sounds good, but (inevitably) more questions:
I know you've discussed this before, but why lecithin? Since you recommend quercetin, does that mean lecithin contains it?
Is that the complete recipe (vodka, lecithin, water and resveratrol) or is it just a base for other additions (whey, PEG, juice, etc.)?
I know this might seem irrelevant when talking about extra years of quality life--but how does it taste?

[zawy]

Somebody needs to put 500 mg in a caffiene-free energy/mood drink. If you can't figure out a soluble formulation, then work out a contract with a small winery. I know of a muscadine/blueberry winery that has grown pretty good. Still small enough to listen, act fast (i.e. change label), and capable of a good gentleman's agreement for fair payment. Lay the ground work now, then wait for the studies to come in. You could have a year jaw-dropping profits before someone big comes in. One of the big hits in the past year was a stupid little vitamin drink, and you know how big energy drinks got in the past 5 years. This is combining the two. Only those of us reading this know how strong the energy factor is for the first few days. Know the future, catch the wave, retire. Knowing the future is so much better than working.

[missminni]

Somebody needs to put 500 mg in a caffiene-free energy/mood drink. If you can't figure out a soluble formulation, then work out a contract with a small winery. I know of a muscadine/blueberry winery that has grown pretty good. Still small enough to listen, act fast (i.e. change label), and capable of a good gentleman's agreement for fair payment. Lay the ground work now, then wait for the studies to come in. You could have a year jaw-dropping profits before someone big comes in. One of the big hits in the past year was a stupid little vitamin drink, and you know how big energy drinks got in the past 5 years. This is combining the two. Only those of us reading this know how strong the energy factor is for the first few days. Know the future, catch the wave, retire. Knowing the future is so much better than working.

Great idea. Fifty cent made a kazillion dollars with a stupid little vitamin drink.
All you need to do is partner with a rapper.

[maxwatt]

.....

I think Maxwatt said that 10mg of quercetin can be achieved by drinking grapefruit juice so maybe drink some of that while taking your resveratrol. Please correct me if I'm wrong. There are also ideas if you take to much it could potentially inhibit SIRT1 activation and might actually inhibit it. So if you take quercetin use in a limited amount.

Thanks for the info_hedgehog. ;-) Now, I'm on a quest for luteolin and piperine. Sounds like the quercitin is easy.

I wouldn't bother with the luteolin, I think it's interchangeable with the quercitin. It too inhibits Sirt1 as does quercetin in large amounts according to my "Toe-meter". You have to weight the amount of sirt1 inhibition vs the sulfonation inhibition. I like a ration of 50 prts resveratrol to 1 part quercetin or luteolin: some sulfonation inhibition without inhbiting too much of the sirtuins.

I rather like this recipe:

-Dissolve 3 grams of resveratrol in 30 ml of 80 proof vodka, set aside. (or use 90% ethanol, adjust proportions)
-take a heaping tsp of lecithin and add to one cup of water; mix until dissolved. Use of a blender speeds the process. I use a Braun mini-primer with mixing jar and blade. Any mini-blender should be good.
-Strain the lecithinated water to remove any lumps of lecithin.
-Add the resveratrol-vodka mix to the water and stir.

The mixture kept in the dark, sealed and refrigerated should be stable for several days. Adding a little vinegar to adjust the pH will prevent conversion to the Cis isomer.

*fixed speling, grammer<---cute

maxwatt--Sounds good, but (inevitably) more questions:
I know you've discussed this before, but why lecithin? Since you recommend quercetin, does that mean lecithin contains it?
Is that the complete recipe (vodka, lecithin, water and resveratrol) or is it just a base for other additions (whey, PEG, juice, etc.)?
I know this might seem irrelevant when talking about extra years of quality life--but how does it taste?

Lecithin functions as a surfactant. It improves delivery to the cell membrane for transport into the cell by presenting greater surface area of resveratrol to the cell.
I don't recommend quercetin, I warn against large amounts as counterproductive, though a small amount might reduce sulfonation and glucuronidation making more resveratrol available. So does taking a higher dose of resveratrol. I think more than 500 mg overwhelms the sulfonation and glucuronation mechanisms, making an order of magnitude difference in availability at that point.
You can add other substances. Whey isn't necessary with this method. PEG can be used instead of lecithin. Juice tastes good. why not.
The drink tastes pretty insipid. Might go better with Jack Daniels than vodka if you like Jack. Maybe pomegranate juice instead of water with the lecithin? Or gapefruit or orange juice?

Edited by maxwatt, 19 January 2008 - 06:39 PM.

[luminous]

Somebody needs to put 500 mg in a caffiene-free energy/mood drink. If you can't figure out a soluble formulation, then work out a contract with a small winery. I know of a muscadine/blueberry winery that has grown pretty good. Still small enough to listen, act fast (i.e. change label), and capable of a good gentleman's agreement for fair payment. Lay the ground work now, then wait for the studies to come in. You could have a year jaw-dropping profits before someone big comes in. One of the big hits in the past year was a stupid little vitamin drink, and you know how big energy drinks got in the past 5 years. This is combining the two. Only those of us reading this know how strong the energy factor is for the first few days. Know the future, catch the wave, retire. Knowing the future is so much better than working.

Great idea. Fifty cent made a kazillion dollars with a stupid little vitamin drink.
All you need to do is partner with a rapper.

Or a few of us (including me and you, since it's our idea) could create an ImmInst resveratrol energy drink and then we could retire--call it ImmErgy, ImmPact, ImmErse, ImmRes or something like that...

Edited by luminous, 19 January 2008 - 09:12 PM.

[niner]

I rather like this recipe:

-Dissolve 3 grams of resveratrol in 30 ml of 80 proof vodka, set aside. (or use 90% ethanol, adjust proportions)
-take a heaping tsp of lecithin and add to one cup of water; mix until dissolved. Use of a blender speeds the process. I use a Braun mini-primer with mixing jar and blade. Any mini-blender should be good.
-Strain the lecithinated water to remove any lumps of lecithin.
-Add the resveratrol-vodka mix to the water and stir.

Maxwatt, can you really get 3 grams into 30ml of 80 proof vodka (40% EtOH)? I use Everclear (95% EtOH), and I don't think I can get 3 grams into 30ml of that. Maybe 2 grams, or a little more, but it's more than twice as concentrated in EtOH... I've never been brave enough to microwave it, and water baths are too much hassle, so I haven't tried heating it.