1084 replies to this topic

[missminni]

I was curious how liquid lecithin would work, and got some. Portions do not disolve, though some fraction seems to. I mixed resveratrol into some liquid lecithin, and got a, orange-colored ball with a tarry consistency. I could eat little pieces, but there was no taste, so it was not pleasant. I mixed a little honey into such a lecithin-resveratrol ball, cut it into little pieces, and ate those. I'm sure my intestines made sort work of it.

I find the easiest way to take resveratrol is dissolved in milk or whey protein or a whey protein drink. I am not 100% certain of the relative bioavailability with this method, and continue to alternate with lecithin. However, I use lecithin granules pre-dissolved in water and filtered to remove any lumps, and find pre-dissolving the resveratrol in an alcoholic beverage helps it to mix in..

This is my preferred method. I have had excellent results taking it this way
and so have my dogs. I recommended it this way to a friend of mine who just started using it, and she
too had noticeable results for herself and her dog.
I am now using half and half instead of milk because it seems to be easier on my stomach.
I was having laxative effects when taking 1g or more. The half and half
seems to help in that respect, although I have no idea why.
It also tastes better.

Are you lactose intolerant? That is why I use whey protein instead of milk, to avoid such prplems.

No. I always drank a lot of milk and yogurt. What about lactose free milk? (Lactaid) That
still has whey protein, correct? That should work well with resveratrol if you are lactose intolerant.

[niner]

http://jcp.sagepub.c...ract/44/10/1151

Dermal Absorption of Camphor, Menthol, and Methyl Salicylate in Humans

For the 8-patch group, the average maximum plasma concentrations (Cmax ± SD) were 41.0 ± 5.8 ng/mL, 31.9 ± 8.8 ng/mL, and 29.5 ± 10.5 ng/mL for camphor, menthol, and methyl salicylate, respectively.
[..] Although unable to determine the absolute dermal bioavailability of these compounds, there appears to be relatively low systemic exposure to these potentially toxic compounds, even when an unrealistically large number of patches are applied for an unusually long time.

This works out to a peak plasma concentration of 0.19 micromolar for methyl salicylate with "an unrealistically large number of patches applied for an unusually long time". It would take 300 times as much just to hit the IC50 for sulfation inhibition, and you really need a higher concentration than that. And that's the Cmax, so you probably need to at least double it again. And this is for a compound that passes through skin extraordinarily well, relative to most. So I guess maybe you do need to bathe in it after all. Thanks for the data, Bix.

[krillin]

Anyone think it not wise to take a green tea supplement? I seem to remember that someone said it might inhibit Sirt.

The paper on stability showed that under oxidizing conditions, that it did not activate Sirt1. This was in vitro; in vivo, oxygen levels are around 5%intracellularly, much lower. Using antioxidants stabilized it so it did activate Sirt1. A little vitamin C with your green tea, sir? I do not think it is really a problem. I drink a lot of green and white tea.

Correct.

Free Radic Biol Med. 2007 Aug 1;43(3):362-71.
Autoxidative quinone formation in vitro and metabolite formation in vivo from tea polyphenol (-)-epigallocatechin-3-gallate: studied by real-time mass spectrometry combined with tandem mass ion mapping.
Sang S, Yang I, Buckley B, Ho CT, Yang CS.
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020, USA.

(-)-Epigallocatechin-3- gallate (EGCG), the most abundant and biologically active compound in tea, has been proposed to have beneficial health effects, including prevention of cancer and heart disease. Based mainly on studies in cell-line systems, in which EGCG is not stable, different mechanisms of action of EGCG have been proposed. It has been proposed also that oxidation of EGCG and its production of reactive oxygen species are responsible for biological activities such as receptor inactivation and telomerase inhibition. It is unclear, however, whether this phenomenon occurs in vivo. In the present study, the stability of EGCG and product formation in Tris-HCl buffer was investigated using real- time mass spectrometry combined with tandem mass ion mapping. With real-time mass data acquisition, we demonstrate for the first time the formation of EGCG quinone, EGCG dimer quinone, and other related compounds. The structural information of the major appearing ions was provided by tandem mass analysis of each ion. A mechanism for the autoxidation of EGCG based on the structural information of these ions was proposed. None of these oxidation products were observed in the plasma samples of mice after treatment with 50 mg/kg EGCG, i.p. daily for 3 days. Instead, the methylated and conjugated metabolites of EGCG were observed. Therefore the roles of EGCG autoxidation in the biological activities of this compound in vivo remain to be investigated further.

PMID: 17602952

[sUper GeNius]

Okay, the obvious question. Why not simply take a boatload of polyphenols? Cocoa, citrus, etc.

[bixbyte]

Okay, the obvious question. Why not simply take a boatload of polyphenols? Cocoa, citrus, etc.

Spending lots of money to conjugate mass quantities of antioxidants? Plasma levels were nil.
Instead of consuming mass quanitites, how about taking them along with synergistic compounds?
Naringen, aspirin, methyl salicylate, bioperine, quercetin ...

[sUper GeNius]

Okay, the obvious question. Why not simply take a boatload of polyphenols? Cocoa, citrus, etc.

Spending lots of money to conjugate mass quantities of antioxidants? Plasma levels were nil.
Instead of consuming mass quanitites, how about taking them along with synergistic compounds?
Naringen, aspirin, methyl salicylate, bioperine, quercetin ...

I am taking curcumin, bioperine, a baby aspirin, along with blueberry, pomegranate, cherry etc. I'm steering clear quercitin. You don't have to spend lots of money to ingest large amounts of polyphenols.

Edit. i am also consuming a decent amount of pure cocoa powder.

Edited by FuLL meMbeR, 04 February 2008 - 06:39 PM.

[kurt]

Does taking resveratrol later in the day (like with dinner) make any difference? I see that most people take it early in the day but for some reasons I find it more convenient to take it with dinner. Am I losing out on anything? I do feel alot of positive effects coming from resveratrol, along with the side effect of strong appetite suppression.

[tintinet]

Does taking resveratrol later in the day (like with dinner) make any difference? I see that most people take it early in the day but for some reasons I find it more convenient to take it with dinner. Am I losing out on anything? I do feel alot of positive effects coming from resveratrol, along with the side effect of strong appetite suppression.

Doubt it much matters, AFAAK, ISTM. Some aver one oughta take a single large dose to spike blood resveratrol levels; others think multiple doses might be better. Try taking it in the AM, if you like, to see for yourself if you're missing out on anything.

[niner]

Does taking resveratrol later in the day (like with dinner) make any difference? I see that most people take it early in the day but for some reasons I find it more convenient to take it with dinner. Am I losing out on anything? I do feel alot of positive effects coming from resveratrol, along with the side effect of strong appetite suppression.

I don't see a difference with 98+% resveratrol. With 50%, you might get some stimulant effect and prefer it in the morning. Since I take mine with alcohol (and PEG/antisolvent) I prefer to take it at night. I take it on at least a semi-empty stomach. If you do take it with dinner, I would recommend taking it 45 minutes before or a couple hours after. If it's mixed with food, it will be diluted in the gut and will not be effective at swamping gut metabolism. We have evidence that this occurs both from CACO2 models and from Boocock's pharmacokinetic studies of oral doses from 0.5 to 5 grams in humans. Large doses will be more efficiently used if they are split into multiple doses of at least a gram each. This may not be needed if the resveratrol is formulated for improved bioavailability: Alcohol/PEG|lecithin, micronized formulations +/- Tween/Captisol/PEG/lecithin/etc. If you must take it with food, high fat would likely be better than high fiber. Sprinkle it on a cheeseburger.

Here's the post with my analysis of Boocock's data: http://www.imminst.o...&...st&p=220205

[notox]

Hello,

I'm using resveratrol since Dec. 2006 and never had a problem to
fall asleep. Even when I take up to 2-3 g. in the evening.

After reading this thread I test dissolving 1g 98% into a 56% liquer
after complete dissolution I add raw cocoa powder until I got a
pasty cream. Then I let macerate the stuff for 10. min and add
boiling water. Drinking it between 5-6 PM(after meal) for the first time keeps
me awake past 03:00 AM (normally I fell asleep withing 10-15 min. at 10 PM).

The next evening I tried the same and I fell asleep around 02:00 AM.
Ok, this could be for another reason and so I wait until weekend and tried
again with the same result and the last try in the middle of the week with
the same outcome. Taking 1g 98% no problem, taking the same amount of
cocoa no problem, drinking the liquer no problem, but taking it all together
no sleep.

Could this be a sign of enhanced bioavailability, or an interaction between cocoa
polyphenols and resveratrol ?

------------------------

Another issue I've had with resveratrol is the following:

2 Days after Christmas I've had a first sign of bronchitis (burning in the upper
part of the lung). So I decided to take 400mg Ibuprofen + 3.600 mg Resveratrol:

2000 mg from 98%
1000 mg from 50%
500 mg from Country Life Formulation
112 mg from Natures Way Formulation

After taking the combination I was fine but had almost no sleep at night.
Next moring I've had fever, ague, pain in the whole body and incredible
headache. I pull on several layers of clothes but still have cold hands and
feet and shiver, while having fever at the same time.

After a few hours I took the same combination again and all symptoms disappeared
followed by a mild euphoria. This was the first time I anticipate that I'm really ill
and the res.+ibuprofen was able to switch off the symptoms in a way that I've never
experienced before.

For the night I decided to stay clean from the stuff and to retry the next day.
This time I used a stopwatch after taking my combo and noticed the following:

50 min.: Hands/Feet get warm shivering stops (start pulling off all the extra clothes)
60 min.: Headache and brainfog disappears
85 min.: No more body pain, feeling strong again. Complete cessation of symptoms + mild euphoria.
After 7h all symtomps start to fade in after 9h feeling completely ill again.

I reiterated the above test next day with the same outcome.

From now on I decided to avoid the combo because I was unsure if it is a good idea to
suppress all symptoms of my malady and if my body needs some fever to fight the
infection. Furthermore I start considering that the liver enzymes that metabolize ibuprofen
may be blocked by res. and that I may have an ibuprofen overdose.

Nevertheless, I decided to tolerate all symptoms until sylvester night and taking the combo
again if I'm still ill. And so it comes, around 7 PM on sylvester I took my combo again and
all symptoms disappeared after 86 min (had a great time with my family then).

In the first days of january I tried a lower dose (1200mg) res. + ibuprofen 4000 and
ibuprofen 400 alone with not nearly the same effect.

The acute phase of my malady last for 10 days, for another 7 days I felt very weak and it
took more than further seven days before the cough stops and a few more days before my
lung was absolutely free and not buring.

In the review I would say it could have been influenza because of the rapid development
of symptoms, persistent headache and weakness after the acute phase. Deducing from the
color of my sputum it was initially a viral infection and for 2-3 days additionally some kind
of bacteria used the opportunity and entered my system.

In all I've not the impression that large doses of res. suppress the immune system because
the acute phase of a normal bronchitis is 7-10 days for me but this was the first time that
I've not used any antibiotics to fight the bacterial infection that several times before has
driven my body temperature >= 40 deg. celsius. Neverthless, I think it was a bit more
than plain bronchitis because of the sustained headache during and weakness after the
acute phase.

P.S.: After reading this forum I found that peak plasma level of resveratrol appears after 1.5h
which is amazingly close to 85 min (the time around all my symptoms disapeared)

Edited by notox, 05 February 2008 - 08:25 AM.

[bixbyte]

2 Days after Christmas I've had a first sign of bronchitis (burning in the upper
part of the lung). So I decided to take 400mg Ibuprofen + 3.600 mg Resveratrol:

......

The acute phase of my malady last for 10 days, for another 7 days I felt very weak and it
took more than further seven days before the cough stops and a few more days before my
lung was absolutely free and not buring.

In the review I would say it could have been influenza because of the rapid development
of symptoms, persistent headache and weakness after the acute phase. Deducing from the
color of my sputum it was initially a viral infection and for 2-3 days additionally some kind
of bacteria used the opportunity and entered my system.

If you had seen an MD and had your Flu Like symptoms diagnosed then you would know your illness.
Do you ever visit a doctor?

[notox]

2 Days after Christmas I've had a first sign of bronchitis (burning in the upper
part of the lung). So I decided to take 400mg Ibuprofen + 3.600 mg Resveratrol:

......

The acute phase of my malady last for 10 days, for another 7 days I felt very weak and it
took more than further seven days before the cough stops and a few more days before my
lung was absolutely free and not buring.

In the review I would say it could have been influenza because of the rapid development
of symptoms, persistent headache and weakness after the acute phase. Deducing from the
color of my sputum it was initially a viral infection and for 2-3 days additionally some kind
of bacteria used the opportunity and entered my system.

If you had seen an MD and had your Flu Like symptoms diagnosed then you would know your illness.
Do you ever visit a doctor?

Our family doctor was out of business between christmas and new year additionally the fever was not
that high that I considerd to go to the hospital.

[niner]

I'm using resveratrol since Dec. 2006 and never had a problem to
fall asleep. Even when I take up to 2-3 g. in the evening.

After reading this thread I test dissolving 1g 98% into a 56% liquer
after complete dissolution I add raw cocoa powder until I got a
pasty cream. Then I let macerate the stuff for 10. min and add
boiling water. Drinking it between 5-6 PM(after meal) for the first time keeps
me awake past 03:00 AM (normally I fell asleep withing 10-15 min. at 10 PM).

The next evening I tried the same and I fell asleep around 02:00 AM.
Ok, this could be for another reason and so I wait until weekend and tried
again with the same result and the last try in the middle of the week with
the same outcome. Taking 1g 98% no problem, taking the same amount of
cocoa no problem, drinking the liquer no problem, but taking it all together
no sleep.

Could this be a sign of enhanced bioavailability, or an interaction between cocoa
polyphenols and resveratrol ?

I don't think that the 98% resveratrol is the problem. Perhaps the liquor is making the methyl xanthines in the cocoa more bioavailable. You could try resveratrol + liquor, but no cocoa, or you could try cocoa + liquor, but no resveratrol. Was it a new batch of cocoa?

[bixbyte]

I think I figured out a way to increase Resveratrol Bio by a couple "X" times the normal plasma level.

If you test this at home, it is at your own risk

Someone should perform some plasma tests after taking.

I took 1 gram of 98% Resveratrol along with 1 gram of Miralax.
Then I had a tall glass of Grapefruit Juice and chased this all down with an
H-2 receptor antagonist called Cimetine (over the counter 200 miligrams of Tagamet)


I felt what I think was a Resveratrol "Rush"

Anyone else ever try RES with Cimitine?????

Edited by bixbyte, 10 February 2008 - 10:24 PM.

[luminous]

Just wanted to share something. Every day, I've been mixing (with a fork) a couple of ounces of high antioxidant juice with whey and resveratrol. The mixture doesn't dissolve perfectly, but it's not bad. Today I added a little Miralax power--about a teaspoon. With the addition of Miralax, everything seems to dissolve much better. The mixture ends up slightly thick, but it's a lot smoother with Miralax than without it.

[niner]

I think I figured out a way to increase Resveratrol Bio by a couple "X" times the normal plasma level.

If you test this at home, it is at your own risk

Someone should perform some plasma tests after taking.

I took 1 gram of 98% Resveratrol along with 1 gram of Miralax.
Then I had a tall glass of Grapefruit Juice and chased this all down with an
H-2 receptor antagonist called Cimetine (over the counter 200 miligrams of Tagamet)

I felt what I think was a Resveratrol "Rush"

Anyone else ever try RES with Cimitine?????

What's the theory behind this? In other words, why would you expect cimetidine to increase the bioavailability of resveratrol? Did you suspend the resveratrol in a solution of Miralax, or did you just swallow them both? I don't think the latter will do much good. A lot of things can cause a rush-y sensation, but I wouldn't expect improved resveratrol plasma levels to be one of them.

[bixbyte]

I think I figured out a way to increase Resveratrol Bio by a couple "X" times the normal plasma level.

If you test this at home, it is at your own risk

Someone should perform some plasma tests after taking.

I took 1 gram of 98% Resveratrol along with 1 gram of Miralax.
Then I had a tall glass of Grapefruit Juice and chased this all down with an
H-2 receptor antagonist called Cimetine (over the counter 200 miligrams of Tagamet)

I felt what I think was a Resveratrol "Rush"

Anyone else ever try RES with Cimitine?????

What's the theory behind this? In other words, why would you expect cimetidine to increase the bioavailability of resveratrol? Did you suspend the resveratrol in a solution of Miralax, or did you just swallow them both? I don't think the latter will do much good. A lot of things can cause a rush-y sensation, but I wouldn't expect improved resveratrol plasma levels to be one of them.

It is anecdotal and I do not have a Plasma dectector laying around.

Must be on an empty stomach to max the Resveratrol.

I had a regular spring water bottle half full with water, warm not refrigerated, I added one gram of miralax; capped it and shook it up till the miralax was dissoled into the water, then I added one gram of 98% RES into the bottle and shook it up until the RES was fully white and milk in color.
Next I had a tall glass of grapefruit juice that I took with one 200 mg cimetine (tagamet).

I think the Tagamet increased the RES powerfull effects.

"Rush" is my own personal word for the heightened abilities I experienced afterwards.

Edited by bixbyte, 10 February 2008 - 10:54 PM.

[bixbyte]

Just wanted to share something. Every day, I've been mixing (with a fork) a couple of ounces of high antioxidant juice with whey and resveratrol. The mixture doesn't dissolve perfectly, but it's not bad. Today I added a little Miralax power--about a teaspoon. With the addition of Miralax, everything seems to dissolve much better. The mixture ends up slightly thick, but it's a lot smoother with Miralax than without it.

Try taking one 200 mg tagamet with the mixture and tell me if you feel the antioxidants?
I think Tagamets might increase the power of Antioxidants.

[maxwatt]

Just wanted to share something. Every day, I've been mixing (with a fork) a couple of ounces of high antioxidant juice with whey and resveratrol. The mixture doesn't dissolve perfectly, but it's not bad. Today I added a little Miralax power--about a teaspoon. With the addition of Miralax, everything seems to dissolve much better. The mixture ends up slightly thick, but it's a lot smoother with Miralax than without it.

Try taking one 200 mg tagamet with the mixture and tell me if you feel the antioxidants?
I think Tagamets might increase the power of Antioxidants.

Cimetidine inhibits, in that it is metabolized via, the P-glycoprotein and organic anion/cation transporters. It is a known inhibitor of the hepatic microsomal cytochrome P450 enzyme system. I've no doubt you experienced some sort of effect, and it could be that inhibition of glucuronidation resulted in significantly higher plasma levels of resveratrol. Manufacturers are adding piperine to achieve this. I wonder what a resveratrol rush feels like.

Just because I find this amusing

[bentl]

I took 1 gram of 98% Resveratrol along with 1 gram of Miralax.
Then I had a tall glass of Grapefruit Juice and chased this all down with an
H-2 receptor antagonist called Cimetine (over the counter 200 miligrams of Tagamet)

Are you taking it BECAUSE it is an H-2 receptor antagonist? If so, it seems that
there may be better/safer ones. I just read the wikipedia entry for Cimetidine and,
although it is OTC, it doesn't sound like something that I would want to play with.

I found the section on "Shortcomings and side effects" to be interesting reading.

Edited by bentl, 11 February 2008 - 06:56 AM.

[bixbyte]

I took 1 gram of 98% Resveratrol along with 1 gram of Miralax.
Then I had a tall glass of Grapefruit Juice and chased this all down with an
H-2 receptor antagonist called Cimetine (over the counter 200 miligrams of Tagamet)

Are you taking it BECAUSE it is an H-2 receptor antagonist? If so, it seems that
there may be better/safer ones. I just read the wikipedia entry for Cimetidine and,
although it is OTC, it doesn't sound like something that I would want to play with.

I found the section on "Shortcomings and side effects" to be interesting reading.

I dosed on an empty stomach.

Seems like an H2 receptor antagonist does increase RES plasma levels anecdotally.

Did you read "other uses" ? Cures Warts

Sure if you are taking 800 mg prescription doses many side effects

Taking 200 mg or you could break one in half 100 mg this is a very small dose.

I think that OTC Cimetine low dose is generally safe.

[notox]

I'm using resveratrol since Dec. 2006 and never had a problem to
fall asleep. Even when I take up to 2-3 g. in the evening.

After reading this thread I test dissolving 1g 98% into a 56% liquer
after complete dissolution I add raw cocoa powder until I got a
pasty cream. Then I let macerate the stuff for 10. min and add
boiling water. Drinking it between 5-6 PM(after meal) for the first time keeps
me awake past 03:00 AM (normally I fell asleep withing 10-15 min. at 10 PM).

The next evening I tried the same and I fell asleep around 02:00 AM.
Ok, this could be for another reason and so I wait until weekend and tried
again with the same result and the last try in the middle of the week with
the same outcome. Taking 1g 98% no problem, taking the same amount of
cocoa no problem, drinking the liquer no problem, but taking it all together
no sleep.

Could this be a sign of enhanced bioavailability, or an interaction between cocoa
polyphenols and resveratrol ?

I don't think that the 98% resveratrol is the problem. Perhaps the liquor is making the methyl xanthines in the cocoa more bioavailable. You could try resveratrol + liquor, but no cocoa, or you could try cocoa + liquor, but no resveratrol. Was it a new batch of cocoa?

I've had resveratrol + liquor several times because I like the idea of complete dissolution
as the ultimate form of micronization. What I learned here is that precipitation occurs in
the stomach and that the particles may build clusters again. And since I've had not surfactant
like PEG, lecitin, etc. by hand I tried to use cocoa, which was from a new batch. I tried to use
liquor + cocoa without resveratrol last night but had no problem to fall asleep and I'll try that
a few times more to rule out that this was the cause of my sleepless nights.

Edited by notox, 11 February 2008 - 08:14 AM.

[bixbyte]

I took 1 gram of 98% Resveratrol along with 1 gram of Miralax.
Then I had a tall glass of Grapefruit Juice and chased this all down with an
H-2 receptor antagonist called Cimetine (over the counter 200 miligrams of Tagamet
I dosed on an empty stomach.

Seems like an H2 receptor antagonist does increase RES plasma levels anecdotally.


Sure if you are taking 800 mg prescription doses many side effects

Taking 200 mg or you could break one in half 100 mg this is a very small dose.

I think that OTC 200 mg Cimetine low dose is generally safe.

http://en.wikipedia....ptor_antagonist



Drug interactions
With regard to pharmacokinetics, cimetidine in particular interferes with some of the body's mechanisms of drug metabolism and elimination through the liver cytochrome P450 pathway. Specifically, cimetidine is an inhibitor of the P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. By reducing the metabolism of drugs through these enzymes, cimetidine may increase their serum concentrations to toxic levels. Examples of drugs affected include: warfarin, theophylline, phenytoin, lidocaine, quinidine, propranolol, labetalol, metoprolol, tricyclic antidepressants, some benzodiazepines, dihydropyridine calcium channel blockers, sulfonylureas, metronidazole, and some recreational drugs such as ethanol and MDMA.



Am I close to a SRT-501 generic equivalent?

Side effects look the same as SRT-501 and my Cimetidine / RES

Look out Sirtris I think I might have a better formula.

Cimetidine causes other medication to become much more powerful.

Resveratrol with Cimetidine is perhaps increasing my serum levels?

There is no toxic level known for Resveratrol?

Anybody able to perform plasma tests for free?

I will try taking the tagamet half an hour before taking RES

Edited by bixbyte, 12 February 2008 - 02:41 AM.

[niner]

http://en.wikipedia....ptor_antagonist

Drug interactions
With regard to pharmacokinetics, cimetidine in particular interferes with some of the body's mechanisms of drug metabolism and elimination through the liver cytochrome P450 pathway. Specifically, cimetidine is an inhibitor of the P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. By reducing the metabolism of drugs through these enzymes, cimetidine may increase their serum concentrations to toxic levels.
The problem is, resveratrol is not significantly metabolized by any of those enzymes. Far and away the most important metabolism of resveratrol is glucuronidation and sulfation. The various CYPs are oxidative enzymes, but resveratrol is already studded with hydroxyls so it doesn't need any more oxidation to get rid of it.

Am I close to a SRT-501 generic equivalent? Sadly, no. The closest thing we have at the moment is ethanol/(miralax/lecithin)

Side effects look the same as SRT-501 and my Cimetidine / RES Has Sirtris reported side effects? It gives people a rush?

Look out Sirtris I think I might have a better formula. I don't think they need to worry.

Cimetidine causes other medication to become much more powerful. If that medication has one of the above CYPs on the critical path to elimination. Resveratrol doesn't.

Resveratrol with Cimetidine is perhaps increasing my serum levels? Well, "anything's possible", as they say, but I don't see what the mechanism would be.

There is no toxic level known for Resveratrol? Some people have GI problems at relatively modest levels. I seems to be hard to kill an animal with it. You have to give them so much that it clogs up their GI tract because there's just too much insoluble stuff. Sort of like eating a bucket full of sand.

Anybody able to perform plasma tests for free? Hedgehog has offered, if you can get the blood drawn and stabilized, and mail it to him.

[bixbyte]

Side effects look the same as SRT-501 and my Cimetidine / RES Has Sirtris reported side effects? It gives people a rush?

In two Phase 1a human clinical studies, SRT501 was found to be well tolerated. In these studies, SRT501 was administered orally, once daily, to 85 healthy male volunteers for seven days, in order to evaluate safety, dose, tolerability and pharmacokinetics. The trial demonstrated dose proportional drug levels in the blood. All of the reported adverse events were reversible and none were serious. In the 85 subjects, the most common adverse events reported were altered blood lipids in six subjects, diarrhea in six subjects, and vomiting in five subjects.


Niner Color is fun!

Don't The symptoms do sound like RES and Cimetidine?

BIX

[niner]

Don't The symptoms do sound like RES and Cimetidine?

Sounds like Everclear/Miralax. That tastes bad enough to make you barf, without a decent mixer.

I like color, but some find it DISTURBING.

[krillin]

Here's something that I thought was relevant, but the full text said

However, cimetidine, sulfaphenazole, and erythromycin did not exhibit any inhibitory effect on morphine glucuronidation (data not shown).

Drug Metab Dispos. 2006 Aug;34(8):1277-82.
Inhibition of UDP-glucuronosyltransferase 2b7-catalyzed morphine glucuronidation by ketoconazole: dual mechanisms involving a novel noncompetitive mode.
Takeda S, Kitajima Y, Ishii Y, Nishimura Y, Mackenzie PI, Oguri K, Yamada H.
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Glucuronidation of morphine in humans is predominantly catalyzed by UDP-glucuronosyltransferase 2B7 (UGT2B7). Since our recent research suggested that cytochrome P450s (P450s) interact with UGT2B7 to affect its function [Takeda S et al. (2005) Mol Pharmacol 67:665-672], P450 inhibitors are expected to modulate UGT2B7-catalyzed activity. To address this issue, we investigated the effects of P450 inhibitors (cimetidine, sulfaphenazole, erythromycin, nifedipine, and ketoconazole) on the UGT2B7-catalyzed formation of morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G). Among the inhibitors tested, ketoconazole was the most potent inhibitor of both M-3-G and M-6-G formation by human liver microsomes. The others were less effective except that nifedipine exhibited an inhibitory effect on M-6-G formation comparable to that by ketoconazole. Neither addition of NADPH nor solubilization of liver microsomes affected the ability of ketoconazole to inhibit morphine glucuronidation. In addition, ketoconazole had an ability to inhibit morphine UGT activity of recombinant UGT2B7 freed from P450. Kinetic analysis suggested that the ketoconazole-produced inhibition of morphine glucuronidation involves a mixed-type mechanism. Codeine potentiated inhibition of morphine glucuronidation by ketoconazole. In contrast, addition of another substrate, testosterone, showed no or a minor effect on ketoconazole-produced inhibition of morphine UGT. These results suggest that 1) metabolism of ketoconazole by P450 is not required for inhibition of UGT2B7-catalyzed morphine glucuronidation; and 2) this drug exerts its inhibitory effect on morphine UGT by novel mechanisms involving competitive and noncompetitive inhibition.

PMID: 16679387

Mol Pharmacol. 2005 Mar;67(3):665-72.
Modulation of UDP-glucuronosyltransferase function by cytochrome P450: evidence for the alteration of UGT2B7-catalyzed glucuronidation of morphine by CYP3A4.
Takeda S, Ishii Y, Iwanaga M, Mackenzie PI, Nagata K, Yamazoe Y, Oguri K, Yamada H.
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Modulation of UDP-glucuronosyltransferase 2B7 (UGT2B7)-catalyzed morphine glucuronidation by cytochrome P450 (P450) was studied. The effects of P450 isozymes on the kinetic parameters of UGT2B7-catalyzed glucuronidation of the morphine 3-hydroxyl group were examined by simultaneous expression of UGT2B7 and either CYP3A4, -1A2, or -2C9 in COS-1 cells. Although coexpression of CYP3A4 with UGT2B7 had little effect on Vmax, the Km was increased by about 9.8-fold compared with the UGT2B7 single expression system. The other P450 isozymes (CYP1A2 and CYP2C9) had some effects on Km and Vmax values. Immunoprecipitation of UGT from solubilized human liver microsomes resulted in coprecipitation of CYP3A4 with UGT2B7. The protein-protein interaction between CYP3A4 and UGT2B7 was further confirmed by overlay assay using glutathione S-transferase-CYP3A4 fusion protein. Addition of CYP3A4 to untreated COS microsomes expressing UGT2B7 had no or minor effects on morphine glucuronidation. In contrast, the formation of morphine-3-glucuronide by detergent-treated microsomes from COS-1 cells expressing UGT2B7 was reduced by CYP3A4, whereas the formation of the 6-glucuronide was enhanced. These results strongly suggest that 1) the glucuronidation activity of UGT2B7 toward morphine is specifically modulated by interaction with CYP3A4 in microsomal membranes and that 2) CYP3A4 alters UGT2B7 regioselectivity so that the ratio of morphine activation/detoxication is increased. This study provides the first evidence that P450 is not only involved in oxidation of drugs but also modulates the function of UGTs.

PMID: 15611481

[niner]

Interesting papers, krillin. There are a lot of UGTs, though- nine in the 1A family and 12 in the 2B family, with hundreds of allelic variations. Like the P450s, they probably have very different substrate specificities. I'm too tired to try to find which one or ones hit resveratrol, but these reports at least raise an interesting question: Could you modify the level of glucuronidation of resveratrol with a compound that interacts through a P450? I don't know if this is a general effect, though I suspect it's not going to be a big factor.

[krillin]

Interesting papers, krillin. There are a lot of UGTs, though- nine in the 1A family and 12 in the 2B family, with hundreds of allelic variations. Like the P450s, they probably have very different substrate specificities. I'm too tired to try to find which one or ones hit resveratrol, but these reports at least raise an interesting question: Could you modify the level of glucuronidation of resveratrol with a compound that interacts through a P450? I don't know if this is a general effect, though I suspect it's not going to be a big factor.

If both of these papers are correct, UGT2B7 only hits the cis form, but it is induced by trans.

Arch Biochem Biophys. 2001 Sep 15;393(2):281-9.
Regioselective and stereospecific glucuronidation of trans- and cis-resveratrol in human.
Aumont V, Krisa S, Battaglia E, Netter P, Richard T, Mérillon JM, Magdalou J, Sabolovic N.
Groupe d'Etude des Substances Naturelles à Intérêt Thérapeutique (EA 491), Université Victor Segalen Bordeaux 2, Bordeaux, France.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenol present in wine, which has been reported to have anti-inflammatory, anti-platelet, and anti-carcinogenic effects. The glucuronidation of this compound and that of the cis-isomer also naturally present, has been investigated in human liver microsomes. Both isomers were actively glucuronidated. The reaction led to the formation of two glucuronides (3-O- and 4'-O-glucuronides), whose structure was characterized by LC-MS and proton NMR. Glucuronidation was regio- and stereoselective. It occurred at a faster rate with the cis-isomer and preferred the 3-position on both isomers. In addition, the glucuronidation of resveratrol was tested using several recombinant UDP-glucuronosyltransferase (UGT) isoforms. The reaction was catalyzed by UGT of the family 1A (UGT1A1, 1A6, 1A7, 1A9, 1A10). The bilirubin conjugating UGT1A1 was mainly involved in the 3-O-glucuronidation of trans-resveratrol, whereas the phenol conjugating UGT1A6 activity was restricted to cis-resveratrol. The UGT1A9 and 1A10 were active toward both isomers. The activity supported by UGT2B7 and UGT2B15 was very low and restricted to cis-resveratrol. UGT1A3, 1A4, 2B4, and 2B11 were unable to form resveratrol glucuronides. Copyright 2001 Academic Press.

PMID: 11556815

Drug Metab Dispos. 2007 May;35(5):699-703.
Resveratrol in human hepatoma HepG2 cells: metabolism and inducibility of detoxifying enzymes.
Lançon A, Hanet N, Jannin B, Delmas D, Heydel JM, Lizard G, Chagnon MC, Artur Y, Latruffe N.
Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 866 (Lipides, Nutrition et Cancer, équipe Biochimie Métabolique et Nutritionnelle), Université de Bourgogne, Faculté des Sciences Gabriel, Dijon, France.

trans-Resveratrol is a polyphenol present in several plant species. Its chemopreventive properties against several diseases have been largely documented. To validate a model for the study of the factors influencing its biological fate at the hepatic level, the metabolism and the efflux of resveratrol were studied in the human hepatoblastoma cell line, HepG2. Comparative high-performance liquid chromatography analysis of cell culture media before and after deconjugation showed that resveratrol was rapidly conjugated; at the concentration of 10 microM, it was entirely metabolized at 8 h of incubation. Two main resveratrol metabolites, monosulfate and disulfate, were identified by atmospheric pressure chemical ionization-mass spectrometry, thanks to their quasi-molecular ion and their characteristic fragmentation. To correlate with the auto-induction of resveratrol metabolism evidenced in HepG2 cells after a pretreatment for 48 h with 10 microM resveratrol, the inducibility of phase II enzymes by resveratrol was studied by real-time quantitative reverse transcriptase-polymerase chain reaction and flow cytometry. Observed, in particular, were an increase in mRNA expression levels of three metabolizing enzymes, two isoforms of UDP-glucuronosyltransferases, UGT1A1 and UGT2B7 (5-fold increased), and a sulfotransferase, ST1E1, in cells pretreated for 24 h with 10 microM resveratrol. These results were correlated with an increase in protein expression, especially after 48 h of treatment. On the other hand, the intracellular resveratrol retention in cells treated with MK571 (3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid), a multidrug resistance-associated protein inhibitor, strongly suggests the involvement of this ABC transporter family in the efflux of resveratrol conjugates from human liver.

PMID: 17287390

[bixbyte]

If both of these papers are correct, UGT2B7 only hits the cis form, but it is induced by trans.

Suppose I could temp shut off your stomach's ability to digest with an H2 antagonist?

The RES would be able to pass into your small intestine and raise your plasma levels before your liver conjugates it.

I beat Sirtris' SRT-501 taking a tagamet.