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Buccal delivery superior?


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#1 sUper GeNius

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Posted 13 August 2008 - 04:47 AM


Has someone posted about this yet?

http://en.wikipedia....iki/Resveratrol

"The most efficient way of administering resveratrol in humans appears to be buccal delivery, that is without swallowing, by direct absorption through the inside of the mouth. When 1 mg of resveratrol in 50 mL solution was retained in the mouth for 1 min before swallowing, 37 ng/ml of free resveratrol were measured in plasma 2 minutes later. This level of unchanged resveratrol in blood can only be achieved with 250 mg of resveratrol taken in a pill form.[21]"
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#2 Anthony_Loera

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Posted 13 August 2008 - 12:24 PM

yeah...

that's why we are going ahead with the gum... I actually downloaded the study to verify it.
We will use the micro res, unless something better comes along...

A

Edited by Anthony_Loera, 13 August 2008 - 12:25 PM.


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#3 Anthony_Loera

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Posted 13 August 2008 - 12:54 PM

This is on page 10 of that study:

Posted Image



A

Edited by Anthony_Loera, 13 August 2008 - 01:00 PM.


#4 malbecman

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Posted 13 August 2008 - 05:03 PM

The study is actually reference #22, not #21, on the Wiki entry.......

#5 malbecman

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Posted 13 August 2008 - 05:08 PM

Cool, 14C dosing of humans....... :)


I wonder how a 250mg or 500mg buccal dose would look instead of just 25mgs......

Edited by malbecman, 13 August 2008 - 05:11 PM.


#6 SearchHorizon

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Posted 13 August 2008 - 05:50 PM

I wonder how a 250mg or 500mg buccal dose would look instead of just 25mgs......

I also wonder how 500 mg buccal dose would look if you hold the resv solution in your mouth for 2 or 5 min instead of just 1 min ...

#7 Anthony_Loera

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Posted 13 August 2008 - 06:32 PM

I wonder how a 250mg or 500mg buccal dose would look instead of just 25mgs......

I also wonder how 500 mg buccal dose would look if you hold the resv solution in your mouth for 2 or 5 min instead of just 1 min ...



Probably look like when my 2 year old tries to brush his teeth... a bit messy?

A

#8 edward

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Posted 13 August 2008 - 08:03 PM

yeah...

that's why we are going ahead with the gum... I actually downloaded the study to verify it.
We will use the micro res, unless something better comes along...

A


I always hold my res in my mouth as long before swallowing, furthermore I "mix" my Res HPMC PEG combo in my mouth with water just for good measure (as I have said before I feel a little silly doing this and my wife looks at me like I am insane) My original motivation for mouth mixing was that when I used a hand mixer or blender I always had Res liquid left over sticking to the sides and the blender blades so I didnt want to waste any, but I found when I first started the mouth mixing I got a Res energy buzz like when I first started Res or whenever I have increased my dosage.

I even in a PM to Hedgehog when he was thinking of doing more blood level testing asked him to include a test of just Res held in the mouth. I think Maxwatt also mentioned putting Res under his tongue with some of his Alcohol of choice and letting it dissolve and absorb.


Anthony,

Anyways I would definitely be interested in buying some micronized Res gum assuming the price was right and there was enough Res in each piece and the Price/Gram of Res made sense. Chewing a stick/piece every few hours might be a good socially acceptable way of keeping blood levels up.

Any idea on when the gum will be coming out, how much it will cost and what mg/piece you guys are looking at. Oh and I do hope you plan on using splenda, stevia or some other non nutritive sweetner (or none at all) in the gum.

Oh by the way, you also might want to look into ingredients that would increase the buccal absorption. I know the tobacco industry came up with things for their smokeless tobacco, granted these are probably less than good for you chemicals but I think certain herbs might do some of the same things. I'm thinking some of the peppers a small dose of capsacin (not enough to make it burn) might do the trick, it might also give a little tingle to signal the user that "its working"

Edited by edward, 13 August 2008 - 08:21 PM.


#9 Anthony_Loera

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Posted 13 August 2008 - 08:33 PM

We are looking at Xylitol with possibly a little Stivia... as sweeteners.

Initial consideration was around 50mg-100mg a piece... I am not sure we can add more than this.
Time frame?... 2-3 months (The packaging appears to be the holdup on this...)

I am just not sure about the flavors... and of course, you heard it here first.

cheers!
A

#10 jCole

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Posted 13 August 2008 - 08:36 PM

We are looking at Xylitol with possibly a little Stivia... as sweeteners.

Initial consideration was around 50mg-100mg a piece... I am not sure we can add more than this.
Time frame?... 2-3 months (The packaging appears to be the holdup on this...)

I am just not sure about the flavors... and of course, you heard it here first.

cheers!
A



I loveeee Stevia, sign me up! :)

#11 SearchHorizon

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Posted 14 August 2008 - 01:26 PM

I wonder how a 250mg or 500mg buccal dose would look instead of just 25mgs......

BTW, that is not 25 mg. It is 23 micrograms per ml. Since 50 ml was used, the total amount resv is 1 mg.

It seems one is talking about ~100x increase in plasma level, compared to oral administration.

#12 Hedgehog

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Posted 14 August 2008 - 02:57 PM

Has someone posted about this yet?

http://en.wikipedia....iki/Resveratrol

"The most efficient way of administering resveratrol in humans appears to be buccal delivery, that is without swallowing, by direct absorption through the inside of the mouth. When 1 mg of resveratrol in 50 mL solution was retained in the mouth for 1 min before swallowing, 37 ng/ml of free resveratrol were measured in plasma 2 minutes later. This level of unchanged resveratrol in blood can only be achieved with 250 mg of resveratrol taken in a pill form.[21]"


This group also got about about 17ng/mL just by putting as much resveratrol into water (23mg/L) and drinking it.

Finally, for comparison, t-RES was also administered to mice in the drinking water (23 mg/l, which corresponds to the highest concentration of t-RES that can be dissolved in water). Mice were drinking ad libitum [2.61 ± 0.27 mg t-RES/kg b.wt. per day in mice (n = 12)] for 10 d and then sacrificed (10.00 h). Under these conditions plasma levels of RES were 0.075 ± 0.025 μM (n = 10; at least 99% was in the trans form). This value did not change significantly if mice were sacrificed in the afternoon (16.00 h) (not shown). Thus, it appears that when RES is included in the drinking water a very low basal level in plasma may be expected.


(SEE ATTACHMENT)
Animals were treated with 20 mg t-RES per kg of body weight. In a group of 5 rabbits all time points were determined in each animal. Five rats or mice were used for each time point. Results are means ± SD.

Has anybody done some number crunching to if this study is in line w/ any other animal plasma studies (just by looking at the numbers they seem pretty high). Until then I would not assume to much. Plus is it even possible to get a concentration of resveratrol in 2mins after just putting in your mouth? I don't think any other study has taken a resveratrol plasma time point @ 2mins. If it is really absorbed that fast then the stomach would take it up in a second. I wonder why other studys typically have a lag? Just a few things to ponder while we figure out this study.

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#13 SearchHorizon

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Posted 14 August 2008 - 05:21 PM

If it is really absorbed that fast then the stomach would take it up in a second.

Yes, but anything absorbed through the stomach has to pass through the liver first. Avoiding this first pass through the liver (e.g., via buccal administration, transdermal administration, etc.) allows resveratrol to survive a bit longer and accumulate in plasma.

This issue of avoiding the first pass through the liver is well known among steroid users. To avoid this issue, steroids are injected, applied transdermally, or taken sublingually.

Edited by SearchHorizon, 14 August 2008 - 05:22 PM.


#14 PWAIN

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Posted 15 August 2008 - 01:16 AM

From another thread...

Would it perhaps be a good idea to mix resveratrol with chewing gum and chew throughout the day to get an ongoing stream of res throughtout the day? Sure keep taking the powder/caps but use this aswell.




yeah...

that's why we are going ahead with the gum... I actually downloaded the study to verify it.
We will use the micro res, unless something better comes along...

A


That is what I like about Anthony, he responds to good ideas. :)

Good on you Anthony.

Resvhead

#15 PWAIN

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Posted 15 August 2008 - 01:30 AM

Just thought I should mention that I have been trying buccal method for the last 3 days.

First day, I put around 1/2 a teaspoon of my old 98% powder between cheeks and teeth. Left it there for one and a half hours.
Last 2 days, I have done the same but with a tad more powder and have left it there overnight - small amount left in the mornings.

The main thing I have noticed is that my eczema has flaired up a bit. This just indicated to me that it is working.

The real disadvantage with this is that you wouldn't do it in a social setting. The stark white powder against the teeth is a frightening sight and the powder tends to get on the lips making me look like some sick patient.

This is where I see the gum comming in.... 24 hours non stop elevated blood Resveratrol levels.

Resvhead

#16 Hedgehog

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Posted 15 August 2008 - 01:33 AM

If it is really absorbed that fast then the stomach would take it up in a second.

Yes, but anything absorbed through the stomach has to pass through the liver first. Avoiding this first pass through the liver (e.g., via buccal administration, transdermal administration, etc.) allows resveratrol to survive a bit longer and accumulate in plasma.

This issue of avoiding the first pass through the liver is well known among steroid users. To avoid this issue, steroids are injected, applied transdermally, or taken sublingually.


Transdermal resveratrol has already been tried a few times. With very very little success. This is why i'm so extremely skeptical about this ONE study. If I had time I would try it out on myself in the lab but for the next few months I won't be able to perform any bioavailibity studies. Plus if this really worked shouldn't there be other studies that have tried this. This paper is from 2002. It has been 6 years since it was published.


Free Radic Biol Med. 2002 Aug 1;33(3):387-98.

#17 SearchHorizon

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Posted 15 August 2008 - 02:05 AM

Edited: sorry, see below.

Edited by SearchHorizon, 15 August 2008 - 02:33 AM.


#18 niner

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Posted 15 August 2008 - 02:27 AM

Transdermal resveratrol has already been tried a few times. With very very little success.

Actually, I have not looked into transdermal delivery -- I was talking mostly about possible benefits one may reap if transdermal resv solution is able to make it past one's skin into plasma.

This is why i'm so extremely skeptical about this ONE study. If I had time I would try it out on myself in the lab but for the next few months I won't be able to perform any bioavailibity studies. Plus if this really worked shouldn't there be other studies that have tried this. This paper is from 2002. It has been 6 years since it was published.

All good points, though what the paper suggests is still intriguing.

On a side note, having come from M&M forum, I have had a chance to read discussions related to oral administration of steroids. Some of that involves modifying a molecular structure of a steroid so that, if orally administred, it can make it past one's liver. One result of these ideas was methylating a steroid molecule.

I wonder if it would be possible to modify resveratrol in a similar manner. (I know Acetylation has been mentioned ... but I doubt that is going to work.).

Actually, acetylation has been tried. It worked pretty well, as I recall, although I don't know if it's been used in humans.

Like Hedgehog, I'm also pretty skeptical of this single, six year old study. Resveratrol is absorbed quite well when taken orally, but because it is so rapidly conjugated both in the gut and in the liver, not very much free resveratrol makes it to the plasma. In theory, buccal absorption would bypass not only the gut enzymes but also the first pass through the liver. Circulation is fairly rapid, so that free resveratrol is going to see the liver within a few minutes anyway, though. However, recall that resveratrol binds to human serum albumin. The albumin could soak up the resveratrol that gets in through the buccal route, protecting it from liver enzymes, and shuttling it around the body. This could provide a mechanism whereby buccal administration could "work", although it's somewhat speculative.

#19 SearchHorizon

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Posted 15 August 2008 - 02:31 AM

Transdermal resveratrol has already been tried a few times. With very very little success.


I think issues that are related to transdermal delivery are different from those related to oral delivery or buccal delivery. In transdermal delivery, one has to worry about getting resv molecule to penetrate one's skin and reach plasma. Therefore, one has to worry about using the right transdermal carrier solution, the size of resveratrol molecule, etc. In oral delivery, one has to worry about protecting resv molecules from the liver. In buccal delivery, one probably doesn't need to worry about those issues.

This is why i'm so extremely skeptical about this ONE study. If I had time I would try it out on myself in the lab but for the next few months I won't be able to perform any bioavailibity studies. Plus if this really worked shouldn't there be other studies that have tried this. This paper is from 2002. It has been 6 years since it was published.

All good points, though what the paper suggests is still intriguing.

On a side note, having come from M&M forum, I have had a chance to read discussions related to oral administration of steroids. Some of that involves modifying a molecular structure of a steroid so that, if orally administred, it can make it past one's liver. One result of these ideas was methylating a steroid molecule. As it turns out, methylation works well.

I wonder if it would be possible to modify resveratrol, so that while it is still active in one's body, it is also protected against one's liver to some extent. (I know Acetylation has been mentioned ... but I doubt that is going to work.)

Edited by SearchHorizon, 15 August 2008 - 02:37 AM.


#20 SearchHorizon

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Posted 15 August 2008 - 01:55 PM

Actually, acetylation has been tried. It worked pretty well, as I recall, although I don't know if it's been used in humans.

I should have been more precise -- I meant tri-acetylation.

#21 Hedgehog

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Posted 15 August 2008 - 04:14 PM

Transdermal resveratrol has already been tried a few times. With very very little success.


I think issues that are related to transdermal delivery are different from those related to oral delivery or buccal delivery. In transdermal delivery, one has to worry about getting resv molecule to penetrate one's skin and reach plasma. Therefore, one has to worry about using the right transdermal carrier solution, the size of resveratrol molecule, etc. In oral delivery, one has to worry about protecting resv molecules from the liver. In buccal delivery, one probably doesn't need to worry about those issues.

This is why i'm so extremely skeptical about this ONE study. If I had time I would try it out on myself in the lab but for the next few months I won't be able to perform any bioavailibity studies. Plus if this really worked shouldn't there be other studies that have tried this. This paper is from 2002. It has been 6 years since it was published.

All good points, though what the paper suggests is still intriguing.

On a side note, having come from M&M forum, I have had a chance to read discussions related to oral administration of steroids. Some of that involves modifying a molecular structure of a steroid so that, if orally administred, it can make it past one's liver. One result of these ideas was methylating a steroid molecule. As it turns out, methylation works well.

I wonder if it would be possible to modify resveratrol, so that while it is still active in one's body, it is also protected against one's liver to some extent. (I know Acetylation has been mentioned ... but I doubt that is going to work.)


Yes but then if you change the structure you probably won't have the same biological functions. The hydroxyl groups are critical for H bonding. Resveratrol has many targets and deleting or adding functional groups will either stop effecting x,y,z proteins and start effecting a,b,c proteins. Unless you have studies that adding/deleting a functional group will still activate certain enzymes such as SIRTA, PCG-(x,y,z). Plus you will have no idea if will actually hurt a person. Hince creating a new molecule will be frowned upon and the FDA will stick it to you like no other.

I guess the point i'm trying to make is that you can still measure a resveratrol analog in the plasma but it is an analog and should not be consider a 1:1 to resveratrol unless there have been studies indicating this.

Plus there is a whole theory that states that the metabolites could be converted back to resveratrol in the cells. There is also a little proof of this concept. Anyways, just trying to show the otherside. :)

#22 sUper GeNius

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Posted 15 August 2008 - 04:24 PM

Transdermal resveratrol has already been tried a few times. With very very little success.

Actually, I have not looked into transdermal delivery -- I was talking mostly about possible benefits one may reap if transdermal resv solution is able to make it past one's skin into plasma.

This is why i'm so extremely skeptical about this ONE study. If I had time I would try it out on myself in the lab but for the next few months I won't be able to perform any bioavailibity studies. Plus if this really worked shouldn't there be other studies that have tried this. This paper is from 2002. It has been 6 years since it was published.

All good points, though what the paper suggests is still intriguing.

On a side note, having come from M&M forum, I have had a chance to read discussions related to oral administration of steroids. Some of that involves modifying a molecular structure of a steroid so that, if orally administred, it can make it past one's liver. One result of these ideas was methylating a steroid molecule.

I wonder if it would be possible to modify resveratrol in a similar manner. (I know Acetylation has been mentioned ... but I doubt that is going to work.).

Actually, acetylation has been tried. It worked pretty well, as I recall, although I don't know if it's been used in humans.

Like Hedgehog, I'm also pretty skeptical of this single, six year old study. Resveratrol is absorbed quite well when taken orally, but because it is so rapidly conjugated both in the gut and in the liver, not very much free resveratrol makes it to the plasma. In theory, buccal absorption would bypass not only the gut enzymes but also the first pass through the liver. Circulation is fairly rapid, so that free resveratrol is going to see the liver within a few minutes anyway, though. However, recall that resveratrol binds to human serum albumin. The albumin could soak up the resveratrol that gets in through the buccal route, protecting it from liver enzymes, and shuttling it around the body. This could provide a mechanism whereby buccal administration could "work", although it's somewhat speculative.


The intriguing thing is that, this buccal info, together with the recent study showing lower doses of r-res being effective, this could explain the French Paradox.

#23 DaffyDuck

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Posted 15 August 2008 - 05:19 PM

The intriguing thing is that, this buccal info, together with the recent study showing lower doses of r-res being effective, this could explain the French Paradox.


This would bode very well for wine tasters who like to swish it around in their mouth then spit it out.

#24 SearchHorizon

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Posted 15 August 2008 - 06:14 PM

Plus there is a whole theory that states that the metabolites could be converted back to resveratrol in the cells. There is also a little proof of this concept. Anyways, just trying to show the otherside. :)

I suppose this depends on the amount of enzyme for reverting inactivated resv. Is it possible that normal cells have certain amount of this enzyme? We know that certain cancerous cells do ...

#25 PWAIN

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Posted 19 August 2008 - 12:08 AM

We are looking at Xylitol with possibly a little Stivia... as sweeteners.


Have you considered Erythritol as a sweetner. When taking an unbiased opinion, it seems to offer the best. May be worth a bit of research.


http://en.wikipedia....wiki/Erythritol

http://en.wikipedia....i/Sugar_alcohol

As an exception, erythritol is actually absorbed in the small intestine and excreted unchanged through urine, so it has no side effects at typical levels of consumption.



Erythritol ((2R,3S)-butane-1,2,3,4-tetraol) is a natural sugar alcohol (a type of sugar substitute) which has been approved for use in the United States[1] and throughout much of the world. It occurs naturally in fruits and fermented foods [2]. At industrial level, it is produced from glucose by fermentation with a yeast, Moniliella pollinis[3]. It is 60-70% as sweet as table sugar yet it is almost non-caloric, does not affect blood sugar, does not cause tooth decay, and is absorbed by the body, therefore unlikely to cause gastric side effects unlike other sugar alcohols. Under U.S. Food and Drug Administration (FDA) labeling requirements, it has a caloric value of 0.2 calories per gram (95% less than sugar and other carbohydrates), but some countries like Japan label it at 0 calories. European legislation actually considers it at 2.4 kcal/g but pending discussion will certainly achieve a 0 kcal/g caloric value by 2009.


Erythritol and human digestion
In the body, erythritol is absorbed into the bloodstream in the small intestine, and then for the most part excreted unchanged in the urine. Because erythritol is normally absorbed before it enters the large intestine, it does not normally cause laxative effects as are often experienced after over-consumption of other sugar alcohols (such as xylitol and maltitol) and most people will consume erythritol with no side effects. This is a unique characteristic, as other sugar alcohols are not absorbed directly by the body in this manner, and consequently are more prone to causing gastric distress.


Note the comment about Xylitol.

#26 sdxl

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Posted 19 August 2008 - 12:56 AM

Erythritol doesn't have the extensive studies done on oral health as xylitol has. It's less sweet, so you need more. It's more expensive compared to xylitol. Most people do not react to the relative small amount of xylitol in a gum.

#27 tintinet

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Posted 19 August 2008 - 06:36 PM

You'd consider Wikipedia unbiased? Big assumption, in my biased opinion! :)

#28 PWAIN

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Posted 19 August 2008 - 11:52 PM

You'd consider Wikipedia unbiased? Big assumption, in my biased opinion! :)


Sorry, that was unclear. I meant that I was unbiased as I had no preferences prior to my investigation. My investigation included a lot more than good ole wikipedia. Wikipedia just seemed to sum up what I read elsewhere. As I say, I am open to factual correction but for instance, lets pick this comment apart:

Erythritol doesn't have the extensive studies done on oral health as xylitol has.
Probably true but from what I read, it does provide for oral health just not so many studies so this sounds like an attempt at distraction.

It's less sweet, so you need more.
This is true as far as I can tell. Give the small amount likely to be needed for gum would it be a problem. Possibly - needs more investigation.

It's more expensive compared to xylitol.
Can't say for sure if this is true or not. I do know that I can buy a single kilo lot for a fairly trivial amount as compared to the likely end cost of gum. This makes me think that this comment is either an in general comment or heavilly biased - ie ignoring the fact that for gum the cost is too trivial to be an issue.

Most people do not react to the relative small amount of xylitol in a gum.
This is a defensive comment. It doesn't really matter that they do or don't react, the issue is that they might and that there is an alternative that this won't happen with. If the alternative is worse in some other area, then this advantage of Erythritol is diminished.

Basically I looked at all the listed available sweetners and just felt that Erythritol seemed pretty good and wondered why it is not used more extensively. It seems to me to be a highly protected market with a huge amount of vested intrests coming into play. This means that the best product may not always be used and I see it as being up to us the end consumer to demand it.

Now if you can show me some good reason why Erythritol is not better than most of the competition, I'll happily change my view point but I will not be swayed by irrational belief systems brought about by marketing more than science. Selection based on factual criteria presented is not bias, just decision making. I defend my descisions until such time as new facts make the decision incorrect.

#29 Hedgehog

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Posted 28 August 2008 - 01:22 AM

Circulation is fairly rapid, so that free resveratrol is going to see the liver within a few minutes anyway, though. However, recall that resveratrol binds to human serum albumin. The albumin could soak up the resveratrol that gets in through the buccal route, protecting it from liver enzymes, and shuttling it around the body. This could provide a mechanism whereby buccal administration could "work", although it's somewhat speculative.



IF albumin did hang onto resveratrol you would probably seen a long half life in plasma studies in mice/rats. However, all we notice is a very quick spike and rapid elimination. But it might reach more cells like you suggested and maybe part of the rapid elimination is that it is actually entering into to cells... However, every speculative.

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#30 stevei

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Posted 19 February 2009 - 12:59 AM

We are looking at Xylitol with possibly a little Stivia... as sweeteners.

Initial consideration was around 50mg-100mg a piece... I am not sure we can add more than this.
Time frame?... 2-3 months (The packaging appears to be the holdup on this...)

I am just not sure about the flavors... and of course, you heard it here first.

Hi Anthony, I was just wondering what happened to this idea? I can't see a gum product on your website, and wondered if you're still working on it, or if the idea was dropped for some reason?




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