1084 replies to this topic

[missminni]

Glucosamine might not be redundant. It inhibits nf_Kappa B. As do creatine and silymarin. as well as resveratrol.

It was so effective when I upped the dose I can't imagine not giving it to him.
When people tell me glucosamine doesn't help them it's inevitably because they are not taking enough.
They think 1500 mg is the right amount to take. If you weigh 45 lbs, it might be, but most people weigh
well over 150 lbs, and at that point 5 grams is necessary for results but most people just take the 1500 mg
dosage recommended on the label. Even if they double that and take 3000 mg, that would still only
be effective for someone who is 100 lbs. It's all about the dosage.

[niner]

ps: Everclear is 95%.

In some states the highest proof one can sell is 151, so in those places Everclear is 75% alcohol (150 proof).

edited for speling and gramer

Wow, I never knew that. In my state, it's zero proof. They consider it too hazardous for us bumpkins. I make periodic runs across the border to obtain it. That's probably illegal too...

[niner]

Why have we seemed to abandon the transdermal application of resveratrol in DMSO? It seems like bypassing the intestine's metabolizing enzymes would be a huge benefit to getting a larger peak serum resveratrol concentration. I mean its got to be better just to deal with the liver metabolizing resveratrol that BOTH the intestines and the liver.

Well, I'm kind of a voice in the wilderness on this, but I believe the best use of transdermal resveratrol is to dose a particular part of the body, like a joint, that is close to the surface. For systemic dosing, you just can't get enough resveratrol through the skin to make that big of an impact. Even with permeation enhancers like DMSO, the flux is quite small. Dodging the intestine is good, and skipping the first pass throught the liver is good too, but the liver is so incredibly efficient at conjugating the resveratrol on the second pass that it just doesn't matter with the small amounts that you can get transdermally. Transdermal delivery for systemic dosing is only used with drugs that are extremely potent, like fentanyl, where the total dose is measured in micrograms. Transdermal LSD would probably work great with the right solvent.

[sUper GeNius]

Why have we seemed to abandon the transdermal application of resveratrol in DMSO? It seems like bypassing the intestine's metabolizing enzymes would be a huge benefit to getting a larger peak serum resveratrol concentration. I mean its got to be better just to deal with the liver metabolizing resveratrol that BOTH the intestines and the liver.

Well, I'm kind of a voice in the wilderness on this, but I believe the best use of transdermal resveratrol is to dose a particular part of the body, like a joint, that is close to the surface. For systemic dosing, you just can't get enough resveratrol through the skin to make that big of an impact. Even with permeation enhancers like DMSO, the flux is quite small. Dodging the intestine is good, and skipping the first pass throught the liver is good too, but the liver is so incredibly efficient at conjugating the resveratrol on the second pass that it just doesn't matter with the small amounts that you can get transdermally. Transdermal delivery for systemic dosing is only used with drugs that are extremely potent, like fentanyl, where the total dose is measured in micrograms. Transdermal LSD would probably work great with the right solvent.

Been there done that. Solvent? The stuff goes write through the skin on its own. That's how its hallucinogenic properties were discovered.

[sUper GeNius]

ps: Everclear is 95%.

In some states the highest proof one can sell is 151, so in those places Everclear is 75% alcohol (150 proof).

edited for speling and gramer

Wow, I never knew that. In my state, it's zero proof. They consider it too hazardous for us bumpkins. I make periodic runs across the border to obtain it. That's probably illegal too...

Hey, pull a Kitty Dukakis. Try some wood alcohol. A little goes a lonnnggg way...

[health_nutty]

Why have we seemed to abandon the transdermal application of resveratrol in DMSO? It seems like bypassing the intestine's metabolizing enzymes would be a huge benefit to getting a larger peak serum resveratrol concentration. I mean its got to be better just to deal with the liver metabolizing resveratrol that BOTH the intestines and the liver.

Well, I'm kind of a voice in the wilderness on this, but I believe the best use of transdermal resveratrol is to dose a particular part of the body, like a joint, that is close to the surface. For systemic dosing, you just can't get enough resveratrol through the skin to make that big of an impact. Even with permeation enhancers like DMSO, the flux is quite small. Dodging the intestine is good, and skipping the first pass throught the liver is good too, but the liver is so incredibly efficient at conjugating the resveratrol on the second pass that it just doesn't matter with the small amounts that you can get transdermally. Transdermal delivery for systemic dosing is only used with drugs that are extremely potent, like fentanyl, where the total dose is measured in micrograms. Transdermal LSD would probably work great with the right solvent.

Ah ha, the fact I was missing is a lot less resveratrol penatrates the skin versus 70% absorption rate of oral administration. Gotcha.

[missminni]

Why have we seemed to abandon the transdermal application of resveratrol in DMSO? It seems like bypassing the intestine's metabolizing enzymes would be a huge benefit to getting a larger peak serum resveratrol concentration. I mean its got to be better just to deal with the liver metabolizing resveratrol that BOTH the intestines and the liver.

Well, I'm kind of a voice in the wilderness on this, but I believe the best use of transdermal resveratrol is to dose a particular part of the body, like a joint, that is close to the surface. For systemic dosing, you just can't get enough resveratrol through the skin to make that big of an impact. Even with permeation enhancers like DMSO, the flux is quite small. Dodging the intestine is good, and skipping the first pass throught the liver is good too, but the liver is so incredibly efficient at conjugating the resveratrol on the second pass that it just doesn't matter with the small amounts that you can get transdermally. Transdermal delivery for systemic dosing is only used with drugs that are extremely potent, like fentanyl, where the total dose is measured in micrograms. Transdermal LSD would probably work great with the right solvent.

I agree. It impacts immediately that way. But I still get an overall noticeable result from trans-dermal application, especially if done just prior to working out.

[bixbyte]

I am still uncertain, should I add Quercetin to my daily RES combination regiment??


Please read this Sardi written news release:

http://www.earthtime...se,253393.shtml




Consumers Being Misled Over Bioavailabity of Resveratrol

SAN DIMAS, Calif., Jan. 9 /PRNewswire/ -- In response to consumer inquiries emanating from a misleading press release issued by a competing dietary supplement company, which falsely claims quercetin inhibits the bioavailability of resveratrol, Longevinex® provides the following information.
"Quercetin is one of the secrets of red wine. It works in tandem with resveratrol to make it more instantly available to tissues throughout the body," says Bill Sardi, spokesperson for Longevinex®, maker of a leading brand resveratrol dietary supplement.

A recently issued press release by a competing dietary supplement company, falsely claims quercetin inhibits bioavailability of resveratrol. "With no scientific substantiation for their claim, they are misleading many consumers," says Sardi.
"This distorts the science," says Sardi. Eight years ago researchers in Italy showed that quercetin is about ten times better at inhibiting immediate attachment of resveratrol to sulfur and glucuronate molecules in the liver than other molecules found in red wine and therefore "improves the bioavailability of resveratrol." Interested consumers can examine the evidence for themselves at the National Library of Medicine, here: [Xenobiotica 2000 Sep; 30(9):857-66 (http://www.ncbi.nlm....=EntrezSystem2. PEntrez.Pubmed.Pubmed_ResultsPanel.Pubm); 2000 Nov; 30(11):1047-54 (http://www.ncbi.nlm....=EntrezSystem2. PEntrez.Pubmed.Pubmed_ResultsPanel.Pubm); 2000 Jun; 30(6):609-17 (http://www.ncbi.nlm....=EntrezSystem2. PEntrez.Pubmed.Pubmed_ResultsPanel.Pubm)]
Sardi asks: "If there is a question over bioavailability of resveratrol when provided with quercetin, then how did Longevinex®, which provides both molecules, produce measurable declines in markers of oxidation and inflammation in endurance athletes in the first successful human study of a resveratrol supplement, at doses far lower than recommended by producers of resveratrol supplements that contain resveratrol only?" A press release describing the study is found here (http://mediaserver.p...d/571938/pr.pdf).
In that study, Longevinex® was found to be biologically active at dose (~120 milligrams) far less than what was used in a recent mouse study (1565 mg equivalent human dose), and far less than is recommended by other brands of resveratrol that do not contain quercetin.
"This is no surprise, since numerous studies indicate quercetin works synergistically to enhance the biological action of resveratrol. The effect is both additive and multiple," says Sardi. [Cancer Letters 2005 Feb 10; 218(2):141-51 (http://www.ncbi.nlm....=EntrezSystem2. PEntrez.Pubmed.Pubmed_ResultsPanel.Pubm); Journal Agriculture Food Chemistry 2005 Mar 23; 53(6):2015-21 (http://www.ncbi.nlm....l=EntrezSystem2 .PEntrez.Pubmed.Pubmed_ResultsPanel.Pub).
What's to hide?
While there is scientific evidence that quercetin makes resveratrol more immediately available, there is no evidence for a claim by a competing company that their undisclosed technology doubles the absorption and utilization of resveratrol. Consumers need to be wary unless independent laboratory tests confirm this claim. "Research studies already estimate about 70% of resveratrol is absorbed, so I don't know how you double that number?" asks Sardi. [Drug Metabolism Disposition 2004 Dec; 32(12):1377-82 (http://www.ncbi.nlm....=EntrezSystem2. PEntrez.Pubmed.Pubmed_ResultsPanel.Pubm)]
Instant and long-term bioavailability
Interested consumers need to distinguish between instant and long-term bioavailability of resveratrol.
"Quercetin can be mischaracterized," says Sardi, "since it allows resveratrol more passes through the liver before it is finally conjugated (attached to) sulfur and glucuronate molecules. Eventually, all resveratrol is metabolized in the liver. Once bound to these molecules, resveratrol is, for a time, not biologically active, but this process prolongs the life of resveratrol in the blood circulation up to 9 hours. Otherwise, resveratrol has a short half life (time it takes for 50% to degrade), about 14 minutes."
"Nature takes over from there, producing an unlocking enzyme called glucuronidase, which is abundant at sites of inflammation, infection and malignancy. This enzyme releases unbound (free) resveratrol at the right time and place. It is nature's drug delivery system," says Sardi. This was all explained back in 2003-2004. [Biochemical Journal 374 (Pt 1):157-63, 2003 (http://www.biochemj....4/bj3740157.htm); J Pharmaceutical Sciences 93:2448-2457, 2004 (http://www3.intersci....wiley.com/cgi- bin/abstract/109572576/ABSTRACT?CRETRY=1&SRETRY=0)]
Dosage concerns
Citing a recent human study where a single high-dose (500-5000 milligrams) of resveratrol did not produce a serious side effect, Biotivia claims their recommendation to take mega-dose resveratrol should be of no concern, but high-dose resveratrol like Biotivia recommends was not absolutely safe. There were side effects with just one mega-dose. There were 51 reported side effects (all transient and reversible) among 40 healthy volunteers, 12 of them at the 500 mg dose, and 20 at the 1000 mg dose. These side effects included abnormal blood tests, over-thinning of the blood, loose stool, headache, and anxiety reactions. [Cancer Epidemiology Biomarkers Prevention 2007 Jun; 16(6):1246-52
For more answers to questions about potency and bioavailability of resveratrol, consumers are invited to visit: http://www.longevinex.com/

[bixbyte]

For more answers to questions about potency and bioavailability of resveratrol, consumers are invited to visit: http://www.longevinex.com/

Quercetin added for more immediate bioavailability*
*Xenobiotica.2000 Jun;30(6):609-17.

Sulphation of resveratrol, a natural product present in grapes and wine, in the human liver and duodenum. Department of Neurosciences, Medical School, Pisa, Italy.

1. Resveratrol, a polyphenolic compound present in grapes and wine, has beneficial effects against cancer and protective effects on the cardiovascular system. It is present in the diet, and the hepatic and duodenal sulphation might limit the bioavailability of this compound. The aim was to study the sulphation of resveratrol in the human liver and duodenum. 2. A simple and reproducible radiometric assay for resveratrol sulphation was developed. It employed 3'-phosphoadenosine-5'-phosphosulphate-[35S] as the sulphate donor and the rates of resveratrol sulphation (mean +/- SD, pmol/min/mg cytosolic protein) were 90 +/- 21 (liver, n = 10) and 74 +/- 60 (duodenum, n = 10, p = 0.082). 3. Resveratrol sulphotransferase followed Michaelis-Menten kinetics and Km (mean +/- SD; microM) was 0.63 +/- 0.03 (liver, n = 5) and 0.50 +/- 0.26 (duodenum, n = 5, p = 0.39) and Vmax (mean +/- SD, pmResveratrol sulphation was inhibited by the flavonoid quercetinol/min/mg cytosolic protein) were 125 +/- 31 (liver, n = 5) and 129 +/- 85 (duodenum, n = 5, p = 0.62). 4. , by mefenamic acid and salicylic acid, two commonly used non-steroidal anti-inflammatory drugs. IC50 of resveratrol sulphation for quercetin was 12 +/- 2 pM (liver) and 15 +/- 2 pM (duodenum), those for mefenamic acid were 24 +/- 3 nM (liver) and 11 +/- 0.6 nM (duodenum), and those for salicylic acid were 53 +/- 9 microM (liver) and 66 +/- 4 microM (duodenum). 5. The potent inhibition of resveratrol sulphation by quercetin, a flavonoid present in wine, fruits and vegetables, suggests that compounds present in the diet may inhibit the sulphation of resveratrol, thus improving its bioavailability.



Now we visit the longevinex website and discover three inexpensive compounds slow the liver from processing RSV into forms that are not useful.
Guess what?
A baby aspirin will do approx half the job of Quercitin according to this study.

ANYBODY?????

[maxwatt]

...(snip)...

Now we visit the longevinex website and discover three inexpensive compounds slow the liver from processing RSV into forms that are not useful.
Guess what?
A baby aspirin will do approx half the job of Quercitin according to this study.

ANYBODY?????

Stick with aspirin, or just take enough resveratrol to swamp the liver processing mechanism.

Quercetin does not prolong the lifespan of C. elegans, the worm used for longevity tests, were resveratrol does. One of Quercetins metabolites inhibits SirT1. My own experience with quercetin were that 250 mg seemed to completely negate the effect of one to two grams of resveratrol, crudely measured via resveratrol's inhibitory effect on nf-Kappa B; resveratrol alone controlled pain and swelling in my big toe, adding quercetin to my regime resulted in pain and swelling within three days. Cessation of quercetin and the pain and swelling receeded.

I believe the amount of quercetin in a glass of citrus juice would be all you need for some inhibition of sulfonation of resveratrol, without blocking the action of Sirt1. (10 to 30 mg I would estimate.) But 250 mg of quercetin was definitely counterproductive for me.

[niner]

IC50 of resveratrol sulphation for quercetin was 12 +/- 2 pM (liver) and 15 +/- 2 pM (duodenum), those for mefenamic acid were 24 +/- 3 nM (liver) and 11 +/- 0.6 nM (duodenum), and those for salicylic acid were 53 +/- 9 microM (liver) and 66 +/- 4 microM (duodenum).

Now we visit the longevinex website and discover three inexpensive compounds slow the liver from processing RSV into forms that are not useful.
Guess what?
A baby aspirin will do approx half the job of Quercitin according to this study.

We talked about this a while back. Note the units of the IC50s: quercetin is picomolar while salicylic acid is micromolar. So that's a factor of a million, but it's more complicated than that. You'll need more than a baby aspirin, but not more than a normal therapeutic dose, if I remember correctly. Taking that much aspirin every day for the rest of your life is a good way to ensure that the rest of your life isn't so long, though. It has a tendency to eventually cause GI bleeds. Quercetin has its own problems. It gets conjugated just like resveratrol. It induces (upregulates) the very conjugative enzymes that you're trying to inhibit. Maxwatt finds that his toe hurts more when he takes it. If someone would do the damn pharmacokinetic experiments; resveratrol PK in humans with and without quercetin with a recheck after taking quercetin daily for a long time, then we'd have the data we really need to sort this one out. At this point in time I can neither confirm nor deny it's efficacy. Seems like it ought to work but I'd like to see data. I'd also like to include net SIRT activation in that data.

[niner]

Stick with aspirin, or just take enough resveratrol to swamp the liver processing mechanism.

Quercetin does not prolong the lifespan of C. elegans, the worm used for longevity tests, were resveratrol does. One of Quercetins metabolites inhibits SirT1. My own experience with quercetin were that 250 mg seemed to completely negate the effect of one to two grams of resveratrol, crudely measured via resveratrol's inhibitory effect on nf-Kappa B; resveratrol alone controlled pain and swelling in my big toe, adding quercetin to my regime resulted in pain and swelling within three days. Cessation of quercetin and the pain and swelling receeded.

I believe the amount of quercetin in a glass of citrus juice would be all you need for some inhibition of sulfonation of resveratrol, without blocking the action of Sirt1. (10 to 30 mg I would estimate.) But 250 mg of quercetin was definitely counterproductive for me.

Hi Maxwatt, you snuck in there while I was composing the next message. I agree about the dietary quercetin, and note that this is about what you find in Sardi's Longevinex- 25mg. Sardi put out a press release talking about a human trial with Longevinex. It was done by a guy at Appalachian State University. (not making it up...) It's due to be reported at a conference in february, no mention of publication yet. Anyway, they found some apparently significant effects on inflammation and markers of oxidation in athletes, using a relatively low dose. It actually sounds pretty interesting.

[bixbyte]

You'll need more than a baby aspirin, but not more than a normal therapeutic dose, if I remember correctly. Taking that much aspirin every day for the rest of your life is a good way to ensure that the rest of your life isn't so long, though.

That is why we try one baby 81 Mg aspirin a day, minutes prior to the RSV dose.
I do not think a single aspirin dose will cause any GI harm.
But will prevent the RSV from liver processing.

YES - NO?

[niner]

You'll need more than a baby aspirin, but not more than a normal therapeutic dose, if I remember correctly. Taking that much aspirin every day for the rest of your life is a good way to ensure that the rest of your life isn't so long, though.

That is why we try one baby 81 Mg aspirin a day, minutes prior to the RSV dose.
I do not think a single aspirin dose will cause any GI harm.
But will prevent the RSV from liver processing.

YES - NO?

NO. A baby aspirin will give you about a 30 uM peak plasma level, one hour after you take it. The IC50 for sulfation inhibition is about 60 uM. You need to be there to cut the sulfation in half, but what you really want is more than half because half won't help much. You also want to keep the salicylic acid at or above that level for a couple hours after you take the res. By definition, you're only at the peak level very briefly. I think to get what you want, you'll need at least one regular size (325 mg) aspirin, preferably two. You should take it about 30-60 minutes before the res. Then, yeah, you should get some inhibition of sulfation. That's more aspirin than I would want to take long term.

[bixbyte]

NO. A baby aspirin will give you about a 30 uM peak plasma level, one hour after you take it. The IC50 for sulfation inhibition is about 60 uM. You need to be there to cut the sulfation in half, but what you really want is more than half because half won't help much. You also want to keep the salicylic acid at or above that level for a couple hours after you take the res. By definition, you're only at the peak level very briefly. I think to get what you want, you'll need at least one regular size (325 mg) aspirin, preferably two. You should take it about 30-60 minutes before the res. Then, yeah, you should get some inhibition of sulfation. That's more aspirin than I would want to take long term.

Hey Niner,

30 micro Moles peak or approx 25% Inhibition of sulfation by taking one 81 MG baby aspirin, half to one hour before RSV dose?
Or do I have to take one baby aspirin every couple hours to maintain this peak?

[niner]

NO. A baby aspirin will give you about a 30 uM peak plasma level, one hour after you take it. The IC50 for sulfation inhibition is about 60 uM. You need to be there to cut the sulfation in half, but what you really want is more than half because half won't help much. You also want to keep the salicylic acid at or above that level for a couple hours after you take the res. By definition, you're only at the peak level very briefly. I think to get what you want, you'll need at least one regular size (325 mg) aspirin, preferably two. You should take it about 30-60 minutes before the res. Then, yeah, you should get some inhibition of sulfation. That's more aspirin than I would want to take long term.

Hey Niner,

30 micro Moles peak or approx 25% Inhibition of sulfation by taking one 81 MG baby aspirin, half to one hour before RSV dose?
Or do I have to take one baby aspirin every couple hours to maintain this peak?

The percent inhibition changes very rapidly with concentration around the 50% point. That's the steepest part of the curve. So instead of getting 25% inhibition at 30uM, you might be getting 5%. Also, the peak level is very transient, so you really need a bigger dose in order to get much out of it. It's frustrating that the dose you need for this is maybe 8-10 times as much as the 81mg we'd like to be taking.

[sUper GeNius]

NO. A baby aspirin will give you about a 30 uM peak plasma level, one hour after you take it. The IC50 for sulfation inhibition is about 60 uM. You need to be there to cut the sulfation in half, but what you really want is more than half because half won't help much. You also want to keep the salicylic acid at or above that level for a couple hours after you take the res. By definition, you're only at the peak level very briefly. I think to get what you want, you'll need at least one regular size (325 mg) aspirin, preferably two. You should take it about 30-60 minutes before the res. Then, yeah, you should get some inhibition of sulfation. That's more aspirin than I would want to take long term.

Hey Niner,

30 micro Moles peak or approx 25% Inhibition of sulfation by taking one 81 MG baby aspirin, half to one hour before RSV dose?
Or do I have to take one baby aspirin every couple hours to maintain this peak?

The percent inhibition changes very rapidly with concentration around the 50% point. That's the steepest part of the curve. So instead of getting 25% inhibition at 30uM, you might be getting 5%. Also, the peak level is very transient, so you really need a bigger dose in order to get much out of it. It's frustrating that the dose you need for this is maybe 8-10 times as much as the 81mg we'd like to be taking.

Hmm. Suppose I rub the aspirin in using DMSO?? ; )

[bixbyte]

The percent inhibition changes very rapidly with concentration around the 50% point. That's the steepest part of the curve. So instead of getting 25% inhibition at 30uM, you might be getting 5%. Also, the peak level is very transient, so you really need a bigger dose in order to get much out of it. It's frustrating that the dose you need for this is maybe 8-10 times as much as the 81mg we'd like to be taking.

So the yield curve is not linear, Do you have the graph?
Realize taking two baby aspirins might raise my RSV sulfation inhibition 5 to 10 %
Quite inexpensive, I bought 60 enteric coated aspirins for a Buck at the dollar store.
Comes out to a dollar a month!
Plus the added benefit that baby aspirins prevent heart attacks.
A Great Investment

[bixbyte]

Hmm. Suppose I rub the aspirin in using DMSO?? ; )

Easier yet and almost nontoxic unless you cover your entire body with this creme.
Only one known overdose case ever recorded.

30% Methyl Salicylate creme otherwise known as Muscle Rub at the Dollar Store

I have been using Muscle Rub (Ben Gay) and similar products for a dozen years, I suffer from Degenerative Disk Disease.
This is the only way I can take megadoses of aspirin without burning out my stomach.
That is why I feel the Resveratrol so well.

FWIW, I had Organic Chem in college chem.
I have made aspirin, tylenol and Methyl Salicylate in organic lab.
Did you know that Aspirin and Methyl Salicylate are two different methods to deliver the same analgesic?

Edited by bixbyte, 01 February 2008 - 01:49 AM.

[health_nutty]

Hmm. Suppose I rub the aspirin in using DMSO?? ; )

Easier yet and almost nontoxic unless you cover your entire body with this creme.
Only one known overdose case ever recorded.

30% Methyl Salicylate creme otherwise known as Muscle Rub at the Dollar Store

I have been using Muscle Rub (Ben Gay) and similar products for a dozen years, I suffer from Degenerative Disk Disease.
This is the only way I can take megadoses of aspirin without burning out my stomach.
That is why I feel the Resveratrol so well.

THANK YOU SO MUCH!

Well, the question is how much aspirin gets in our bloodstream from topical application? Niner?

[niner]

Hmm. Suppose I rub the aspirin in using DMSO?? ; )

Easier yet and almost nontoxic unless you cover your entire body with this creme.
Only one known overdose case ever recorded.

30% Methyl Salicylate creme otherwise known as Muscle Rub at the Dollar Store

I have been using Muscle Rub (Ben Gay) and similar products for a dozen years, I suffer from Degenerative Disk Disease.
This is the only way I can take megadoses of aspirin without burning out my stomach.
That is why I feel the Resveratrol so well.

THANK YOU SO MUCH!

Well, the question is how much aspirin gets in our bloodstream from topical application? Niner?

If it's like everything else, not very much. It's a fairly polar molecule, so I wouldn't expect it to transdermally absorb very well. (Aspirin, that is- methyl salicylate will get in better) Also, as if that's not bad enough news (sorry bixbyte) methyl salicylate is the methyl ester of salicylic acid, and that will not hydrolyze very well in the body. (It better not, if you want to keep your eyesight...) Now, methyl salicylate may or may not have similar activity in terms of inhibiting sulfotransferases as salicylic acid, but there's no guarantee there. My guess would be not as good.

[bixbyte]

If it's like everything else, not very much. It's a fairly polar molecule, so I wouldn't expect it to transdermally absorb very well. (Aspirin, that is- methyl salicylate will get in better) Also, as if that's not bad enough news (sorry bixbyte) methyl salicylate is the methyl ester of salicylic acid, and that will not hydrolyze very well in the body. (It better not, if you want to keep your eyesight...) Now, methyl salicylate may or may not have similar activity in terms of inhibiting sulfotransferases as salicylic acid, but there's no guarantee there. My guess would be not as good.

Niner,


MY GUESS is you are Guessing or do not know that Methyl salicylate easily hydrolyzes to Salicylic Acid on the skin?

I had organic chem in college.

The Book I sited is my college organic chem.
Methyl Salicylate is one of the many expirements.

Introduction to Organic Laboratoy Technique
by PAVIA LAMPMAN and KRIZ.

(my book is available on amazon)

My college organic chem Lab Book:


The medicinal character is probably due to the fact methyl salicylate is easily hydrolyzed to Salicylic acid....

Methyl Salicylate can be taken internally or absorbed through the skin. Thus it finds much use in liniment preparations. When applied to the skin it produces a mild burning or soothing sensation, which is probably due to the action of its phenolic hydroxyl group. The ester also has a pleasant odor, and is used to a minor extent as a flovoring principle.

Edited by bixbyte, 01 February 2008 - 09:27 PM.

[niner]

If it's like everything else, not very much. It's a fairly polar molecule, so I wouldn't expect it to transdermally absorb very well. (Aspirin, that is- methyl salicylate will get in better) Also, as if that's not bad enough news (sorry bixbyte) methyl salicylate is the methyl ester of salicylic acid, and that will not hydrolyze very well in the body. (It better not, if you want to keep your eyesight...) Now, methyl salicylate may or may not have similar activity in terms of inhibiting sulfotransferases as salicylic acid, but there's no guarantee there. My guess would be not as good.

MY GUESS is you are Guessing or do not know that Methyl salicylate easily hydrolyzes to Salicylic Acid on the skin?

My college Lab Book:

The medicinal character is probably due to the fact methyl salicylate is easily hydrolyzed to Salicylic acid....

Methyl Salicylate can be taken internally or absorbed through the skin. Thus it finds much use in liniment preparations. When applied to the skin it produces a mild burning or soothing sensation, which is probably due to the action of its phenolic hydroxyl group. The ester also has a pleasant odor, and is used to a minor extent as a flovoring principle.

Bix, I was talking about transdermal absorption of Aspirin, not methyl salicylate at the top. Regarding methyl salicylate, you are correct. It does mostly hydrolyze, so I was wrong about that. This means that you are ingesting a mole of methanol for every mole of methyl salicylate that you consume, at least with an oral dose. A report at inchem.org has the acceptable daily intake of methyl salicylate for humans at a fairly low 0.5 mg/kg. The LD50 for various animals is substantially higher, on the order of 1-2 gm/kg. The lowest dose of methanol I found leading to blindness in humans was 0.1 mL/kg, so that would be a lot of methyl salicylate, about 24 grams for a 70kg adult. I must have been conditioned over the years to think of methanol as highly toxic; the anti-Aspartame crowd champions this concept.

Nevertheless, as a way of getting a high enough systemic level of salicylic acid to inhibit sulfation to any noticeable extent, I don't think transdermal methyl salicylate is going to do it, unless you cover a lot of skin.

http://jrnlappliedre...l2Iss1/Hull.htm says:

In order for a drug to be a practical candidate for transdermal delivery, [...] The drug should also be potent enough to compensate for the limited ability to move a therapeutic dose through a convenient area of skin. In practical terms, this means, for most drugs, a daily dose of 1 to 2 mg. Presently there are several types of drugs that are being delivered transdermally, including testosterone, estrogen, nitroglycerin, nicotine, fentanyl (a potent opioid analgesic), scopolamine (for motion sickness), and clonodine (to lower blood pressure).

[bixbyte]

NO. A baby aspirin will give you about a 30 uM peak plasma level, one hour after you take it. The IC50 for sulfation inhibition is about 60 uM. You need to be there to cut the sulfation in half, but what you really want is more than half because half won't help much. You also want to keep the salicylic acid at or above that level for a couple hours after you take the res. By definition, you're only at the peak level very briefly. I think to get what you want, you'll need at least one regular size (325 mg) aspirin, preferably two. You should take it about 30-60 minutes before the res. Then, yeah, you should get some inhibition of sulfation. That's more aspirin than I would want to take long term.

Nevertheless, as a way of getting a high enough systemic level of salicylic acid to inhibit sulfation to any noticeable extent, I don't think transdermal methyl salicylate is going to do it, unless you cover a lot of skin.

Niner,
One must know is Methyl Salicylate Mole per Mole to Aspirin dermally? (MS is likely safe in extremely large doses)
or what is the exact concentration of transdermal MS to achieve 60 microMoles of RSV sulfation inhibition IC50?
Since we can apply large amounts of MS to human skin and not suffer the side effects of Aspirins.
A novel application I just figured out for Methyl Salicylate.
Bix

[niner]

NO. A baby aspirin will give you about a 30 uM peak plasma level, one hour after you take it. The IC50 for sulfation inhibition is about 60 uM. You need to be there to cut the sulfation in half, but what you really want is more than half because half won't help much. You also want to keep the salicylic acid at or above that level for a couple hours after you take the res. By definition, you're only at the peak level very briefly. I think to get what you want, you'll need at least one regular size (325 mg) aspirin, preferably two. You should take it about 30-60 minutes before the res. Then, yeah, you should get some inhibition of sulfation. That's more aspirin than I would want to take long term.

Nevertheless, as a way of getting a high enough systemic level of salicylic acid to inhibit sulfation to any noticeable extent, I don't think transdermal methyl salicylate is going to do it, unless you cover a lot of skin.

Niner,
One must know is Methyl Salicylate Mole per Mole to Aspirin dermally? (MS is likely safe in extremely large doses)
or what is the exact concentration of transdermal MS to achieve 60 microMoles of RSV sulfation inhibition IC50?
Since we can apply large amounts of MS to human skin and not suffer the side effects of Aspirins.
A novel application I just figured out for Methyl Salicylate.
Bix

Actually, if you did manage to get enough salicylic acid transdermally to be over 60 uM for a reasonable length of time, you might see the same side effects as you would with oral aspirin. The GI problems with aspirin and other NSAIDS are related to their COX-1 inhibition. COX-1 inhibition is a side effect of inhibiting COX-2, the inflammatory evil twin. This is why everyone was so excited about Vioxx, Celebrex, etc when they first came out, because they were COX-2 specific inhibitors with very little COX-1 effect. That way, the thinking went, you could take them for a long time without GI problems. Turns out they had other problems of their own, but that's another story. Anyway, the COX-1 inhibition is a systemic effect; since COX-1 is related to GI tract homeostasis, inhibition of it, whether the route is oral or otherwise, may result in ulcerations of the GI mucosa. It is probably a worse problem if you take it orally, since local concentrations will be at least transitorily higher, but developing systemic concentrations sufficient to inhibit sulfotransferases will probably still elicit the GI problems.

After all that, I did manage to find the permeation constant for methyl salicylate and it is an unusually permeant compound. The only things I saw that were more permeant were solvents like chloroform, methanol, or aniline.
Methyl salicylate's permeation constant is given as slightly less than 10 um/cm(2) hr. For comparison, transdermal Aspirin is about a thousand fold slower. Methyl salicylate's constant results in a flux of about 1.5 mg/cm(2) hr, so if you covered a 10cm X 10cm area with methyl salicylate, and kept it soaking, like with a saturated cloth, after an hour you would get about 150mg through. This doesn't mean that the 150mg would get into systemic circulation, however. Some amount of it would stay where it was applied, in the subcutaneous fatty tissue, muscle, and other compartments, which is why things like BenGay work. I don't know what the ratio would be without seeing some PK data. A wild guess would be that half got through within the hour, but that could be off in either direction. Because this is occurring over the course of an hour, the liver would have had an hour to start knocking off the salicylic acid, and it would be continuously getting excreted. Because of the slowness of transdermal absorption, it would be that much harder to overwhelm the liver and kidneys and obtain a decent plasma level. So methyl salicylate is sufficiently permeant that you wouldn't need to bathe in it, but to get a plasma level sufficient to impact resveratrol metabolism, you'd probably need to soak about a thousand square centimeters, i.e. much of your back, for several hours. Even then, you wouldn't necessarily be clear of the GI problems that COX-1 inhibitors are famous for.

Source for permeation data: http://www.nature.co...l/5602287a.html supplemental material.

[bixbyte]

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

Dermal Absorption of Camphor, Menthol, and Methyl Salicylate in Humans
Debra Martin, BS, Jennifer Valdez, MS, James Boren, PhD and Michael Mayersohn, PhD
From the Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, Arizona (Ms. Martin, Dr. Mayersohn); Scottsdale Police Department, Laboratory Division, Scottsdale, Arizona (Ms. Valdez); and Radiant Research, Inc., Tucson, Arizona (Dr. Boren).


Camphor, menthol, and methyl salicylate occur in numerous over-the-counter products. Although extensively used, there have been no estimates of human exposure following administration via dermal application. Furthermore, there is little information about the pharmacokinetics of those compounds. The authors report the plasma concentrations of the intact compounds as a function of dose following dermal patch application. Three groups of 8 subjects (4 male, 4 female) applied a different number of commercial patches (2, 4, or 8) to the skin for 8 hours. Plasma samples were assayed using sensitive and selective gas-chromatographic methods. 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. The corresponding values for the 4-patch group were 26.8 ± 7.2 ng/mL, 19.0 ± 5.4 ng/mL, and 16.8 ± 6.8 ng/mL. The harmonic mean terminal half-lives were 5.6 ± 1.3 hours, 4.7 ± 1.6 hours, and 3.0 ± 1.2 hours for camphor, menthol, and methyl salicylate, respectively. The 2-patch group had measurable but low plasma concentrations of each compound. Low-dose dermal application for an extended time results in low plasma concentrations of all 3 compounds. Four and 8 patches, when applied for 8 hours, gave measurable and nearly proportional plasma concentrations. 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.

[luminous]

Well, I thought I'd outsmart the lecithin mixing issues that maxwatt has experienced by using "liquid" lecithin. I swear it has just about the exact consistency as rubber cement--it might even make a nice, fume-free substitute. This stuff does not mix with water-based liquids AT ALL, and I think you'd even have a challenge stirring it into oil-based liquids. I tried to incorporate the lecithin with my usual mixture of acai-goji-blueberry-cherry-pomegranite juice, whey (with stevia) and, of course, resveratrol. The second I threw in the lecithin (about 2 teaspoons), it immediately sucked all the resveratrol and whey powder into it like a black hole. I drank the juice but had to discard the lecithin ball. Had I tried to swallow it, I'm just sure it would have stayed in my system for seven years. I nearly cried over the wasted resveratrol...

[maxwatt]

Well, I thought I'd outsmart the lecithin mixing issues that maxwatt has experienced by using "liquid" lecithin. I swear it has just about the exact consistency as rubber cement--it might even make a nice, fume-free substitute. This stuff does not mix with water-based liquids AT ALL, and I think you'd even have a challenge stirring it into oil-based liquids. I tried to incorporate the lecithin with my usual mixture of acai-goji-blueberry-cherry-pomegranite juice, whey (with stevia) and, of course, resveratrol. The second I threw in the lecithin (about 2 teaspoons), it immediately sucked all the resveratrol and whey powder into it like a black hole. I drank the juice but had to discard the lecithin ball. Had I tried to swallow it, I'm just sure it would have stayed in my system for seven years. I nearly cried over the wasted resveratrol...

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..

[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.

[maxwatt]

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.