11 replies to this topic

[sUper GeNius]

See:

http://money.cnn.com...tune/index3.htm

The article says 501 is a disgusting tasting liquid. Surprsing that it is not a capsule. Can anyone gather any ideas as to the formulation knowing that it is a liquid? Could it be ethanol based?

[proteomist]

Resveratrol dissolved in ethanol will precipitate as the ethanol is removed, either by dilution into stomach contents or absorption of the ethanol. My guess is that this is a 1:1 admixture of resveratrol and beta-cyclodextrin, possibly/probably with other ingredients present as well. This would greatly increase the water-solubility of resveratrol, and account for the liquid formulation. Alternatively, it could be some oil or micelle based thing.

But how do we account for ten-fold higher levels in the blood? My understanding is that 50-75% of orally administered resveratrol is taken up in the gut. Of that, maybe 5-10% reaches the plasma in the unmodified form. So, a highly solubilized form could offer only about a two-fold increase by bringing the absorbtion to 100%. So something else is going on. It's possible that by making the drug very rapidly available to the gut epithelium, the effective concentration in these cells is made high enough to significantly exceed saturation of the modifying enzymes. There is evidence this effect comes into play somewhat simply by giving higher oral doses. SRT501 might take much better advantage of this by giving a very high, but short resveratrol flux.

Beta-cyclodextrin has been shown to form a 1:1 complex with resveratrol. FWIW, food grade b-cyclodextrin costs about $1.20 a gram. You'd need about a 3:1 mass ratio with resveratrol to make this, as cyclodextrin is about three times heavier than resveratrol. Unfortunately, you'd also need a decent basic chem lab, as making the complexes would involve dissolving both species in a solvent mixture, probably 50% ethanol, in which they're both soluble and then slowly evaporating out the organic fraction so as to force the resveratrol to complex with the cyclodextrin. FWIW, I plan to try making some of this is the relatively near future.

Alternatively/additionally, Sirtris might be doing the obvious and including quercitin and/or bioperine.

Also interesting to note in the article is the statement that they will probably not bring Srt501 to market, except possible for some limited indications. This is pretty much what I've been speculating.

Edited by proteomist, 20 May 2007 - 05:34 PM.

[sUper GeNius]

Resveratrol dissolved in ethanol will precipitate as the ethanol is removed, either by dilution into stomach contents or absorption of the ethanol. My guess is that this is a 1:1 admixture of resveratrol and beta-cyclodextrin, possibly/probably with other ingredients present as well.  This would greatly increase the water-solubility of resveratrol, and account for the liquid formulation. Alternatively, it could be some oil or micelle based thing.

But how do we account for ten-fold higher levels in the blood? My understanding is that 50-75% of orally administered resveratrol is taken up in the gut. Of that, maybe 5-10% reaches the plasma in the unmodified form. So, a highly solubilized form could offer only about a two-fold increase by bringing the absorbtion to 100%. So something else is going on. It's possible that by making the drug very rapidly available to the gut epithelium, the effective concentration in these cells is made high enough to significantly exceed saturation of the modifying enzymes. There is evidence this effect comes into play somewhat simply by giving higher oral doses. SRT501 might take much better advantage of this by giving a very high, but short resveratrol flux.

Beta-cyclodextrin has been shown to form a 1:1 complex with resveratrol. FWIW, food grade b-cyclodextrin costs about $1.20 a gram. You'd need about a 3:1 mass ratio with resveratrol to make this, as cyclodextrin is about three times heavier than resveratrol. Unfortunately, you'd also need a decent basic chem lab, as making the complexes would involve dissolving both species in a solvent mixture, probably 50% ethanol, in which they're both soluble and then slowly evaporating out the organic fraction so as to force the resveratrol to complex with the cyclodextrin. FWIW, I plan to try making some of this is the relatively near future.

Alternatively/additionally, Sirtris might be doing the obvious and including quercitin and/or bioperine.

Also interesting to note in the article is the statement that they will probably not bring Srt501 to market, except possible for some limited indications. This is pretty much what I've been speculating.

Interesting that when I 'quote' your reply I see that you added three other paragraphs. What7s with th eforum software?

Anyway, regarding the "ten-fold blood levels" Sinclair said that their formulation resulted in 10x blood concentration than the t-res being sold as supplements. He may have been referring to the smaller dose "first generation" products that contained no more than 25mg per cap. Perhaps our 500mg and 1000mg doses are producing higher blood levels proportionally.

[tom a]

Here's a link to the only published patent app from Sirtris that mentions SRT501.

Patent app mentioning SRT501

SRT501 is brought up at the end. The patent app focuses on the use of sirtuin activators for diseases causing loss of vision in old age.

I'd be curious to hear reactions from others about the description of how SRT501 is used in the patent app.

[proteomist]

Well, you just cracked it open. That patent details how they make (or at least made at the time) SRT501, and I was right, it is a cyclodextrin solution. Specifically it's an admixture with Captisol. [thumb]

So, who wants to place an order for some SRT501? I'll take bids on the first hundred-gram batch. [lol] Note to mods: not a commercial post, as I am kidding. Maybe.

Edit: Not really kidding. [wis] I'll have to appraise the legal and regulatory aspects of making some of this for sale for research purposes, but if it looks viable I may well do so. I'd be interested in hearing some feedback on the interest in such a product.

Here's a link to the only published patent app from Sirtris that mentions SRT501.

Patent  app mentioning SRT501

SRT501 is brought up at the end. The patent app focuses on the use of sirtuin activators for diseases causing loss of vision in old age.

I'd be curious to hear reactions from others about the description of how SRT501 is used in the patent app.

Edited by proteomist, 20 May 2007 - 07:06 PM.

[sUper GeNius]

proteomist,

There appears to be three or four different formulations with differing concentrations of t-res. Also, is there any mention of the real effectiveness at producing higher blood concentrations vs straight t-res? If we know that, we can get an idea of the dosages of 98% t-res we should be taking.

Also, are there any substances available to us that we can take along with our 98% t-res that will provide some of the benefits of Captisol?

[proteomist]

I'll have to read the patent more carefully, but they were looking at various formulations for occular administration.

The major benefit would be in getting enough resveratrol to the cell to efficiently activate Sirt1. You need to get ~10-20 um concentrations in cells to get decent activation. With plain resveratrol, even if the conjugates act as a storage and delivery form (and we don't know for sure they do, but I think it's likely) you have an inherent time release effect. To make a coarse analogy, think of it as the difference between crack and powder cocaine. The main difference between the two is serum concentration profile; the smoked form gives a very high, but brief serum level as compared to the powder. This has rather significant consequences for the effects.

In terms of other adjuvants, I would still add quercitin, and probably bioperine, personally. I'll need to mull that over a little more though, before I can give you a good answer.

proteomist,

There appears to be three or four different formulations with differing concentrations of t-res. Also, is there any mention of the real effectiveness at producing higher blood concentrations vs straight t-res? If we know that, we can get an idea of the dosages of 98% t-res we should be taking.

Also, are there any substances available to us that we can take along with our 98% t-res that will provide some of the benefits of Captisol?

[sUper GeNius]

I'll have to read the patent more carefully, but they were looking at various formulations for occular administration.

The major benefit would be in getting enough resveratrol to the cell to efficiently activate Sirt1. You need to get ~10-20 um concentrations in cells to get decent activation. With plain resveratrol, even if the conjugates act as a storage and delivery form (and we don't know for sure they do, but I think it's likely) you have an inherent time release effect.  To make a coarse analogy, think of it as the difference between crack and powder cocaine. The main difference between the two is serum concentration profile; the smoked form gives a very high, but brief serum level as compared to the powder. This has rather significant consequences for the effects.

In terms of other adjuvants, I would still add quercitin, and probably bioperine, personally. I'll need to mull that over a little more though, before I can give you a good answer.

proteomist,

There appears to be three or four different formulations with differing concentrations of t-res. Also, is there any mention of the real effectiveness at producing higher blood concentrations vs straight t-res? If we know that, we can get an idea of the dosages of 98% t-res we should be taking.

Also, are there any substances available to us that we can take along with our 98% t-res that will provide some of the benefits of Captisol?

I quote this paragraph:


"[1328] The use of compositions of the invention is not limited to treating vision impairment. The compositions of the invention can also be used for treating and/or inhibiting a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases and neuronal disorders, cardiovascular disease, blood clotting (coagulation) disorders, inflammation, cancer, and/or flushing, etc. Additional exemplary uses of compositions of the invention are disclosed in US Publication 2005/0096256. "

Covering ALL of their bases in the one patent it seems.

Now, as far as your coke vs crack analogy, can we determine whether it is a good idea or not to take our 98% t-res with food? What about one single dose/day? Seems to me that perhaps on an empty or near empty stomach would be better than with a meal. Or perhaps taken with a substance that emulates their Captisol.

[rwoodin]

I know nothing of chemistry so please allow me to ask a far fetched question. Would a creatine and sugar (dextrose) mixture be of any benefit in achieving a higher cellular resveratrol concentration?

[proteomist]

I'm working on going through the actual patent application and extracting some figures from it. I'll post that soon. There are some interesting things we can conclude.

As to the with/without food: probably without, but the long absorption time scale I'm seeing for raw resveratrol probably means that it doesn't matter much. Either way it's going to be slow.

[malbecman]

Now, as far as your coke vs crack analogy, can we determine whether it is a good idea or not to take our 98% t-res with food? What about one single dose/day? Seems to me that perhaps on an empty or near empty stomach would be better than with a meal. Or perhaps taken with a substance that emulates their Captisol.

I've always advocated and taken my 5 mg/kg/day on an empty stomach and in a single bolus dose in order to try and maximize blood levels and subsequent cellular levels. The best method of administration, in terms of reaching peak blood levels, would be IV or smoking/snorting the stuff but I don't advocate that.

Now, seeing that some additives/emulsifiers may help with absorption and blood levels looks very promising....

[malbecman]

Here's a link to the only published patent app from Sirtris that mentions SRT501.

Patent  app mentioning SRT501

I noticed that one of the Patent firms they hired is: FISH & NEAVE IP GROUP. Definitely one of the heavy hitters in the IP realm so Sirtris is hiring the big guns....