16 replies to this topic

[treonsverdery]

Nature paper about Glamorous new chemical three orders of magnitude more powerful than resveratrol

http://www.ncbi.nlm....Pubmed_RVDocSum

Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival10, 11, 12, 13, 14. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol

[Hedgehog]

Nature paper about Glamorous new chemical three orders of magnitude more powerful than resveratrol

http://www.ncbi.nlm....Pubmed_RVDocSum

Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival10, 11, 12, 13, 14. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol

The only problem is that they are not natural and thus you need FDA approval for (SRT1460, SRT2183, and SRT1720)

[treonsverdery]

well thinking globally
perhaps there are different countries with differing drug standards such that these items will be rapidly approvable

Its kind of a nifty idea: are there countries where drugs are rapidly approved that a US physician can then prescribe treatments from; that is if a US physician likes the idea of paracetamol which has european approval what is the official structure to accomplish that

like perhaps a clinic linkage: I'm prescribing paracetamol which is not FDA approved; Dr Eastern Europenzsky will coprescribe then act as online pharmacist
or keeping it all AMA standing plus state license approved:

Your medical profile trees out perfectly to prescribe paracetamol; thats not FDA approved; fortunately I can refer you with your diagnotic tree to Dr Eastern Europenzsky who will immediately prescribe plus act as online pharmacist

I'm not knowledgeable but I believe each state has its own prescription drug law; many states likely approve foreign prescriptions

Edited by treonsverdery, 14 February 2008 - 07:04 AM.

[Hedgehog]

well thinking globally
perhaps there are different countries with differing drug standards such that these items will be rapidly approvable

Its kind of a nifty idea: are there countries where drugs are rapidly approved that a US physician can then prescribe treatments from

Kinda,

on a global level there is a big push for standard testing and requirments. ATM US biotech companies have to do show and do different tests to get approval in the EU. Which makes it hard for US and EU biotechs.

Look at the ICH. I forget the details but I think the US and rest of the world will start following these guidlines more. Which I guess in theory will allow biotechs to get their drugs faster to the markets. I forget all the details of what is going to happen but you get the idea. Plz correct me on the details thnx...
http://www.ich.org/c.../276-254-1.html

Edited by hedgehog_info, 14 February 2008 - 06:58 AM.

[malbecman]

Looks like they have just about every employee of Sirtris as an author.........

[malbecman]

Wait a minute, check out the dose they used in one of the expts for their SRT501:

"SRT501, a much less potent SIRT1 activator, also lowered fasting blood glucose in Lepob/ob mice after 3 weeks (1,000 mg per kg (body weight))."


1 gram per kg? Scaling factors aside, just based on a weight equivalency, I would need an ~75 gram dose?????


edit: here are some additional details of a different expt, similar dosing for SRT501:

"SRT501 (500 or 1,000 mg per kg (body weight)) and SRT1720 (100 mg per kg (body weight)) were dosed in all efficacy studies once daily by oral gavage. During these studies we did not measure food intake or metabolic rates so there may be uncertainty about how the compound is working. We did measure body weight during these studies and this did not change."

Edited by malbecman, 14 February 2008 - 05:06 PM.

[malbecman]

Here is their vehicle, anyone recognize HPMC and DOSS? I'm guessing a Methyl Cellulose polymer and something else....


"SRT1460 (100 mg/kg), SRT1720 (100 mg/kg), SRT501 (500 mg/kg) and rosiglitazone (5 mg/kg) were
administered once daily via oral gavage. The vehicle used was 2% HPMC + 0.2%
DOSS."

[Hedgehog]

Here is their vehicle, anyone recognize HPMC and DOSS? I'm guessing a Methyl Cellulose polymer and something else....


"SRT1460 (100 mg/kg), SRT1720 (100 mg/kg), SRT501 (500 mg/kg) and rosiglitazone (5 mg/kg) were
administered once daily via oral gavage. The vehicle used was 2% HPMC + 0.2%
DOSS."

DOSS = Sodium Dioctyl Sulfosuccinate? I guess it is sorta like SDS? Probably tastes better too!

[bixbyte]

Nature paper about Glamorous new chemical three orders of magnitude more powerful than resveratrol

http://www.ncbi.nlm....Pubmed_RVDocSum

Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival10, 11, 12, 13, 14. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol

1: Nature. 2007 Nov 29;450(7170):712-6

Published November 29, 2007

Bang a drum

Anything new?

[bixbyte]

Here is their vehicle, anyone recognize HPMC and DOSS? I'm guessing a Methyl Cellulose polymer and something else....


"SRT1460 (100 mg/kg), SRT1720 (100 mg/kg), SRT501 (500 mg/kg) and rosiglitazone (5 mg/kg) were
administered once daily via oral gavage. The vehicle used was 2% HPMC + 0.2%
DOSS."

DOSS = Sodium Dioctyl Sulfosuccinate? I guess it is sorta like SDS? Probably tastes better too!

SDS caution harmful if swallowed

http://ptcl.chem.ox....ate_sodium.html

Toxicology
Harmful if swallowed. May be harmful if inhaled or absorbed through skin. Skin and respiratory irritant. Severe eye irritant.
Toxicity data
(The meaning of any toxicological abbreviations which appear in this section is given here.)
ORL-RAT LD50 1900 mg kg-1
IPR-RAT LD50 590 mg kg-1
ORL-MUS LD50 2643 mg kg-1
IVN-MUS LD50 60 mg kg-1

Risk phrases
(The meaning of any risk phrases which appear in this section is given here.)
R22 R38 R41.

[malbecman]

Here is a listing of a DOSS formulation with prop glycol from the Mason Chemical Company that claims low toxicity of it.


Macat® DOSS-70PG S/DOSS-75E
Products


Dioctyl Sodium Sulfosuccinate

MACAT DOSS-70PG S is a 70% active di-2-ethylhexyl sodium sulfosuccinate in water and propylene glycol, DOSS-75E is 75% active in water and ethanol. DOSS-70PG S and DOSS-75E have broad FDA Status, and offers compatibility in a wide range of solvent systems for use as a versatile wetting, dispersing, emulsifying and detergent ingredient.

The exceptional quality of MACAT DOSS-70PG S/DOSS-75E allows for use in a wide range of markets and applications. DOSS-70PG S/DOSS-75E delivers rapid reduction in surface tension for improved wetting, adhesion, gloss and color resolution, and flow characteristics in Ink & Overprint Varnish Systems. In Emulsion Polymerization, DOSS-70PG S/DOSS-75E provides efficient particle generation at low concentrations for production of latexes with low particle size and narrow distribution. Use as a wetting and dispersing agent in Textiles and Paper, and penetrating and emulsifying agent in Dry Cleaning Formulations.

MACAT DOSS-70PG S/DOSS-75E is biodegradable (>66% by 28 days in the closed bottle test), exhibits very low toxicity with an Acute oral LD50 (Rats) of >4g/kg and Acute dermal LD50 (Rabbit) of >10g/kg, causes minimal eye irritation, and not considered a primary dermal irritant. INCI Name: Diethylhexyl Sodium Sulfosuccinate, CAS# 577-11-7

INCI Name: Diethylhexyl Sodium Sulfosuccinate
CAS# 577-11-7

Edited by malbecman, 14 February 2008 - 06:20 PM.

[malbecman]

DOSS has a max. tolerated dose of 100mgs in humans according to this article which tested its laxative effects:

Effect of oral dioctyl sodium sulfosuccinate on intake-output studies of human small and large intestine.
Chapman RW, Sillery J, Fontana DD, Matthys C, Saunders DR.

Dioctyl sodium sulfosuccinate (DSS) is an anionic detergent that is used widely as a laxative and promoted as a stool softener. Although many anecdotal reports attest to the laxative and stool softening efficacy of DSS, no controlled trials have been performed to document the effect of DSS on small or large bowel function in humans. We have compared, therefore, the effects of 100 mg of DSS three times daily (the maximum recommended dose) with placebo in a randomized, single blind, crossover study in two groups of subjects. First, 6 healthy ileostomates were studied while they ate a constant diet for 8 days. Dioctyl sodium sulfosuccinate administered for 4 days did not increase the daily ileal output of carbohydrate, total fatty acids, bile acids, nitrogen, or water. Cholesterol excretion was decreased while taking DSS (p less than 0.05). Second, 6 healthy volunteers were studied while eating a constant diet of 20 g of fiber plus 30 radiopaque markers daily so that mean daily transit time could be measured. After equilibration, a 7-day collection of stool was weighed and lyophylized to measure fecal water. Dioctyl sodium sulfosuccinate had no effect on stool weight, stool frequency, stool water, or mean transit time. We conclude that 300 mg/day of DSS does not increase ileal or colonic output of solids or water in healthy human subjects.

PMID: 2410320

[Anthony_Loera]

Isn't it 1000x in vitro, and about 5x in vivo?

I ask as I don't have the paper.

[Anthony_Loera]

I think Inawe stated some stuff a bit back about it taking 5 times the amount of rsv than of SRT1720...

http://www.imminst.o...o...st&p=210955

"I'm having a hard time trying to reconcile the "thousand times more
potent in biochemical tests", and the "five times more of it"."
-Inawe

Edited by Anthony_Loera, 14 February 2008 - 06:49 PM.

[edward]

I read this article on one of my weekly bookstore runs (authored by just about every Sirtris employee I have ever seen in print) and yes it was interesting but as hedgehog mentioned in post #2 of this thread the point is moot at this time as these Sirtris "inventions" are not available even on the grey market (if they were I think they would be out of most peoples price range). The day a Sirtris drug gets FDA approval and is available at my local pharmacy I will be on my way to my doctor's office to get a script and a $20 copay later (good insurance) and ill have my SIRT activator supply for a month which sure beats even the best T-Res prices, not to mention the hassle of dissolving in whatever cocktail floats your boat... Until then I read such articles as hopefully foreshadowing of good things to come but of little practical value for the here and now.

Edited by edward, 14 February 2008 - 07:25 PM.

[inawe]

We, the guinea pigs, rats or mice taking RSV and thinking about
similar stuff are in a bind. Do we believe guys trying to sell stock in a company, researchers pouring
stuff on cells in vitro, or what?
Without the burden of much knowledge, I try to get some idea of what's
behind the resveratrol craze. I reached the conclusion it's not a calorie
restriction mimetic. CR works because there is less glucose feeding
the Krebs cycle than under a "normal" diet. As a consequence, less
NAD+ is used up in generating energy from glucose. The extra available NAD+
participates, together with SIRT1, in deacetylation of histones and
other stuff . Probably, NAD+ is the limiting factor and not SIRT1.
Once more: CR leads to more NAD+ available for deacetylation, not
higher expression or activity of Sirtuins.
What RSV does is to lower the Michaelis constant of SIRT1 for both the
acetylated substrate and NAD+. Just accelerates the process as long as
there is NAD+. Quite different from CR.
From the above one can see that in vitro (no glucose, etc) research cannot provide an
accurate indication of what would happen in vivo with the full engine
on.
I think I should relay on experiments in vivo on mammals: mice, rats
myself and other Imminst members. RSV makes us feel a little bit
better, a little bit more exercise, a little bit less pain, etc. Key
words: A LITTLE BIT. Not 1000 times. This is because RSV seems to act
on different pathways (a little bit).
That's why I take RSV: a little bit of effect. Something 1000 times
more potent I'll be afraid to touch. And by the way, 1000 times more
potent in deacetylation doesn't make any sense. Once NAD+ are used up
the process stops.

[Hedgehog]

We, the guinea pigs, rats or mice taking RSV and thinking about
similar stuff are in a bind. Do we believe guys trying to sell stock in a company, researchers pouring
stuff on cells in vitro, or what?
Without the burden of much knowledge, I try to get some idea of what's
behind the resveratrol craze. I reached the conclusion it's not a calorie
restriction mimetic. CR works because there is less glucose feeding
the Krebs cycle than under a "normal" diet. As a consequence, less
NAD+ is used up in generating energy from glucose. The extra available NAD+
participates, together with SIRT1, in deacetylation of histones and
other stuff . Probably, NAD+ is the limiting factor and not SIRT1.
Once more: CR leads to more NAD+ available for deacetylation, not
higher expression or activity of Sirtuins.
What RSV does is to lower the Michaelis constant of SIRT1 for both the
acetylated substrate and NAD+. Just accelerates the process as long as
there is NAD+. Quite different from CR.
From the above one can see that in vitro (no glucose, etc) research cannot provide an
accurate indication of what would happen in vivo with the full engine
on.
I think I should relay on experiments in vivo on mammals: mice, rats
myself and other Imminst members. RSV makes us feel a little bit
better, a little bit more exercise, a little bit less pain, etc. Key
words: A LITTLE BIT. Not 1000 times. This is because RSV seems to act
on different pathways (a little bit).
That's why I take RSV: a little bit of effect. Something 1000 times
more potent I'll be afraid to touch. And by the way, 1000 times more
potent in deacetylation doesn't make any sense. Once NAD+ are used up
the process stops.

I see your view. But they aren't going to selling the drug a single compound. For example they may have a 5mg slow release tablet that will allow a low level release of this potent compound. In any case I still probably wouldn't want to take it until there had been many studies and verified in humans regarding tox issues.
My personally view on Sirtris is that they simply wanted to see if resveratrol works in humans like it does in other animals. For example does it resemble their animal models? From what I have been hearing it appears to have the same mechanism of action. Now knowing this they can focus on their potent compounds and use the best one which often isn’t the most potent one.