Sirtris 3rd quarter conference call today

I don't think I can catch it live today but if anyone is interested, details are below. I"ll prolly catch the webcast later. Let me know if anyone hears any scientific goodies.....


Sirtris Pharmaceuticals To Webcast Conference Call for Third Quarter 2007 Financial Results
Thursday November 1, 8:00 am ET

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Sirtris Pharmaceuticals, Inc. (NASDAQ:SIRT - News), a biopharmaceutical company focused on discovering and developing small molecule drugs to treat diseases of aging such as Type 2 Diabetes, announced today announced that it will report financial results for the third quarter of 2007 on Monday, November 12, 2007, after the U.S. financial markets close.

Management will provide an update on the Company and discuss third quarter results via conference call on Monday, November 12, 2007, at 4:30 p.m. EST. To access the call, please dial 800-289-0572 (domestic) or 913-981-5543 (international) five minutes prior to the start time and provide the passcode 3453511. A replay of the call will be available from 6:00 p.m. EST on November 12, 2007 until November 25, 2007. To access the replay, please dial 888-203-1112 (domestic) or 719-457-0820 (international), and provide the passcode 3453511.

A live audio webcast of the call also will be available on the "Investors" section of the Company's website, www.sirtrispharma.com. An archived webcast will be available on the Sirtris website approximately one hour after the call and will be archived for 14 days.

Anyone listen in on this or watch the webcast yet? I don't think I'll be able to catch up with it until this weekend.....

Click HERE to rent this advertising spot for SUPPLEMENTS (in thread) to support LongeCity (this will replace the google ad above).

Anyone listen in on this or watch the webcast yet?  I don't think I'll be able to catch up with it until this weekend.....

Monday, Nov 12 is the date for the webcast.

You can listen here http://phx.corporate...9&p=irol-irhome

Right, sorry, my mistake. It's been one of those weeks around here....... [wis]

There are actually several webcasts on their site.

This one alluded to resveratrol extending the life span of mice on a normal diet by 30%. (Sirtris Pharmaceuticals at CIBC World Markets 18th Annual Healthcare Conference). Also claimed resveratrol is not sufficiently bio-available in humans, but they have a vested interest in that claim, and several contributors to the resveratrol thread, including Malbecman, have contributed to the elucidation of methods to increase resveratrol bio-availability in a manner similar to their SRT-501 formulation.

The list of webcasts is here WEBCAST LIST. You have to register, but it's painless. If the link doesn't work, go the SIRTRIS website, and click on the investors page.

Just found this on Dow Jones Newswire and was wondering if anyone knows if it is "new" news.

"Sirtris said that its scientists have developed SIRT1 activating molecules that the company said "are chemically distinct from resveratrol and are 1,000 times more potent." "

Just found this on Dow Jones Newswire and was wondering if anyone knows if it is "new" news.

"Sirtris said that its scientists have developed SIRT1 activating molecules that the company said "are chemically distinct from resveratrol and are 1,000 times more potent." "

This is most likely one of their nce's (new chemical entity). In their roadshow presentation, these were the most potent sirtuin activators. SRT501 (not chemically distinct from Resv) is their product closest to finishing trials.

some notes from today:



are testing a combination of sirt501 and metformin for diabetes. they believe it will work in conjunction with other diabetes drugs, rather than replace.

lowers glucose like many other drugs, but unique in that increases insulin sensitivity

increases the number of mitochondria

sounds like they will start targeting the other Sirtuins for cancer targeting treatments next year

trials going well in india on diabetes patients not currently taking other drugs - negligible if any side effects unlike current drugs

sometime in phase II of diabetes treatment, they will partner with a large pharma experienced in diabetes trials and distribution (glasko smith klein?)

they met with a unnamed pharma recently, who tried to find independent verification of Resevertrol and their treatments, but all experts are associated with
company - implying that sirtris has a lock on the intellectual property. over 100 patents

NCE 1000 times more potent than resveratrol, and resulting in better glucose and insulin control

NCE's favorable expression on PGC1-Alpha, unlike resveratrol

they issued a press release about an upcoming article in the Journal of Nature on their NCE's ability to express the SIRT1








* disclaimer, i hold a position in SIRT

Edited by bodyhacker_com, 28 November 2007 - 10:28 PM.

So what are the NCEs based upon? Or was that not disclosed?

Sitris dropped like a rock on high volume and took out my stops. Does anyone know what happened? Do insiders know about some poor trial results?

Sitris dropped like a rock on high volume and took out my stops. Does anyone know what happened? Do insiders know about some poor trial results?

can't find anything, but on previous pops jp morgan downgraded it, and so did piper jaffray - not for doubts about the company or it's approach, but because it's going to be so long before it's approaches are proven in phase III trials, and even longer before it turns a profit. so perhaps they are again recommending to their clients to sell into the strength.

many early investors, venture capital, and hedge funds were in at the IPO price of $10, or lower, and are perfectly happy to use the increased liquidity from the news to take a 60, 70%, or 80% profit and move on to the next target.





* disclaimer, i hold a position in SIRT

Edited by bodyhacker_com, 30 November 2007 - 07:27 PM.

Sitris dropped like a rock on high volume and took out my stops. Does anyone know what happened? Do insiders know about some poor trial results?

can't find anything, but on previous pops jp morgan downgraded it, and so did piper jaffray - not for doubts about the company or it's approach, but because it's going to be so long before it's approaches are proven in phase III trials, and even longer before it turns a profit. so perhaps they are again recommending to their clients to sell into the strength.

plus, many venture capital and hedge funds were in at the IPO price of $10 and are perfectly happy to use the increased liquidity from the news to take a 60, 70%, or 80% profit and move on to the next target.

The slides shown where used for the initial public offering, and appear old.
The NCE news also appears to be old news, just re-announced... a bit of spam for some folks here.

I think I posted the links to the WO Patents of what I believed are the NCE's that Sirtris filed somewhere in the posts. Search for it in these forums, you may find the link.

A

likely all rehashed news, but at least we learned they met with a pharma company recently and plan on partnering with a company experienced in diabetes in phase II sometime.

Edited by bodyhacker_com, 30 November 2007 - 07:10 PM.

likely all rehashed news, but at least we learned they met with a pharma company recently and plan on partnering with a company experienced in diabetes in phase II sometime.

I don't know what markers they were planning to use for diabetes, but for the simplest one, blood glucose, RSV doesn't do a thing. On the other hand, it's very effective against constipation.

looks like it's getting hit because SRT501 will be pretty much obsolete due to the NCEs, and even the NCE's don't lower blood glucose as much as Avandia.

they noted the comparison of their NCEs vs Avandia in their slide presentation yesterday, however they implied it would work in conjunction with other drugs to improve diabetes symptoms more than each could do alone.

pretty nauseating move regardless of the reason


http://www.fool.com/...tock-price.aspx


By Brian Orelli November 30, 2007

1 Recommendation

What's better than a glass of red wine? Well, my vote would be for two glasses of red wine. However, when you're trying to use a drug that would require a patient to drink 1000 bottles of wine to get the proper dose, the correct answer is: a more potent drug.

Sirtris Pharmaceuticals (Nasdaq: SIRT) published an article this week in Nature that characterized its discovery of drugs that are 1000 times more potent than resveratrol, the compound found in red wine that makes mice live longer and lowers blood sugar levels in obese mice. Even with the increased potency, the drugs appear to be less potent than GlaxoSmithKline's (NYSE: GSK) diabetes drug, Avandia.

Sirtris plans to get the drugs into clinical trials in the first half of next year, presumably because it's still working on preclinical safety studies.

Sirtris is currently testing SRT501, its proprietary formulation of resveratrol, in combination with metformin, the general version of Bristol-Myers Squibb's (NYSE: BMY) Glucophage, in type 2 diabetes patients. Results from the phase I-B trial should be available by early next year, but with more potent compounds now available, I wouldn't be surprised if SRT501 doesn't have a long life -- ironic, don't you think?

While Sirtris' science is exciting, I'm having trouble getting excited about its valuation. Even with the euphoria around the announcement subsiding, as seen by today's 15% drop in the stock price, the stock still looks a little overpriced for a company with one drug in phase 2 trials. It's going to be a while before Sirtris has a drug on the market, so investors would be well advised to not rush into buying it at these prices. In the meantime, check out other developmental stage drug companies with drugs farther along or companies with diabetes drugs already on the market, such as Amylin Pharmaceuticals (Nasdaq: AMLN) or Eli Lilly (NYSE: LLY).

What is interesting is that this research started (in part) because David Sinclair wanted to lower the cost of resveratrol for the average 75kg person.

(At least this was mentioned in his 'conclusions' section in the Nature paper "Therapeutic potential of resveratrol: the in vivo evidence")

Excerpt below:
"...administering a daily dose
to a human weighing 75 kg with 100 mg per kg (body
weight) of resveratrol would require 2.7 kg of resveratrol
a year, at a current cost of about US$6,800. Therefore,
blocking the metabolism of resveratrol, developing
analogues with improved bioavailability, or finding
new, more potent compounds that mimic its effects will
become increasingly important."

The NCE's need to be super cheap to make AND does everything regular resveratrol does besides activate the SIRT1 gene to really intend to take over the resveratrol market. I hope it does, it would actually be a good thing if the NCE's are found to be cheaper and have an increase in benefits for the average person. At this time I think the Jury is still out on whether SIRT1 activation at 100% or 900% really has an increase in benefits.

At this present time, I am being led to believe (by our consultant) that a subjects body can only benefit so much from resveratrol for a particular disease, after which benefits level off no matter how much resveratrol is taken. It is my understanding that the NCE's with SIRT1 activation have not been tested against disease at this time, only SIRT1 activation. I hope they test them against diseases soon.

another quick Excerpt:
"The mechanism by which resveratrol exerts such a
range of beneficial effects across species and disease models
is not yet clear. Attempts to show favourable effects
in vitro have met with almost universal success, and
have led to the identification of multiple direct targets
for this compound. However, results from pharmacokinetic
studies indicate that circulating resveratrol is
rapidly metabolized, and cast doubt on the physiological
relevance of the high concentrations typically used for
in vitro experiments. Further experiments are needed to
show whether resveratrol or its metabolites accumulate
sufficiently in tissues to recapitulate in vitro observations,
or whether alternative higher-affinity targets, such
as quinone reductase 2 (QR2; also known as NQO2)11,
have the key roles in its protective effects. In vivo results
have therefore become increasingly important in our
attempts to understand how resveratrol is effective in
the treatment of disparate diseases."

Just my 2 cents.

Anthony Loera

Edited by Anthony_Loera, 30 November 2007 - 09:36 PM.

Here is the Figure 1 from the latest Nature paper on the effects of resveratrol and the NCEs on diabetes. Potency curves look the same but now we get to see the structures of the NCEs, very different than resveratrol.....






edited for typos

Edited by malbecman, 01 December 2007 - 12:50 AM.

I haven't read the complete paper, but there are some comments in
Nature/news
http://www.nature.co...s.2007.305.html.
Like:
"After sifting through half a million chemicals, the group found several that activate Sirt1 at much lower doses than resveratrol does. One of the compounds, SRT1720, is about a thousand times more potent in biochemical tests.
Westphal’s team gave a small dose of SRT1720 to fattened-up mice, and the rodents’ blood sugar fell compared with fat mice not given a drug. The drug matched a proven type 2 diabetes treatment in restoring insulin sensitivity in the obese animals. SRT1720 also lowered blood sugar in two other rodent models used to test diabetes drugs, they report today in Nature 2.
Resveratrol also fights diabetes by restoring insulin sensitivity, but
it took at least five times more of it than SRT1720 to do the job."

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

I haven't read the complete paper, but there are some comments in
Nature/news
http://www.nature.co...s.2007.305.html.
Like:
"After sifting through half a million chemicals, the group found several that activate Sirt1 at much lower doses than resveratrol does. One of the compounds, SRT1720, is about a thousand times more potent in biochemical tests.
Westphal’s team gave a small dose of SRT1720 to fattened-up mice, and the rodents’ blood sugar fell compared with fat mice not given a drug. The drug matched a proven type 2 diabetes treatment in restoring insulin sensitivity in the obese animals. SRT1720 also lowered blood sugar in two other rodent models used to test diabetes drugs, they report today in Nature 2.
Resveratrol also fights diabetes by restoring insulin sensitivity, but
it took at least five times more of it than SRT1720 to do the job."

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

I'm having some difficulty understanding that too, though I'm not in the field, so my ignorance of how that might work is pretty complete. I guess I wonder if it might imply that the very thing that is now considered a defect in the use of resveratrol, namely that it is mostly conjugated when it enters the body, and so has limited bioavailability, is actually a major virtue, because it enables the resveratrol to be targeted by the body to the specific tissues that most importantly require it. That is, even though SRT1720 is 1000 times more effective in vitro, the body doesn't know how to target its effect as it does resveratrol, so most of that efficiency is just lost.

Obviously this is just speculation by someone untrained, so take it as such. But I've always been unimpressed with the argument that resveratrol can't be effective because so little of it comes through in pure form into the bloodstream. If that were so, then we simply shouldn't be seeing the dramatic effects we do in Sinclair's or Auxwerx's mice. Certainly if resveratrol were naturally present in the environment and clearly beneficial, then one might expect that in the course of evolution a mechanism would be enabled to target that very scarce chemical to achieve maximal effects. I do wonder if the emphasis Sirtris and others have put on making supposedly more "bioavailable" versions of resveratrol and related compounds might not prove misplaced, and perhaps indeed precisely counterproductive in the end. Again, I can't get around the seeming implication of both Sinclair's and Auxwerx's experiments that it must be the conjugated, and not the pure form of resveratrol in the blood stream that is most responsible for the observed effect.

I'm also having some problems understanding what the consequences are of the "percentage of control" plotted in the images in the post just above yours. If SRT1720 has a "percentage of control" which tops out at about 750%, and resveratrol tops out at about 200%, what are the implications? Does that mean that we might achieve effects with SRT1720 that we can never achieve with resveratrol, no matter what the dose? Can someone explain to me what this might mean? I guess I had thought rather naively that the more one took of resveratrol, say, the more of an effect one would get in terms of activation of Sirt1, and that, say, Auxwerx's mice represented something toward the upper end of the possible effect. Is the implication of the greater "percentage of control" of SRT1720 that it might in principle achieve effects well beyond those of Auxwerx's mice?

Edited by tom a, 01 December 2007 - 07:56 PM.

I haven't read the complete paper, but there are some comments in
Nature/news
http://www.nature.co...s.2007.305.html.
Like:
"After sifting through half a million chemicals, the group found several that activate Sirt1 at much lower doses than resveratrol does. One of the compounds, SRT1720, is about a thousand times more potent in biochemical tests.
Westphal’s team gave a small dose of SRT1720 to fattened-up mice, and the rodents’ blood sugar fell compared with fat mice not given a drug. The drug matched a proven type 2 diabetes treatment in restoring insulin sensitivity in the obese animals. SRT1720 also lowered blood sugar in two other rodent models used to test diabetes drugs, they report today in Nature 2.
Resveratrol also fights diabetes by restoring insulin sensitivity, but
it took at least five times more of it than SRT1720 to do the job."

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

I'm having some difficulty understanding that too, though I'm not in the field, so my ignorance of how that might work is pretty complete. I guess I wonder if it might imply that the very thing that is now considered a defect in the use of resveratrol, namely that it is mostly conjugated when it enters the body, and so has limited bioavailability, is actually a major virtue, because it enables the resveratrol to be targeted by the body to the specific tissues that most importantly require it. That is, even though SRT1720 is 1000 times more effective in vitro, the body doesn't know how to target its effect as it does resveratrol, so most of that efficiency is just lost.

I don't think that conjugation has anything to do with targeting, other than targeting the drug for excretion. That's the role of the conjugative (and oxidative) metabolic enzymes.

Obviously this is just speculation by someone untrained, so take it as such. But I've always been unimpressed with the argument that resveratrol can't be effective because so little of it comes through in pure form into the bloodstream. If that were so, then we simply shouldn't be seeing the dramatic effects we do in Sinclair's or Auxwerx's mice. Certainly if resveratrol were naturally present in the environment and clearly beneficial, then one might expect that in the course of evolution a mechanism would be enabled to target that very scarce chemical to achieve maximal effects. I do wonder if the emphasis Sirtris and others have put on making supposedly more "bioavailable" versions of resveratrol and related compounds might not prove misplaced, and perhaps indeed precisely counterproductive in the end. Again, I can't get around the seeming implication of both Sinclair's and Auxwerx's experiments that it must be the conjugated, and not the pure form of resveratrol in the blood stream that is most responsible for the observed effect.

I think a big cause of confusion here is that rodents are not as good as humans are at conjugating resveratrol. It's a lot more bioavailable in rodents than in man. If you look at the plasma levels of free resveratrol in rodents vs. man for a given mg/kg dose, you see the rodents have a higher plasma level than we do.

There's been speculation that the conjugates may have some activity, or that they may be getting "de-conjugated" by e.g. glucuronidases close to the site of action. As far as I know, that's only speculation at this point.

I'm also having some problems understanding what the consequences are of the "percentage of control" plotted in the images in the post just above yours. If SRT1720 has a "percentage of control" which tops out at about 750%, and resveratrol tops out at about 200%, what are the implications? Does that mean that we might achieve effects with SRT1720 that we can never achieve with resveratrol, no matter what the dose? Can someone explain to me what this might mean? I guess I had thought rather naively that the more one took of resveratrol, say, the more of an effect one would get in terms of activation of Sirt1, and that, say, Auxwerx's mice represented something toward the upper end of the possible effect. Is the implication of the greater "percentage of control" of SRT1720 that it might in principle achieve effects well beyond those of Auxwerx's mice?

This is a bit of a puzzler. It might have been an artifact of the analytical method; I haven't read the full paper yet so I can't really say. I think what's happening is that an EC50 (concentration required for 50% of full effect) is being determined for each compound. That's why you see the characteristic sigmoid curves. Each compound has a different curve shape, because each is having different effects on the binding of the protein target for deacetylation. If the compound is able to generate a stronger effect at the midpoint of the curve, then that dose is "worth more" than a dose with a shorter curve. Really, this should ultimately be folded into the potency definition, and it's possible that it already has been. I don't think that it means that you will see grossly different physiological effects from the different compounds, assuming you take enough of each one.

I don't think that conjugation has anything to do with targeting, other than targeting the drug for excretion. That's the role of the conjugative (and oxidative) metabolic enzymes.

I believe I read on these forums that there is at least some evidence that t-res conjugates do in fact have some efficacy, perhaps through deconjugation in target cells.

I don't think that conjugation has anything to do with targeting, other than targeting the drug for excretion. That's the role of the conjugative (and oxidative) metabolic enzymes.

I appreciate that conjugation is most often used to target chemicals for excretion. But sometimes, I understand, it is also used to target them for deconjugation in tissues that most require it.

I think a big cause of confusion here is that rodents are not as good as humans are at conjugating resveratrol. It's a lot more bioavailable in rodents than in man. If you look at the plasma levels of free resveratrol in rodents vs. man for a given mg/kg dose, you see the rodents have a higher plasma level than we do.

I've seen the claim made a number of times that pure resveratrol is considerably more biovavailable in rodents than in man, but I've never seen a reference that demonstrates that. In all the cases I've seen, the amount of pure resveratrol in the blood of any mammal has always been exceedingly low -- so low that one wonders how it might possibly have the dramatic effects seen in the Sinclair and Auxwerx mice (though of course it's not entirely clear what the required level might be). If there's a reference that shows that in rodents that the level is sufficient that it might induce those effects (as opposed to the levels found in men), I'd be very interested finally to see it. It would be very good to see that they actually achieve levels in rodents similar to those that work in in vitro studies.

There's been speculation that the conjugates may have some activity, or that they may be getting "de-conjugated" by e.g. glucuronidases close to the site of action. As far as I know, that's only speculation at this point.

Certainly it's only speculation, but, so far as I have been able to make out, it's also just speculation that the levels of pure resveratrol available in rodents might possibly be enough to achieve the sort of effects found in the experimental mice. I appreciate that speculating a mechanism to de-conjugate is a significantly larger leap, but I gather that the body employs such mechanisms for other chemicals. I guess my own reaction so far is one of some real scepticism that the exceedingly low levels of pure resveratrol available in (apparently) all tested mammals might account for the observed dramatic effects in the experimental mice. This inclines me to think that the more plausible explanation might be that this de-conjugation mechanism exists, even if there is yet no direct evidence that it does (which of course is why scientists would have a great deal of difficulty assuming it in any of their studies, even if were the more plausible explanation).

This is a bit of a puzzler. It might have been an artifact of the analytical method; I haven't read the full paper yet so I can't really say. I think what's happening is that an EC50 (concentration required for 50% of full effect) is being determined for each compound. That's why you see the characteristic sigmoid curves. Each compound has a different curve shape, because each is having different effects on the binding of the protein target for deacetylation. If the compound is able to generate a stronger effect at the midpoint of the curve, then that dose is "worth more" than a dose with a shorter curve. Really, this should ultimately be folded into the potency definition, and it's possible that it already has been. I don't think that it means that you will see grossly different physiological effects from the different compounds, assuming you take enough of each one.

I'm not sure I understand this explanation. The curves plot "percentage of control" vs. concentration of the chemical (presumably in some substance in vitro?). I'm not sure how you see the plots as somehow representing an attempt to see the effects at a fixed level of concentration (i.e., the concentration required for 50% of full effect in your interpretation). As for the sigmoid shape, my guess is that it's pretty common for drugs to have a sigmoid shape in their effects at increasing levels of concentration (though I guess sometimes they might have an inverted U).

Edited by tom a, 02 December 2007 - 05:32 PM.

In the Sirtris narrative, their SRTs up-regulate SIRT1 which acts as
an enzyme for deacetylating histones. Sirtris believes this can lead
to a treatment for diabetes (that's what their current trials are for).
If as somebody guessed SRT1720 is one thousand times more potent than
RSV for activating deacetylation but only 5 times more effective
against diabetes, what can we conclude? I think the logic conclusion
is that histone deacetylation is not the most effective pathway to
attack diabetes.

In the Sirtris narrative, their SRTs up-regulate SIRT1 which acts as
an enzyme for deacetylating histones. Sirtris believes this can lead
to a treatment for diabetes (that's what their current trials are for).
If as somebody guessed SRT1720 is one thousand times more potent than
RSV for activating deacetylation but only 5 times more effective
against diabetes, what can we conclude? I think the logic conclusion
is that histone deacetylation is not the most effective pathway to
attack diabetes.

I'm not sure that that conclusion makes sense. If SRT1720 is 1000 times more potent than resveratrol, you'd ordinarily expect that it would take only 1/1000th as much to achieve the same level of activation of deacetylation (or whatever it is that both do), and thereby achieve the identical effect on diabetes (or whatever). In fact, it takes 1/5th as much. There's something there that needs explaining.

I've had a chance to glance over the paper. They say "These compounds are
selective for activation of SIRT1 versus the closest sirtuin homologues, SIRT2 and SIRT3 (SIRT2: resveratrol, SRT1460 and SRT2183 EC1.5.300 mM, SRT1720 EC1.5537 mM; SIRT3: resveratrol, SRT1460, SRT1720 and SRT2183 EC1.5.300 mM)."

I interpret this to mean that SRT1720, 1460 and 2183 selectively activate SIRT1, but are little more effective than resveratrol for SIRT and SIRT3. I think they've hinted they are developing substances to selective activate these genes. So resveratrol is an all-around player, the NCE's are specialists.

As for the action on SIRT1, I think they mean the activation of the gene is more effective (by a factor of 1000) as measured by deacetylation activity, but that the per cent of activation is only several times greater than for resveratrol. At least that's my preliminary interpretation. Thoughts, anyone?

From several papers I read I got the impression that RSV activity is
not restricted to up-regulating SIRT1. I noticed that it can lead to
slight improvements in lipid profile, stamina, recovery and strength.
But doesn't touch blood glucose. All in all, I think it is a useful
supplement to take but I have to figure out how to solve the IBS
effect.
Sirtris only focuses on sirtuin activity and in particular on diabetes
treatment (at the present time). At Nature/News I read the, by now, (in)famous statement of
a thousand higher potency of SRT1720, which is only 5 times more
effective than RSV in treating diabetes. The guess is that the higher
potency is as a deacetylation facilitator. If it were 1000 times more
potent as a laxative I wouldn't like to be in the same room as
SRT1720.
1000 better deacetylation but only 5 times more effective against
diabetes means to me that histone deacetylation is not the key to
fighting diabetes.
But what do I know?

I wonder, what benefits will taking STR501 provide to people with type II diabetes if it doesn't affect blood glucose? Isn't diabetes diagnosed from glucose levels in the first place?

Stephen

I wonder, what benefits will taking STR501 provide to people with type II diabetes if it doesn't affect blood glucose? Isn't diabetes diagnosed from glucose levels in the first place?

Stephen

Well, Sirtris is giving SRT501 together with metformin. There is going to be some effect.

I wonder, what benefits will taking STR501 provide to people with type II diabetes if it doesn't affect blood glucose? Isn't diabetes diagnosed from glucose levels in the first place?

Stephen

At the very least a B12 deficiency.

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I don't think that conjugation has anything to do with targeting, other than targeting the drug for excretion. That's the role of the conjugative (and oxidative) metabolic enzymes.

I appreciate that conjugation is most often used to target chemicals for excretion. But sometimes, I understand, it is also used to target them for deconjugation in tissues that most require it.

I'm not aware of any cases where the body is using xenobiotic metabolism to target compounds for anything other than excretion, but sometimes drug designers will do that. In a "pro-drug" approach, a compound that is susceptible to conjugation will have a protecting group placed on the site of conjugation. For example, if you acetylate the 3'-OH of resveratrol, it will not be sulfated there, and will have an easier time getting into cells. Intracellular esterases will then cleave off the acetyl group, resulting in free resveratrol now safely ensconced in the cell. Is that the sort of thing you were thinking of?

I think a big cause of confusion here is that rodents are not as good as humans are at conjugating resveratrol. It's a lot more bioavailable in rodents than in man. If you look at the plasma levels of free resveratrol in rodents vs. man for a given mg/kg dose, you see the rodents have a higher plasma level than we do.

I've seen the claim made a number of times that pure resveratrol is considerably more biovavailable in rodents than in man, but I've never seen a reference that demonstrates that. In all the cases I've seen, the amount of pure resveratrol in the blood of any mammal has always been exceedingly low -- so low that one wonders how it might possibly have the dramatic effects seen in the Sinclair and Auxwerx mice (though of course it's not entirely clear what the required level might be). If there's a reference that shows that in rodents that the level is sufficient that it might induce those effects (as opposed to the levels found in men), I'd be very interested finally to see it. It would be very good to see that they actually achieve levels in rodents similar to those that work in in vitro studies.

This post: http://www.imminst.o...&...st&p=197228 talks about it; one reference is there and others are upthread of it. Generally speaking, this kind of information is the domain of pharmacokinetics. If you search for resveratrol pharmacokinetic in pubmed, various papers will come up.

There's been speculation that the conjugates may have some activity, or that they may be getting "de-conjugated" by e.g. glucuronidases close to the site of action. As far as I know, that's only speculation at this point.

Certainly it's only speculation, but, so far as I have been able to make out, it's also just speculation that the levels of pure resveratrol available in rodents might possibly be enough to achieve the sort of effects found in the experimental mice. I appreciate that speculating a mechanism to de-conjugate is a significantly larger leap, but I gather that the body employs such mechanisms for other chemicals. I guess my own reaction so far is one of some real scepticism that the exceedingly low levels of pure resveratrol available in (apparently) all tested mammals might account for the observed dramatic effects in the experimental mice. This inclines me to think that the more plausible explanation might be that this de-conjugation mechanism exists, even if there is yet no direct evidence that it does (which of course is why scientists would have a great deal of difficulty assuming it in any of their studies, even if were the more plausible explanation).

In Auwerx's Cell paper, the peak plasma level was 32 uM, according to Anthony's excel sheet in the post I referenced. I think the EC50 for SIRT1 deacetylation is near there, so it's reasonable; certainly more that "just speculation". Deconjugation is certainly something to consider. Active transport mechanisms that concentrate the resveratrol at the site of action are another possibility.

This is a bit of a puzzler. It might have been an artifact of the analytical method; I haven't read the full paper yet so I can't really say. I think what's happening is that an EC50 (concentration required for 50% of full effect) is being determined for each compound. That's why you see the characteristic sigmoid curves. Each compound has a different curve shape, because each is having different effects on the binding of the protein target for deacetylation. If the compound is able to generate a stronger effect at the midpoint of the curve, then that dose is "worth more" than a dose with a shorter curve. Really, this should ultimately be folded into the potency definition, and it's possible that it already has been. I don't think that it means that you will see grossly different physiological effects from the different compounds, assuming you take enough of each one.

I'm not sure I understand this explanation. The curves plot "percentage of control" vs. concentration of the chemical (presumably in some substance in vitro?). I'm not sure how you see the plots as somehow representing an attempt to see the effects at a fixed level of concentration (i.e., the concentration required for 50% of full effect in your interpretation). As for the sigmoid shape, my guess is that it's pretty common for drugs to have a sigmoid shape in their effects at increasing levels of concentration (though I guess sometimes they might have an inverted U).

The EC50 (concentration required for 50% effect) is a measure of the potency of an effector substance. The reason that enzymologists use the 50% of full effect number is because that is where the effect is most sensitive to concentration. If you tried to characterize the potency of a drug by looking at 100% effect, for example, you could have an infinite number of concentrations that gave you 100% effect. You need to scan the range from 0% to 100% in order to get a good value for the EC50. It's computed from data points over the full curve.