21 replies to this topic

[kismet]

What does benfotiamine do for healthy (non-diabetic) life extensionists? It is expected to decrease the intracellular AGE-burden, but are there any studies to back this up?
I've been challanged to provide evidence for benfotiamine's ability to effectively lower the AGE-burden on our body. My first thought was to dig up some studies were benfotiamine was tested on healthy subjects to see if it effectively reduces (intracellular) AGEs. Unfortunately I couldn't find any phase I trials (probably not public?) or sufficient data to support such claims.

Michael (whose opinion is worth a lot to me) seems to like benfotiamine, I just don't know why, maybe he has seen studies that I've missed or has access to unpublished data. Mabye I'm missing the big picture anyway...

How should it work?
As far as I know "Shunting of glycolytic intermediates from the Embden-Meyerhof pathway (glycolysis) to the reductive PPP (pentosephosphate pathway) in anaerobic glycolysis." is the relevant mechanism of action.

Human data
We know that Benfotiamine works terrific in diabetics "600mg Reduces intracellular CML by 40% in diabetics, levels of intracellular methylglyoxal-derived AGE were reduced by almost 70 %" [1]

The only interesting study I found showed that 600mg B plus alpha-lipoic reduced angiopoietin-2, a marker of methylgloxal glycation, even below that of healthy people (but that was just eyeballed, not significant) and GlcNAc (Intracellular N-acetylglucosamine-modified protein) seemed to be improving even at the conclusion of the trial, but did not fall below the levels of the control group. [2]

Another study, another explanation
After ingesting carbo-hydrate rich meals even normo-glycemic people may show dangerously high (?) blood sugar levels. So benfotiamine ingestion right after such a meal might be a good idea to redirect those reactive glycolytic intermediates?
At least in diabetics it does exactly that, both CML and MG levels rise 4hours after a highe AGE meal (HAGE), which is completely preventd by benfotiamine. [5]

In rodents
Neither benfotiamine (70mg/kg) nor thiamine affected glomerular AGEs (CEL and MG-H1) compared to control groups. In 2 out of 4 cases benfotiamine significantly, but slightly, decreased HbA1c levels. TK activity was only slightly increased compared to controls. In controls dietary thiamine already exceeded the recommended daily allowance by 6-fold, maybe this contributed to the insignificant findings. [3]

No significant effect on CML, CEL, GH1 and MG-H1 (glyoxal and methylglyoxal derived AGEs, respectively) or fructosyl-lysine in plasma-protein. [4] But some plasma AGEs (FL) may be not affected by benfotiamine at all.
If we only look at thiamine, it looks more promising, both CML and CEL were lowered by thiamine compared to controls (not significant once again), but neither GH1 nor MG-H1 were affected.

Statistical fluke?
Maybe the rodent studies were not designed to detect (small) differences in control animals?

Or what else did I get wrong? Where's the data supporting benfotiamine use?

[1] http://www.tbinet.or...enfotiamine.pdf
[2] Diabetologia. 2008 Oct;51(10):1930-2. Epub 2008 Jul 29.
Oral benfotiamine plus alpha-lipoic acid normalises complication-causing pathways in type 1 diabetes.
[3] Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine.
Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ.
Diabetes. 2003 Aug;52(8):2110-20.
http://diabetes.diab.../full/52/8/2110
[4] High-dose thiamine therapy counters dyslipidemia and advanced glycation of plasma protein in streptozotocin-induced diabetic rats.
Karachalias N, Babaei-Jadidi R, Kupich C, Ahmed N, Thornalley PJ.
Ann N Y Acad Sci. 2005 Jun;1043:777-83.
[5] Diabetes Care. 2006 Sep;29(9):2064-71.
Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Stirban A et al. Heart and Diabetes Center NRW, Georgstrasse 11, 32545 Bad Oeynhausen, Germany.

Edited by kismet, 03 December 2008 - 10:11 PM.

[Skötkonung]

I'm definitely interested to see the discussion generated by your question!

I am under the assumption that both diabetic and non-diabetic people are exposed to AGEs and both utilize the same metabolic pathways to clear AGE accumulation.

In the case for certain pathologic conditions such as diabetes, AGE formation can be increased beyond normal levels leading to oxidative stress and chronic inflammation. As a result of increased prevalence, glycation inhibitors such as Benfotiamine are used to reduce AGE / RAGE levels in diabetic individuals. Given that healthy individuals suffer the same vulnerabilities to even moderate AGE exposure over a longer time period, I believe it is hypothesized that glycation inhibitors will also be effective way of preventing oxidative stress and chronic inflammation seen in older adults (atherosclerosis, asthma, arthritis).

Perhaps we won't see the same efficacy as diabetics when using benfotiamine, but even if a fraction of the AGE related damage is prevented, then they merit use. I have yet to see any significant amount of studies showing that benfotiamine won't work in non-diabetic humans.

http://www.lef.org/m...otiamine_01.htm

Edited by shawn57187, 04 December 2008 - 12:26 AM.

[sUper GeNius]

I have a question. Assuming it's going to work to prevent AGE's, does one need to take it with each meal, or would taking it once a day, (with a meal) give ongoing protection throughout the day?

[Skötkonung]

I have a question. Assuming it's going to work to prevent AGE's, does one need to take it with each meal, or would taking it once a day, (with a meal) give ongoing protection throughout the day?

From what I have read, it seems to last quite a long time in the human body so taking it after every meal might be excessive. Although someone might have a better answer, below are some excerpts I have pulled from the LEF article cited in my above post:

Subjects who received 100 mg/day of benfotiamine had faster and higher peak levels than those receiving standard thiamine supplements, achieving nearly double the levels and allowing an amazing 420% increase in total 24-hour tissue exposure after a single dose.

Subjects took 100 mg of either benfotiamine, thiamine disulfide, or fursultiamin (another thiamine derivative), and their blood levels of thiamine were measured repeatedly over a 10-hour period, along with biochemical markers of whether cells were actually "seeing" the effects of thiamine. Benfotiamine produced a more rapid and earlier increase in blood and displayed significantly increased bioavailability, compared with either of the other two formulations. These researchers concluded that benfotiamine is the best form of thiamine for therapeutic use.

[Lufega]

These researchers concluded that benfotiamine is the best form of thiamine for therapeutic use.

It all depends on what you're trying to achieve. Benfotiamine does not cross the Blood brain barrier so it affects peripheral nerves only. Only sulbutiamine and TTFD cross the BBB. I've read about otherwise healthy people testing their transketolase levels to check their B1 status and some are showing up surprisingly deficient. Any B1 derivatives will influence CNS/PNS repair even in healthy people. This can be a good adjunct to using methyl B12 to improve brain function.

http://www.medscape....warticle/583556.

I wrote about this before

http://www.imminst.o...mp;#entry277720

With that said, I've had essential tremors since I was 19. I used 900 mg benfotiamine for 1 months and the tremors were reduced by about 90%. It's pretty amazing. I can only imagine what it did for AGEs. I just started using oral TTFD (tetrahydrofurfuryl disulfide) and TTFD cream (authia) to repair a little problem I have with my ANS.

Edited by Lufega, 04 December 2008 - 07:58 AM.

[Advanc3d]

where can i get bulk benfotiamine?

[kismet]

I just wanted to research benfotiamine before buying, sold as "milgamma" in Europe, a months supply would cost me ~30$. I didn't think it would be that hard to find positive studies to justifty the expense.

I think there's a pattern I missed, because I thought thiamine and benfotiamine should work the same way. Maybe they are synergistic?
There is a pattern, but take it with a grain of salt, neither finding is significant and the percentages may look impressive, but the accuracy is probably very, very low, because the absolute values and changes of treated diabetic rats were much higher than those seen with controls.

Thiamine strongly affects CML and CEL in diabetic rats, slightly decreases CML (-5%) and CEL (-30%) in controls. [2] But in the other study CEL did not change or maybe it was ever so slightly decreased (-1%?). [1]

Benfotiamine on the other hand rather strongly affects glyoxal and methylglyoxal derived AGEs (G-H1, MG-H1) in diabetic rats, slightly decreased MG-H1 in healthy rats [1] (-10%), but no change in [2]. G-H1  did not change in the healthy controls. CEL was decreased ever so slightly. [2] This fits the human data, as B. strongly decreased "a marker of methylgloxal glycation" in diabetics, even below the levels of healthy subjects.
Additionally B. slightly lowers fructosyl-lysine in plasma protein of both diabetic and healthy rats, whereas thiamine doesn't.
Plasma protein thiols were higher (less oxidative stress the study says) [1]. Again fits the human data, which shows an increase in plasma antioxidant capacity in dialysis patients.

Considering none of the changes reached statistical significance, we should really take this with a grain of salt.

[1] Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine.
Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ.
Diabetes. 2003 Aug;52(8):2110-20.
http://diabetes.diab.../full/52/8/2110
[2] High-dose thiamine therapy counters dyslipidemia and advanced glycation of plasma protein in streptozotocin-induced diabetic rats.
Karachalias N, Babaei-Jadidi R, Kupich C, Ahmed N, Thornalley PJ.
Ann N Y Acad Sci. 2005 Jun;1043:777-83.

Edited by kismet, 04 December 2008 - 09:54 AM.

[balance]

"I have a question. Assuming it's going to work to prevent AGE's, does one need to take it with each meal, or would taking it once a day, (with a meal) give ongoing protection throughout the day?"


I thought about this many months ago. I figured it would be best to spread it with each meal for protection, however, Krillin then told me that given the large half-life of 3-4 days it wouldn't be neccessary, he said all at once should be fine. Don't know how he, and others, feel about this currently.


I personally used to take 1000mg benfotiamine, and currently take between 250-500mg depending on what I eat that day. Could the fat-soluble nature of benfotiamine interfere with the results of some of the trials? Just a suggestion, maybe they didn't give it with fat? Or maybe I'm just wrong here, don't know.

[Skötkonung]

I just wanted to research benfotiamine before buying, sold as "milgamma" in Europe, a months supply would cost me ~30$. I didn't think it would be that hard to find positive studies to justifty the expense.

I think there's a pattern I missed, because I thought thiamine and benfotiamine should work the same way. Maybe they are synergistic?
There is a pattern, but take it with a grain of salt, neither finding is significant and the percentages may look impressive, but the accuracy is probably very, very low, because the absolute values and changes of treated diabetic rats were much higher than those seen with controls.

Thiamine strongly affects CML and CEL in diabetic rats, slightly decreases CML (-5%) and CEL (-30%) in controls. [2] But in the other study CEL did not change or maybe it was ever so slightly decreased (-1%?). [1]

Benfotiamine on the other hand rather strongly affects glyoxal and methylglyoxal derived AGEs (G-H1, MG-H1) in diabetic rats, slightly decreased MG-H1 in healthy rats [1] (-10%), but no change in [2]. G-H1 did not change in the healthy controls. CEL was decreased ever so slightly. [2] This fits the human data, as B. strongly decreased "a marker of methylgloxal glycation" in diabetics, even below the levels of healthy subjects.
Additionally B. slightly lowers fructosyl-lysine in plasma protein of both diabetic and healthy rats, whereas thiamine doesn't.
Plasma protein thiols were higher (less oxidative stress the study says) [1]. Again fits the human data, which shows an increase in plasma antioxidant capacity in dialysis patients.

Considering none of the changes reached statistical significance, we should really take this with a grain of salt.

[1] Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine.
Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ.
Diabetes. 2003 Aug;52(8):2110-20.
http://diabetes.diab.../full/52/8/2110
[2] High-dose thiamine therapy counters dyslipidemia and advanced glycation of plasma protein in streptozotocin-induced diabetic rats.
Karachalias N, Babaei-Jadidi R, Kupich C, Ahmed N, Thornalley PJ.
Ann N Y Acad Sci. 2005 Jun;1043:777-83.

Are you implying that benfotiamine doesn't have any capacity for theraputic use in healthy adults because the evidence supporting its use is statistically irrelevant?

If so, I suggest you read:
Stirban A, Negrean M, Stratmann B, et al. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care. 2006 Sep;29(9):2064-71.


And more comprehensively, reading the LEF article that contains over 60 citings for you to review:

http://www.lef.org/m...otiamine_01.htm

[kismet]

Are you implying that benfotiamine doesn't have any capacity for theraputic use in healthy adults because the evidence supporting its use is statistically irrelevant?

Aww, come on! You must be kidding *g* If I did, why would I take the time to point out all the minor, but non-significant, (positive) changes. But thanks nonetheless, I'll read the article(s), when I have more time.
LEF, though, will be probably biased to some degree. I've been looking for data in healthy humans, which is severly lacking (either it's non existant or hardly accessible or I simply missed it) one way or the other.

Off to read the cancer & benfotiamine thread.

EDIT:
Having recently researched B. I also stumbled across some of the cancer data, but my subconsciousness immediately ignore it. That's an embarrassing bias to see the positive data only, isn't it?

Edited by kismet, 04 December 2008 - 10:18 PM.

[Shepard]

There is very little data on any type of supplementation in healthy humans because no one wants to fund a study to see what happens in healthy people. All the money is in diseased/deranged states. I think you're taking the right approach to the topic, but the data isn't just lacking for benfotiamine, it's not there for a lot of things.

Edited by shepard, 05 December 2008 - 02:47 AM.

[niner]

I thought about this many months ago. I figured it would be best to spread it with each meal for protection, however, Krillin then told me that given the large half-life of 3-4 days it wouldn't be neccessary, he said all at once should be fine. Don't know how he, and others, feel about this currently.

I take benfotiamine once a day.

[sUper GeNius]

Who's dropping benfotiamine now that Michael has made his most recent post?

[pycnogenol]

I take benfotiamine once a day.

Me too. I was taking 150 mg once a day (excluding the weekends) with a meal but have upped it to 250 mg per day, LEF brand.

I'm not dropping Benfotiamine anytime soon.

Edited by pycnogenol, 13 December 2008 - 03:16 PM.

[mustardseed41]

Who's dropping benfotiamine now that Michael has made his most recent post?

I'm upping my dose because of Michael.

[niner]

Who's dropping benfotiamine now that Michael has made his most recent post?

I lowered the dose from 150 to 80 on MR's argument. My own HbA1C results suggest that it's not a miracle anyway. Either that or whatever good things it does are not reflected in HbA1C. Or, since I've only gotten that test once so far, a third possibility is that I was in REALLY bad shape before the anti-glycation supps. I'll be repeating it early next year, and will play around with diet and supplements until I get it at least below 5%. I was 6.4% last time, which is OK if you're a diabetic, but sucks as far as I'm concerned.

[spacetime]

So most people aren't going to drop it? I'm on my last bottle and wondering if I should reorder it.

[kismet]

So most people aren't going to drop it? I'm on my last bottle and wondering if I should reorder it.

I think you should stick to Duke's Allstar supplements list (even though I cannot vouch for all of the supplements due to a lack of research on my side, but you probably can trust him on the issue) or a similar, maybe even more conservative, list. At least try to include those supplements first.

niner, Benfotiamine was never show to reduce HbA1C even in diabetics, only intra-cellular AGEs and their markers are reduced, which most probably are not easy to measure.

[rwac]

These researchers concluded that benfotiamine is the best form of thiamine for therapeutic use.

It all depends on what you're trying to achieve. Benfotiamine does not cross the Blood brain barrier so it affects peripheral nerves only. Only sulbutiamine and TTFD cross the BBB. I've read about otherwise healthy people testing their transketolase levels to check their B1 status and some are showing up surprisingly deficient. Any B1 derivatives will influence CNS/PNS repair even in healthy people. This can be a good adjunct to using methyl B12 to improve brain function.

http://www.medscape....warticle/583556.

I wrote about this before

http://www.imminst.o...mp;#entry277720

With that said, I've had essential tremors since I was 19. I used 900 mg benfotiamine for 1 months and the tremors were reduced by about 90%. It's pretty amazing. I can only imagine what it did for AGEs. I just started using oral TTFD (tetrahydrofurfuryl disulfide) and TTFD cream (authia) to repair a little problem I have with my ANS.

Lufega, did you notice any side effects from the TTFD ? specifically bad body odor ("smell like a skunk") ?

[Lufega]

The TTFD does smell like garlic a bit in both the pills and the cream, but it's tolerable. I do notice that when I sweat a lot, my axilla does have a hint of a garlic aroma, but it's very faint and goes unnoticed for the most part.

[Sillewater]

Benfotiamine exhibits direct antioxidative capacity and prevents induction of DNA damage in vitro.

Schmid U, Stopper H, Heidland A, Schupp N.
Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany.
BACKGROUND: Complications in diabetes mellitus are partially mediated by enhanced formation of reactive oxygen species. Among the factors involved in reactive oxygen species formation, advanced glycation end products play a key role. Owing to a reduced activity of the enzyme transketolase, which requires diphosphorylated thiamine (vitamin B(1)) as cofactor, an accumulation of those deleterious glucose metabolites especially in diabetic patients can be observed. Benfotiamine, a lipophilic thiamine diphosphate prodrug, prevented early renal and retinal changes in animal studies, and reduced neuropathic pain in clinical studies. Several mechanisms for these activities have been described. We investigated for the first time direct antioxidant abilities of benfotiamine. Additionally, a potential DNA protective effect of benfotiamine was analysed. METHODS: Oxidative stress was detected by flow cytometry, antioxidative capacity was measured with the ferric reducing ability of plasma (FRAP) assay, two endpoints for genomic damage were assessed: the comet assay and the micronucleus test, and the expression and activity of transketolase was quantified. RESULTS: Benfotiamine prevented oxidative stress induced by the mutagen 4-nitroquinoline-1-oxide (NQO), the uremic toxin indoxyl sulfate, and the peptide hormone angiotensin II in three different kidney cell lines. Cell-free experiments showed a direct antioxidant effect of benfotiamine, which might account for the protective effect. Oxidative DNA damage, induced by angiotensin II, was completely prevented by benfotiamine. Incubation with benfotiamine increased transketolase expression and activity in the cells. CONCLUSIONS: Benfotiamine shows a direct antioxidant action. This effect of benfotiamine may be involved in the improvement of diabetic late complications, including peripheral neuropathy.

Could be an effective antioxidant, however not able to find in vivo data.

[pycnogenol]

Could be an effective antioxidant, however not able to find in vivo data.

That's because you gotta pay to play for that type of information. It ain't usually free.

Edited by pycnogenol, 15 January 2009 - 11:41 PM.