Benfotiamine and Sulbutiamine

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MarcR
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Benfotiamine and Sulbutiamine

Postby MarcR » Sat Mar 28, 2015 11:49 am

In this post from the conference thread, Julie says,
Juliegee wrote:I have much more to share on this tomorrow- specifically the importance of a specialized B1, thiamine, to optimize our brain's utilization of glucose. (It looks like Dr. Bredesen is already on to this- phew.)

Did anyone mention sulbutiamine? I have taken it off and on for several years because of its purported nootropic properties due to its ability to shuttle thiamine past the blood-brain barrier. Effects on me are not obvious, but some people swear by it. Lately I have only taken it once in a while - my supply is uncapped, so it can't just go down the hatch with all the other supplements.

I added benfotiamine a couple of months ago because it showed up in the Bredesen protocol - no obvious effects on me.

Anyway, here's a 2008 mouse study that compares the two and casts doubt on benfotiamine's ability to get thiamine to the brain:
Conclusion: Our results show that, though benfotiamine strongly increases thiamine levels in blood and liver, it has no significant effect in the brain. This would explain why beneficial effects of benfotiamine have only been observed in peripheral tissues, while sulbutiamine, a lipid-soluble thiamine disulfide derivative, that increases thiamine derivatives in the brain as well as in cultured cells, acts as a central nervous system drug. We propose that benfotiamine only penetrates the cells after dephosphorylation by intestinal alkaline phosphatases. It then enters the bloodstream as S-benzoylthiamine that is converted to thiamine in erythrocytes and in the liver. Benfotiamine, an S-acyl derivative practically insoluble in organic solvents, should therefore be differentiated from truly lipid-soluble thiamine disulfide derivatives (allithiamine and the synthetic sulbutiamine and fursultiamine) with a different mechanism of absorption and different pharmacological properties.

The researchers learned empirically as they developed their experimental procedure that benfotiamine is not lipophilic as often claimed, and they considered the biochemistry directly and offered a possible explanation for confusion on this point:
Wada et al. already noted that benfotiamine was sparingly soluble in organic solvents such as benzene, chloroform and methanol, but was readily soluble in aqueous media at pH≥8.0.[31] This is not surprising as the phosphoryl group of benfotiamine has two negative charges at alkaline pH. Here, we confirm that benfotiamine is sparingly soluble in water at pH≤7.0 and cannot be dissolved in octanol or oils. Thus benfotiamine should not be classified as a "lipophilic" compound as many authors still do.[10,24,25,38] Indeed, benfotiamine appears unable to diffuse across cell membranes. We have shown here that intracellular thiamine content is not increased in cultured neuroblastoma incubated in the presence of 10 µM benfotiamine, while it was increased ten-fold after incubation with 10 µM sulbutiamine.[29] Moreover, after a chronic treatment of rats with sulbutiamine intracellular thiamine derivatives were increased by respectively 250% (thiamine), 40% (ThMP), 25% (ThDP) and 40% (ThTP).[14]

This is in apparent contradiction with results obtained with cultured cells of endothelial origin,[18-20,39] showing that benfotiamine is able to counteract glucose toxicity in these cells by increasing transketolase activity. However, the benfotiamine concentrations used were 50-100µM, much higher than in our study. Hammes et al. even report that there was no effect on transketolase activity in cultured endothelial cells at 10 or 25µM.[18] In any event, this is no proof that benfotiamine is able to cross the membranes: indeed, cultured endothelial cells seem to possess an ecto-alkaline phosphatase.[40] It is therefore likely that, in these cells, the added benfotiamine is at least partially dephosphorylated to S-benzoylthiamine that can enter the cells as in the case of the intestinal mucosa. The slow dephosphorylation to S-benzoylthiamine might also explain the lag period observed between the addition of benfotiamine to thiamine-depleted Neuro 2a cells and the increase in intracellular thiamine derivatives (Fig. 6). In erythrocytes, it was shown that fursultiamine, a lipophilic disulfide, is rapidly incorporated into the cells while benfotiamine is not.[41] Taken together, these results strongly suggest that benfotiamine is unable to cross plasma membranes unless it is dephosphorylated.

They conclude by speculating that sulbutiamine may even be more effective at benfotiamine's purported sweet spot:
Furthermore our results on cultured neuroblastoma cells show that benfotiamine, in contrast to sulbutiamine, does not easily cross cell membranes (Figs 5 and 6). It would therefore be interesting to test whether a thiamine disulfide compound such as sulbutiamine or fursultiamine, would not be more efficient and act at lower concentrations than benfotiamine in counteracting diabetic complications.
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Re: Benfotiamine and Sulbutiamine

Postby marthaNH » Sat Mar 28, 2015 1:07 pm

Whew. Will return to this on a day off. Thanks!

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Re: Benfotiamine and Sulbutiamine

Postby Stavia » Sun Mar 29, 2015 12:44 pm

oh my. So many maybe's. With reference to it being highlighted at the conference that Julie and Martha went to, maybe just a small group of researchers' topic? Or will this turn out to be bigger than a side line in the future?

How can we be sure this is safe? I felt bloody awful on methylated folate and B12.
And on the flip side, Merouleau what formulation do you use, and where do you get it from? I saw only a few on iherb.
what to do....what to do....

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Re: Benfotiamine and Sulbutiamine

Postby MarcR » Sun Mar 29, 2015 2:19 pm

Stavia wrote:Merouleau what formulation do you use, and where do you get it from?

I use this product from Hard Rhino: Sulbutiamine 99% Powder. I wouldn't recommend mixing with food or drink as it has a strong bitter flavor - it's best for most people to cap it using something like The Capsule Machine.
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Re: Benfotiamine and Sulbutiamine

Postby MichaelR » Thu May 07, 2015 2:09 pm

All:

First, I should make the discl0sure that in a prior career I was actually responsible for researching and bringing either the first or the second B supplement to the North American market (I and a competitor worked in mutual ignorance of one another's efforts until both began publicly advertizing the fact), when it was completely unknown here. I still have some pride in that initiative along with my generally mixed feelings about supplements and highly jaded view of the rest of the supplement industry. I'd appreciate this fact not being discussed in open forum, as I value my privacy, but y'all should know.

The issues raised around benfo's biochemistry in the passage of the mouse study that merouleau quotes (Volvert et al., 2008 below), that are actually pretty well-understood, and don't actually do anything to explain their null finding, for which there are more plausible explanations. The material below is from a 2013 review by Dr. Gibson and colleagues. The TL/DR version is that the real reason Volvert et al didn't see any elevation in brain thiamin because their study was too short, and that to understand why benfo raises the metabolically active form of brain thiamin, you have to look not just at what benfo itself does to cells exposed to the parent molecule, but the way it is taken up from the gut, transported thru' the circulation, and then crosses the blood-brain barrier. If that's enough info on this subject for you, do still continue on further down for more "actionable" information — and a caution:

Thiamine is a water soluble compound that does not penetrate membranes very well. This decreases its absorption from the gut and its movement into cells and across the blood brain barrier. Thus, thiamine derivatives that are able to increase cell thiamine more efficiently than thiamine have been developed …

Benfotiamine is perhaps the best studied of these derivatives. … Benfotiamine contains an open thiazole ring that is closed on reduction within the cell. [Yes, this is here based on endothelial cells, as the mouse study authors suggest -- read on! -MR] Benfotiamine enters cells more easily than thiamine and maintains the active form of thiamine (TPP) for longer periods. Thiamine absorption from benfotiamine is about five times as great as from conventional thiamine supplements (Loew, 1996). Peripheral cells take in five- to twenty-five-fold as much thiamine in the form of [thiamin derivatives] as they do of an equal amount of regular thiamine ...

Studies in humans show that benfotiamine increases blood thiamine and thiamine diphosphate much more than equivalent dosages of thiamine (Frank et al., 2000; Loew, 1996). Benfotiamine only penetrates the cells after de-phosphorylation by intestinal alkaline phosphatases. It then enters the bloodstream as S-benzoylthiamine that is converted to thiamine in erythrocytes and in the liver. Following oral administration of 250 mg benfotiamine in humans, thiamine peaks within one hour in blood, and returns to normal by 25 hours. However, thiamine diphosphate [the active form of thiamin -MR] peaks in blood at about 5 hours at about 2 times control value and remains at that level for 25 hours (Ziems et al., 2000) [and mice have roughly the same pharmacokinetics -MR] ... During this time, brain thiamine does not increase. ...

Thiamine normally enters the brain through low capacity transporters. Thiamine is then phosphorylated to thiamine disphosphate ester ( [TDP], frequently referred to as thiamine pyrophosphate, TPP), which is the form of thiamine that is required for thiamine dependent enzymes [ie, that actually carries out the biochemical "work" of thiamin -MR]. …

The reported effects after longer-term administration (10-14 days) vary. In one report, thiamine does not increase in brain (Volvert et al., 2008 [merouleau's quoted study]), whereas in the other (Pan et al., 2010b) brain thiamine is elevated. ... One study showed a 90% increase in thiamine diphosphate levels in brain of rats that received benfotiamine in their diet for 6 months followed by 6 months of thiamine (Netzel et al., 2000 ). In the paper in which plaque levels were diminished (see below) (Pan et al., 2010b), the treatment was over an eight-week period. However, thiamine was only measured one hour after a single dosage or after a 10-day trial. In both, benfotiamine increased the levels of thiamine but not TMP or TDP in brain, whereas the levels of all were increased in blood. [Again, this was after a single dose or 10 days; Netzel et al., 2000 finds TDP elevated in the brain after long-term administration -MR]. As with all the studies, the increase in blood and liver was much larger than in brain (Pan et al., 2010b). Our unpublished studies in mice demonstrate that six months of benfotiamine feeding increases blood thiamine by 40 fold and brain thiamine by over 50% (Dumont et al.).
The rest of the paper is of great interest in making the case for the role of thiamin-dependent enzymes in potentially sustaining or restoring the thiamin-dependent enzymes involved in the impaired energy metabolism observed in AD patients, people at genetic or familial risk, and people with prodromal AD, and thus the potential for supplementation with some form of thiamin to prevent or slow the progression of the disease, and spends a significant amount of time comparing and contrasting different thiamin derivatives; I'll exerpt a small amount of the former and nearly all of the latter, and the full text is freely available thanks to wise legislation and the equally-wise investment of American citizens' and businesses' tax dollars.

Reduced glucose metabolism is an invariant feature of Alzheimer’s Disease (AD) and an outstanding biomarker of disease progression … (FDG-PET) studies in patients with AD show decreased glucose uptake bilaterally in posterior cingulate, precuneus, parietotemporal and frontal cortex. Greater decreases in FDG uptake correlate with greater cognitive impairment along the continuum from normal cognitive status to mild cognitive impairment (MCI) to AD dementia (Langbaum et al., 2009). A great advantage in patients with a disease causing mutation is that the temporal response of the changes can be followed. In patients that are genetically inclined to develop AD, changes in brain glucose metabolism occur decades before the development of symptoms (Reiman et al., 2004). There are no reports of normal glucose metabolism in brains of AD patients.

Increases in several markers of oxidative stress also indicate altered metabolism in patients with AD. In autopsy brains, markers of oxidative stress such as acrolein are more pervasive than plaques or tangles (Calingasan et al., 1999). Advanced glycation end products (AGE) occur in 75-95% of pyramidal neurons, which far exceeds the percentage of tau positive neurons (Munch et al., 2002). Markers of oxidative stress occur in peripheral cells formation in even mildly cognitively impaired patients (Torres et al., 2011). In animal models of plaque formation, markers of oxidative stress in brain and urine increase before plaques occur in brain (Praticò et al., 2001). Despite major advances in early diagnosis, neuroimaging, and biomarker research, no disease-modifying therapies are currently available …

In spite of the tight linkage of glucose metabolism to brain function and to the decline in AD, only a very limited number of studies have tried to understand why it is diminished. In related efforts, many experiments to enhance mitogenesis [the replication of the energy-producing mitochondria in the cell –MR] (Burchell et al., 2010) or diminish oxidative stress in the brain (Dumont and Beal, 2011; Eckert et al., 2011) have been completed, but none of the therapies have translated to the clinic…

Thiamine (vitamin B1)-dependent processes occupy critical steps in glucose metabolism … that are diminished in patients with AD. … Further, the reductions in thiamine-dependent processes are highly correlated to the decline in clinical dementia rating scales. ... Brain glucose metabolism depends on three thiamine-dependent enzymes (Figure 1): transketolase (TK), the pyruvate dehydrogenase complex (PDHC) and the α-ketoglutarate dehydrogenase complex (KGDHC). [The latter enzyme is the most consistently impaired in AD and AD prodromes -MR] …

In animal models, thiamine deficiency exacerbates plaque formation, promotes phosphorylation of tau and impairs memory.

[Thiamin Derivatives As Potential AD Prophylactics]
Benfotiamine is perhaps the best studied of these derivatives. … Sulbutiamine is a lipophilic derivative of thiamine that more readily crosses membranes than thiamine. Chronic administration of sulbutiamine improves long-term memory formation in mice (Micheau et al., 1985). Chronic treatment with sulbutiamine improves memory in an object recognition task and reduces some amnesic effects of dizocilpine in a spatial delayed-non-match-to-sample task (Bizot et al., 2005). Fursultiamine has not been studied as extensively as sulbutiamine of benfotiamine. Studies show that it increases brain thiamine as effectively as benfotiamine (Pan et al., 2010b).

Measuring thiamine levels in brain may not provide an adequate measure of the functional consequences of thiamine supplements. For example, one group claims benfotiamine increases brain thiamine (Pan et al., 2010a), whereas others claim it does not (Volvert et al., 2008). Another report found slight increases after six months (Netzel et al., 2000). Others report that both benfotiamine and fursultiamine increase brain thiamine, but not thiamine esters, and only benfotiamine diminishes plaques (Pan et al., 2010a). Measures of the functional consequences of thiamine supplementation provide an effective screen for thiamine-mimetics that may correct a functional thiamine deficiency in brain. The reversal of the decline in the activities of KGDHC and transketolase following [thiamin deficiency] provides a measure of the functional consequences of thiamine (Gibson et al., 1984). The various thiamine derivatives have not been tested in this manner. A limitation of any method is that providing thiamine (or a derivative) to thiamine sufficient animal models may not provide an adequate method to test for effects in functional deficient in patients…

Thiamine supplements and AD pathology
The studies described above suggest that supplementation with thiamine or thiamine derivatives may be able to reverse AD pathological processes. Remarkably, supplements with thiamine derivatives decrease plaque formation and improve memory, even in mice that are genetically engineered to make plaques. Specifically, recent studies in mice show supplementing with the thiamine derivative benfotiamine diminish plaque formation and improve memory (Pan et al., 2010b). Another thiamine derivative, fursultiamine, is not effective, and our unpublished studies show that thiamine does not diminish plaque formation. The precise basis for this selectivity between thiamine and different thiamine derivatives is a matter of speculation, and is discussed in more detail later in the review. The inability of thiamine and fursultiamine to reverse plaques may be related to their ability to enhance thiamine dependent processes within the brain....

Diabetes, AD and thiamine
Diabetes predisposes to AD …. Hyperglycaemia increases the formation of AGE [Advanced glycation end products]. ... AGEs appear to be important components in the pathology of AD and diabetes. In AD brains, intracellular accumulation of AGE occurs in 75-95% of pyramidal neurons, which far exceeds the percentage of tau positive neurons. They also occur by the age of 35-45 years (Munch et al., 2002). In addition, AGEs may represent a driving force in acceleration of amyloid deposition and plaque formation (Loske et al., 2000). High levels of AGEs occur in neurofibrillary tangles (Jono et al., 2002) and CSF (Ahmed et al., 2005). The Mini-Mental State Examination (MMSE) score correlates negatively with oxidant-induced protein modification (Ahmed et al., 2005). Thus, the evidence for AGE is overwhelming for AD. These results raise the question of whether the AGEs in AD are due to a functional [thiamin deficiency] and/or if increasing thiamine availability in brain could overcome these deficits. …

Hyperglycaemia increases the formation of AGE
Thiamine, especially the thiamine derivative benfotiamine, reduces hyperglycemia induced AGE in endothelial cells (La Selva et al., 1996; Stracke et al., 2001; Thornalley et al., 2001). Benfotiamine can also diminish cerebral oxidative stress associated with diabetes (Reggiani et al., 1984). [The cited study doesn't show this; I think they meant to cite (1) below. Note Note that this was quite a high dose, and it was INJECTED rather than oral benfotiamine. Note that this also seems to imply that circulating unmetabolized benfo is able to raise functional thiamin in the brain, perhaps undergoing the needed conversion in circulating cells or BBB endothelial cells -MR] ...

Strong evidence suggests that benfotiamine or thiamine does this [reduces metabolically-generated AGE] by inducing transketolase. The data suggests that activation of transketolase reduces the AGE by activation of non-oxidative branch of the pentose phosphate shunt (Hammes et al., 2003; Stracke et al., 2008). Growing cells in high glucose is one model of diabetes. Culturing cells with high glucose does not significantly depress transketolase, but the addition of thiamine or its derivatives to stressed cells increases transketolase and diminishes the toxic metabolites. If the increase in transketolase is blocked by using antisense oligonucleotides, thiamine is no longer neuro-protective. Thiamine does not increase transketolase in controls (Hammes et al., 2003). [It is not clear to me where they get this from the cited paper; the effect on transketolase in nondiabetic controls in vivo certainly is not reported one way or the other -MR] Successful treatment of diabetic peripheral neuropathy by activation of transketolase with thiamine-mimetics suggests a similar strategy may work in AD.(Hammes et al., 2003; Stracke et al., 2008). … Thiamine may also be protective in AD and diabetes by acting at a transcriptional level. …

Although thiamine-dependent processes appear to be appropriate therapeutic targets, the few previous trials have been minimally effective. One cause of the failure was that all were greatly under-powered so neither positive nor negative results are credible. …The studies with thiamine were for short time periods and had small numbers of patients (i.e., they were poorly powered).
They then go on to discuss several small and mostly short-term studies with thiamin or its derivatives in human AD patients. Most are at least suggestive of benefit, but none are really convincing; this may be because they're underpowered, as the authors suggest, or that intervening in full-on AD may be too late to exert profound effects, particularly if the benefits are mediated in substantial part via preventing the formation of AD neuropathology and/or AGEing of intracellular proteins. And, of course, it's also possible it just doesn't work ...

Safety Concerns
Now, after reading the above, I am sure that a lot of people are going to get very excited and start taking benfo supplements, and/or supplements of the other lipophilic derivatives or megadoses of thiamin proper. Some caution is in order.

Gibson et al emphasize the safety of benfo in clinical trials, but those trials are nearly all of very short in duration, with the longest being a two-year trial of benfotiamine in Type I diabetics, which (a) was in a population that is much more severely thiamin deficient and subject to oxidative stress than asymptomatic people in AD risk groups, and thus less likely to suffer any effects of subchronic overdose; and more importantly (b] found no effect of benfotiamine on diabetic polyneuropathy over that time period, despite the benefits observed in previous (shorter and smaller) trials. (The study was critiqued on methodological grounds by authors with some expertise in benfo, but who got that expertise in part from work funded by its European sponsor, but most of the objections are minor and the authors responded pretty cogently to most of the objections). If you're looking to benfo to exert many similar effects in the brain in humans, this is not a favorable sign on efficacy, and it's still limited evidence on long-term safety. The European Food Safety Authority did a mandated scientific review and evaluation of benfotiamine, and found no standard two-year rodent toxicity and carcinogenesis studies had been done.

My sole direct concern about a possible long-term risk of benfotiamine supplementation is the role of transketolase in promoting the progression of many cancers — not in initiating them, but in pushing them into more aggressive stages — and doing so exactly by increasing the cancer cell's ability to metabolize glucose, just as we might hope for it to do in AD (albeit primarily thru' glycolysis and not complete oxidative metabolism):

Roie of Transketolase in Cancer
Cancer cells utilize glucose maximally as a main source of energy supply and substrates for proliferation through glycolytic metabolic pathways [1,2]. Inhibition of the activity of the key enzymes (e.g., transketolase/transadolase) in these metabolic networks, resulting in significant limitation of glucose utilization, provides an ideal strategy for an effective therapy of cancer. A number of our previous studies have shown that inhibition of activity of either transketolase in the pentose phosphate cycle, or glycogen phosphorylase causes cell cycle arrest leading to cancer cell apoptosis.Cancer cells utilize glucose maximally as a main source of energy supply and substrates for proliferation through glycolytic metabolic pathway.s Inhibition of the activity of the key enzymes (e.g., transketolase/transadolase) in these metabolic networks, resulting in significant limitation of glucose utilization, provides an ideal strategy for an effective therapy of cancer. A number of our previous studies have shown that inhibition of activity of either transketolase in the pentose phosphate cycle, or glycogen phosphorylase causes cell cycle arrest leading to cancer cell apoptosis.
I discussed this possible possible cancer risk of benfotiamine several years ago. Here is a collection of studies on the role of thiamine, TDP, and its metabolism in some cancers, and a second collection of studies focused on the specific involvement of transketolase and/or transketolase-like 1, an enzyme with close homology with transketolase, and that was long assumed to be dependent on TDP; in fact, tumors overexpressing TKL1 respond to oxythiamine, a drug that blocks thiamin metabolism. The actual mechanism of oxythiamine is not certain, and there is now even some evidence suggesting that TKL1 may not be dependent on thiamine diphosphate. Whatever the truth may be, several studies do seem to link the effect on thiamine or TDP itself in some cancers (see the first collection above). This might explain the early finding that cancer patients are often thiamine deficient: their tumors are greedily sucking up all the thiamine they can get to fuel their furious metabolism.

Note that my rather emphatic language in that post was in relation to healthy people at no particular risk of diabetes or of AD; obviously, the risk:reward calculus is substantially rejiggered in this group, but I would not say it is simply canceled out. I would say, without providing medical advice, that I would consider it canceled out for myself or a loved one if I actually had AD.


Reference
1: Wu S, Ren J. Benfotiamine alleviates diabetes-induced cerebral oxidative damage independent of advanced glycation end-product, tissue factor and TNF-alpha. Neurosci Lett. 2006 Feb 13;394(2):158-62. Epub 2005 Oct 28. PubMed PMID: 16260089.
Last edited by MichaelR on Sun May 10, 2015 4:38 pm, edited 2 times in total.

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Re: Benfotiamine and Sulbutiamine

Postby Julie G » Thu May 07, 2015 5:49 pm

Thanks for sharing, Michael. We're lucky to have your expertise on this. Unfortunately, your cautions put us between a rock and a hard place again- sigh :? E4 carriers are used to this...

I recently heard Dr. Gibson speak on this topic. He made a pretty convincing argument in favor of benfotiamine supplementation ESPECIALLY in our population- as we demonstrate problems with cerebral glucose metabolism as early as our 20s and 30s. My notes from his talk are below, followed by a question for you.

Dr. Gibson asserted that the brain's ability to use glucose (as measured by FDG-PET scan) is the MOST strongly correlated biomarker with Alzheimer's- NOT amyloid plaque. Despite the fact that the brain comprises 2% of the human body, it is the most metabolically demanding organ- using 20% of the the glucose supply. A loss of glucose to the brain is strongly correlated with amyloid plaque and tau. This cerebral glucose hypometabolism can even be measured in skin biopsies (fibroblast cultures) that demonstrate altered internal calcium stores.

Reduced cerebral glucose utilization creates oxidative stress. He asserted that neuronal mitochondria is very sensitive to oxidative stress. Nitration is a marker of this stress that impairs KGDHC (alpha-ketoglutarate dehydrogenase complex ) an important mitochondrial constituent. KGDHC is protective. Strategies to up regulate it include: sirtuins, NAD, and ketones. KGDHC is dependent on Vitamin B1, thiamine. This B vitamin has a function very different than any other B vitamin. A thiamine deficiency is very dangerous. It is exemplified by a condition called Wernicke-Korsakoff Syndrome. ALL diabetics are deficient in thiamine. ALL Alzheimer's patients are deficient in thiamine. Interestingly, Chinese scientists are using thiamine as a biomarker for AD.

Glucose metabolism, and it's subsequent oxidative stress, drive amyloid plaque and tau. A thiamine deficiency impairs glucose metabolism. Supplementing with Vitamin B1 can briefly rectify, but it's quickly used up and the body is unable to hold a steady supply. Benfotiamine can supply a more continuous supply. Supplementing with benfotiamine has also been shown to decrease amyloid plaque and tau. The neurons, which appeared to have died (apoptosis) from lack of cerebral fuel, have been shown to be revived with thiamine supplementation. It has been proven to be safe. A dosage of 300mg, twice daily was recommended. Concurrently supplementing with NAC helps.


I appreciate that you'd forego your own cautions for yourself or a loved one if you had DXed Alzheimer's, but understanding that it takes years (decades) for Alzheimer's disease pathology to develop AND a thiamine deficiency exacerbates glucose metabolism -a problem E4 carriers already demonstrate- don't you think addressing this earlier for our population makes sense? Is there a safer way to deal with this?

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Re: Benfotiamine and Sulbutiamine

Postby MarcR » Sat May 09, 2015 1:36 am

Michael, 3.5 years after you initiated this discussion on LongeCity, this post suggested that supplementing thiamine allows non-cancerous cells to compete more effectively for glucose and helps starve any nascent tumors as long as blood glucose levels are kept low. He doesn't address your primary evidence, the 2001 Comin-Anduix paper, except to imply that it's out of date. Amusingly, he gets the date wrong - "1999 study".

Even so, I find his idea intuitively appealing, and I also like the paper he cites. It's too technical for me to follow perfectly, but I think the gist is that tumor cells upregulate one form of transketolase (TKTL1) without the assistance of thiamine; therefore, we are better off optimizing the thiamine status of our non-cancerous cells to upregulate all three forms of transketolase throughout our bodies and thereby optimize overall cellular energy production. It's all very speculative.

This 2013 review cites 150 studies and concludes that we do not know if supplementing thiamine will increase or reduce our cancer risk. Along the way it identifies a number of research gaps.

My ε4 allele predisposes me to cellular hypometabolism. Thiamine bolsters cellular metabolism. I exercise, eat well, and feel healthy, so I'm going to support that by continuing to supplement (albeit at a reduced level). If my healthy cells are in fine fettle, I'm going to trust them to prevent cancer. Maybe I'll get cancer as a result; maybe I'll delay or avoid Alzheimer's; maybe I'll just waste a few bucks; but that's the choice I'm making today.

I appreciate the food for thought and will follow this topic with interest going forward.
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Re: Benfotiamine and Sulbutiamine

Postby MichaelR » Sun May 10, 2015 4:33 pm

merouleau wrote:Michael, 3.5 years after you initiated this discussion on LongeCity, this post suggested that supplementing thiamine allows non-cancerous cells to compete more effectively for glucose and helps starve any nascent tumors as long as blood glucose levels are kept low.
This doesn't really make any sense, biologically. Normal cells aren't "competing" for thiamin or glucose in a way that would let them starve out a cancer. Cancer cells suck in an enormous amount of glucose and thiamin because they are engaged in furious cell proliferation (which requires synthesis of nucleic acids, which requires thiamin-dependent enzymes) and glycolysis (which also involves thiamin-dependent enzymes), and thus require an abnormal amount of these — but all of this is the result of the mutations that drive the extra cell replication (and, in many cases, mutations in thiamin transporters to actively take in more thiamin, and/or transketolase and other thiamin-dependent enzymes or their regulators to enable them to use the extra thiamin more).

Normal cells are just going about their business, and aren't "trying" to do these things, and by definition don't have the mutations required to do them, either: they aren't dividing, or are dividing very slowly (depending on the cell type), and are just trying to carry out normal metabolism. In particular, most healthy cells not "trying" to fight the cancer, and certainly wouldn't try to do so through their growth: that would lead to a secondary, perhaps benign tumor, which wouldn't do anyone any good. There's no competition that they can "win" at, in other words. Giving them extra thiamine is like putting more gas into a car: it prevents them from running out of gas, but doesn't make it go any faster — and it doesn't let a Mini outspeed a Maserati. Extra thiamine might let people with existing cancer avoid some of the effects of secondary thiamin deficiency induced by the hogging of the vitamin by the cancer, but that doesn't do anything to inhibit the progression of the cancer to more malignant phases.

The high glucose thing also doesn't make any sense: diabetes puts you at risk of cancer, but almost certainly not because of hyperglycemia: instead, the elevations in insulin and IGF-1 (both proliferative hormones) and signaling by phosphatidylinositol-3-kinase (PI-3-kinase) are implicated. Indeed, even Fine and Feinman (who are advocates of low-carb diets and running clinical trials of low-carb diets in cancer patients) don't think that you can just starve a cancer of glucose:
at first we thought we might starve tumors by limiting dietary carbohydrate (CHO), obviously a major source of blood glucose. It took us less than a day of literature review to recognize that CHO restriction would not starve most cancers because they are usually excellent at pirating glucose at blood glucose concentrations way below the normal range. ... We realized that gluconeogenesis and release from glycogen stores would prevent blood glucose concentration from falling to a level low enough to starve cancer cells. However, it became clear that by reducing insulin signaling, dietary CHO reduction would cause many effects which were known to inhibit cancer growth. Some of these were systemic, such as ketosis triggered at CHO restriction to less than 50 grams/day. Ketosis had been reported to inhibit cancer growth in cell culture studies in our lab and others, animal cancer studies and a case study of two children with brain tumors. Other expected effects are changes in all the intracellular signaling molecules downstream of the insulin receptor, which regulate their growth, proliferation, and resistance to apoptosis (cell death signals known in all cells), etc. In the last blogpost, Richard [Feinman] described an animal study which demonstrated insulin’s involvement in downstream signaling and response to diet in cancer. Cancers are now being treated with drugs that individually target these intracellular signaling molecules that are controlled by insulin. These new drugs have shown some efficacy but are often limited by side effects due to the drug interactions with normal tissues. Normal tissues, however, are tolerant of the effects of reduced insulin signaling. This is apparent from the safety of low CHO diet investigations in overweight people and people with diabetes as well as healthy subjects of normal weight. It seemed reasonable to us that a low CHO insulin inhibiting (INSINH) diet could target the same molecules as the drugs and could plausibly inhibit or even kill cancer cells, but would be safe for normal tissues. [all emphasis in original]
Plasma glucose concentration falls only mildly, remaining in the normal range in normal-weight individuals and in those trying to lose weight using low-carbohydrate diets. Simple tumor glucose starvation is therefore unlikely in humans. Strict carbohydrate limitation, however, leads to distinct changes in signaling pathways and downstream metabolism, including moderate ketosis, fatty acid synthase inhibition, reduced secretion of insulin, insulin-like growth factors, and several inflammatory cytokines.(1)
Overexpression of the insulin-independent glucose transporter-1 (GLUT-1) and hexokinase facilitates the increased glucose uptake needed to supply the energy needs of these cancers. … Conversely, we proposed previously that insulin inhibition (INSINH), by altering the metabolic microenvironment, may inhibit many human cancers evolutionarily adapted to a markedly different, specifically hyperinsulinemic, state. We also previously reported on the growth and adenosine triphosphate inhibition in multiple aggressive cancer cell lines when grown in supplemental ketone body medium that are not seen in control fibroblasts. ... [C]alorie restriction shares many of the downstream signaling pathways of the insulin receptor. ... Other insulin receptor ligands, including insulin-like growth factor-1 (IGF-1) and IGF-2, share extensive homology and downstream signaling pathways with insulin, but have more potent mitogenic and antiapoptotic effects. … Conversely, decreased insulin secretion induces metabolic and molecular responses, including the inhibition and downregulation of ... [multiple] proposed cancer therapy targets of drugs such as rapamycin, wortmannin, bevacizumab, metformin, among many others.(2)
merouleau wrote:He doesn't address your primary evidence, the 2001 Comin-Anduix paper
He doesn't actually address any of the evidence I cited at the time, nor the collection of studies on the role of thiamine, TDP, and its metabolism in some cancers I posted here (though, of course, he hasn't necessarily seen the latter ;) ). Nor does he present any evidence supporting his own hypothesis, which I see no one in the literature advocating and which for reasons cited is in my view quite implausible.
merouleau wrote:I also like the paper he cites. It's too technical for me to follow perfectly, but I think the gist is that tumor cells upregulate one form of transketolase (TKTL1) without the assistance of thiamine; therefore, we are better off optimizing the thiamine status of our non-cancerous cells to upregulate all three forms of transketolase throughout our bodies and thereby optimize overall cellular energy production.
Hm... they are focused on the idea on TKTL1 as the key transketolase variant present in cancer and the possible role of variant transketolases in diabetes and AD, but I'm skimming thru' the paper and using the 'find' function, and can't find anywhere that the authors suggest either that TKTL1 is not thiamin-dependent or that we should adopt the strategy you suggest; per contra, they clearly cite and don't attempt to rebut the evidence supporting supplemental thiamin as a potential enabler of cancer, and specify that transketolases in cancer cellsare activated by thiamin:
Since we could demonstrate the presence of a second transketolase enzyme in humans, the observed enzymatic results can no longer be interpreted as the consequence of a single transketolase protein unless discrimination between the enzymatic activities of the different transketolase enzymes is performed. Furthermore, if an enzyme needs a cofactor, the enzymatic activity can be altered by the cofactor. If more than a single enzyme with an identical cofactor are present, activation of the enzymatic activity by application of a cofactor is the sum of activation of the different enzymes. Transketolase enzyme activities in tumor cells have been activated by application of thiamine, or inhibited by thiamine analogs [which compete against real thiamin for binding sites on thiamin-dependent enzymes, inhibiting their activity -MR]. The obtained results have been interpreted as the consequence of the TKT [standard transketolase] gene. We could show that only the TKTL1 transketolase is upregulated in tumors, indicating that the TKTL1 transketolase is the relevant transketolase to inhibit. ...

Besides this, transketolase enzyme reactions represent also a target for therapeutic intervention in cancer. Transketolase enzyme reactions of the nonoxidative PPP play a crucial role in nucleic acid ribose synthesis utilizing glucose carbons in tumor cells. ... The importance of transketolases for tumor cell metabolism is underlined by the fact that the application of specific transketolase inhibitors to tumors induces a dramatic reduction in tumor cell proliferation. In addition, the activation of transketolases by application of thiamine stimulates tumor growth. ...

If the TKTL1-based glucose metabolism is important for tumorigenesis, the absence of TKTL1 enzyme activity should inhibit tumor proliferation. Inhibition of TKTL1 enzyme activity can be performed by cofactor analogues, substrate analogues, inhibitory small compounds and depletion of substrates. Inhibition of transketolase enzyme reaction by cofactor analogues (e.g. oxythiamine) and small compounds (Genistein63; AVEMAR64,65) have already been performed, and tumor proliferation could be successfully inhibited. Future analysis will show whether the tumor-inhibitory effect is due to an inhibition of TKTL1 transketolase.
What did they say that got you thinking along those lines? In any case, the fact that giving these tumors thiamin promotes their growth and malignancy, and giving thiamin antimetabolites inhibits it, is the key point, not which specific thiamin-dependent enzymes are actually involved in the tumor-promoting effect — right?
merouleau wrote:This 2013 review cites 150 studies and concludes that we do not know if supplementing thiamine will increase or reduce our cancer risk. Along the way it identifies a number of research gaps.
Frustratingly inconclusive — I agree.

References
1: Fine EJ, Segal-Isaacson CJ, Feinman R, Sparano J: Carbohydrate restriction in patients with advanced cancer: a protocol to assess safety and feasibility with an accompanying hypothesis. Community Oncology. 2008 Jan; 5:2-26

2: Fine EJ, Segal-Isaacson CJ, Feinman RD, Herszkopf S, Romano MC, Tomuta N, Bontempo AF, Negassa A, Sparano JA. Targeting insulin inhibition as a metabolic therapy in advanced cancer: a pilot safety and feasibility dietary trial in 10 patients. Nutrition. 2012 Oct;28(10):1028-35. doi: 10.1016/j.nut.2012.05.001. Epub 2012 Jul 26. PubMed PMID: 22840388.

marthaNH
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Re: Benfotiamine and Sulbutiamine -- and B supps generally

Postby marthaNH » Sun Aug 09, 2015 12:39 pm

I have been very gradually adding modest doses of supplements to my personal routine over the last year or two. For a long time -- actually most of my adult life, I guess -- I used Red Star Vegetarian support formula nutritional yeast for my B's. That is a brewer's type of yeast specifically bred for nutritional purposes and supplemented with B12 (pretty sure the non-methyl type) and others. Over time I became wary of mega-doses of all sorts, so I found a nutritional yeast (from Whole Foods) that contained ONLY naturally occurring nutrients, and used that to "cut" the Red Star. I've decided not to buy any more Red Star so that I can be a bit more judicious about supplementing my B's.

The Whole Foods yeast is just food -- but it's food that provides a low-methionine 7g of protein, 25% of the RDA for niacin, and almost 50% of folate. It supplies modest amounts of B6, no thiamine or B12 to speak of. So I have recently added occasional sub-lingual methyl B-12 (I also eat liver and scallops) and am going to order some Benfotiamine, a decision based on the various sources mentioned in this thread.

I am also looking at some kind of choline supplement (I tend not to hit the recommended dosage with diet). Is there a reason to buy Citicoline or a Choline supp that includes Inositol? I can get Choline Bitartrate in bulk, and I like to buy that way -- any reason not to? Then, finally, there's B6, which I just haven't researched at all. Don't know about nicotinamide, either.

I'm a 3/4. My dad developed alzheimer's in his mid-70s (he was probably also 3/4, based on family histories, no AD among my mother's six siblings that we know of) and had none of the risk factors that seem to be most common -- not overweight, reasonably active (I mean, he kept walking the golf course and the neighborhood), no insulin resistance that I ever heard of, a smart and engaged, very sociable sort of person all his life. Drank more alcohol than an E4 should, I guess (couple martinis every night, sometimes wine with dinner, too), and was very, very stressed by my mother's long, difficult, terminal illness, then a house fire. He had a volatile personality and vented a lot of rage. I never knew whether that was good for him or not -- it stressed the rest of us, for sure!

As far as I can tell, I have no particular methylation issues (one red, a lot of yellows, and some greens from genetic genie -- but six no-calls, too). No sensitivities to foods. Only one bad experience with skin allergies during a time I was dealing with over-the-top stress. Unfortunately, I treated that with Claritin for a good many months (anticholinergic). That was 16 to 19 years ago. One bad bonk on the head (auto accident) but never heard the word "concussion". That was 30-some years ago.

Just trying to prudently cover the possible bases. It seems to me that I fatigue more easily (mentally) than I used to, and at one point I found myself facing the fact that I had mentally "lost a step". If anything, my cognition has improved since I started hanging out with you guys, taking fish oil, losing weight, getting blood pressure down to good levels and very minimal medications. I have been careful about saturated fat after getting too-high LDL-P results, that came down with vigilant diet, curious about where it is now.

Dad died in April and I went kind of quiet for a while, had had enough of AD and wanted to think about other things. Also thought I was getting a little OCD with the diet tracking and such -- maybe lost more weight than I should have. Wandering back now and ready to deal with getting some fresh labs and researching these supplements. Best to all. Thanks for any thoughts you feel like sharing.

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Re: Benfotiamine and Sulbutiamine

Postby Julie G » Sun Aug 09, 2015 7:22 pm

(((Martha))) I just wanted to chime in and tell you how great it is to see you posting again. I don't blame you for taking a break, my friend. You have been through a lot with the loss of your Dad. I am so proud of you for making all of the positive changes that you have.

I have little of substance to add regarding your supplement questions. The citicholine I use is CDP choline by Jarrow. I use 250mg and have to be sure to take it in the AM as it gives me a burst of energy. I have switched my B-6 to Dr. Bredesen's recommendation: Pyridoxal 5' phosphate, 20mg.

Wow, SIX no-calls in your methylation seems strange... You kind of have no idea of what you're really dealing with :?


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