Vitamin B1 as a potential treatment for Alzheimer's Disease (AD)

[NewACC]

Just have

 

[HealthisWealth]

how about benfothaimine. The brand doctors best has an added L-leucine. The other brand life extension has an added hydrochloride. There is also bulk supplements just pure poweder

@NewACC

 

[NewACC]

how about benfothaimine. The brand doctors best has an added L-leucine. The other brand life extension has an added hydrochloride. There is also bulk supplements just pure poweder

@NewACC

If you can buy bulk benfothiamine it would be good. Thiamine hydrochloride or nitrate form doesn't change brain thiamine level significantly

 

[Veritas IV]

If you can buy bulk benfothiamine it would be good. Thiamine hydrochloride or nitrate form doesn't change brain thiamine level significantly

Apparently Benfotiamine does not cross the blood brain barrier either, In rats it will increase B1 in the brain if megadosed for 6 months. Here's a study that focuses more on Benfotiamine but others are mentioned and compared as well:

Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives​

( Lipid-soluble Thiamine Disulfide derivatives would be referring to fat soluble Allithiamine, Sulbutiamin and Fursultiamine and NOT Benfotiamine )

(Snippets of the article, for the full article, click the link or read the PDF attachment)
Lipid-soluble thiamine precursors have a much higher bioavailability than genuine thiamine and therefore are more suitable for therapeutic purposes. Benfotiamine (S-benzoylthiamine O-monophosphate), an amphiphilic S-acyl thiamine derivative, prevents the progression of diabetic complications, probably by increasing tissue levels of thiamine diphosphate and so enhancing transketolase activity. As the brain is particularly sensitive to thiamine deficiency, we wanted to test whether intracellular thiamine and thiamine phosphate levels are increased in the brain after oral benfotiamine administration.

Results​

Benfotiamine that is practically insoluble in water, organic solvents or oil was solubilized in 200 mM hydroxypropyl-β-cyclodextrin and the mice received a single oral administration of 100 mg/kg. Though thiamine levels rapidly increased in blood and liver to reach a maximum after one or two hours, no significant increase was observed in the brain. When mice received a daily oral administration of benfotiamine for 14 days, thiamine derivatives were increased significantly in the liver but not in the brain, compared to control mice. In addition, incubation of cultured neuroblastoma cells with 10 μM benfotiamine did not lead to increased intracellular thiamine levels. Moreover, in thiamine-depleted neuroblastoma cells, intracellular thiamine contents increased more rapidly after addition of thiamine to the culture medium than after addition of benfotiamine for which a lag period was observed.

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.

Mechanism of action of benfotiamine​

In 1961, Wada et al. reported the physicochemical properties of benfotiamine and its possible use as a therapeutic agent [31]. Benfotiamine is more easily absorbed by the body and oral administration results in higher thiamine and ThDP blood levels in animals than an equivalent dose of thiamine. A few years, later Shindo and coworkers [32-35] studied in more detail the mechanism of absorption and the metabolic fate of benfotiamine in animal tissues. Their results suggested that benfotiamine (given orally) is first dephosphorylated to S-benzoylthiamine by the ecto-alkaline phosphatase present in the brush borders of intestinal mucosal cells. The more lipophilic S-benzoylthiamine then diffuses through the membranes of intestinal and endothelial cells and appears in the venous mesenteric blood. A significant part of S-benzoylthiamine is captured by erythrocytes [34] and converted to free thiamine through a slow non-enzymatic transfer of the S-benzoyl group to SH groups of glutathione. In the liver, the remainder can be enzymatically hydrolyzed to thiamine and benzoic acid by thioesterases present in the hepatocytes. On the other hand, thiamine disulfide derivatives require a reduction either enzymatically in the liver by glutathione or non enzymatically in blood by glutathione and possibly other substrates [36]. In the present work, we show that after oral administration of benfotiamine to mice, free thiamine appears in the liver at a fast rate, reaching a maximum after one hour, while in the blood the maximum is reached only after two hours (Fig. (Fig.3).3). We therefore propose that most of the S-benzoylthiamine present in the mesenteric blood is captured by the liver and transformed into thiamine. The excess thiamine formed is then rapidly released into the blood stream, as shown by the fast decrease of thiamine content in the liver after 1 – 2 hours (Fig. (Fig.3).3). Such a scheme is in agreement with an earlier report that, after infusion of benfotiamine to the small intestine of the dog, mainly free thiamine (not S-benzoylthiamine) was detected in the carotid blood [35]. Free thiamine is not lipophilic and cannot cross the blood-brain barrier by simple diffusion. Transport of blood thiamine to the brain parenchyma is carrier-mediated and it is a slow process [37]. In the present study, we find that blood thiamine concentration in the control animals is approximately 0.4 μmol/l, a value close to the half-maximal activation constant for the high affinity transport of thiamine across the blood-brain barrier [8]. Though a second, low affinity, component of thiamine transport was also observed, its contribution was small. Thus, raising free blood thiamine concentrations does not necessarily lead to an important increase in thiamine transport across the blood-brain barrier. It is therefore not very surprising that benfotiamine administration does not lead to an increase in total thiamine content of the brain (Figs (Figs2,2, ,33 and and4).4). It should be noted however that one study showed a 90% increase of ThDP levels in the brains of rats that received a dose of 1645 mg of benfotiamine/kg of diet for 6 months [27].

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]

So apparently Benfotiamine is not fat soluble, it's a relic attribute since proven inaccurate, and water soluble only under specific circumstances.

Some of you may have read this study already, but for me it's been quite informative. I had many questions about Benfotiamine, especially when compared to lipid soluble disulfide derivatives, this article has answered nearly all of them.

They all have their therapeutic specialties, some are better for certain conditions than others, but a rough order of effectiveness would be: Lipid soluble disulfide derivatives > Benfotiamine > Water soluble B1 (HCL, Mononitrate etc) < ---- Edit: There are exceptions to be made here, especially if taken in high quantity.

Edit: see mostlylurking's reminder below about HCL, there are no hard fast rules sometimes.

 

[mostlylurking]

but a rough order of effectiveness would be: Lipid soluble disulfide derivatives > Benfotiamine > Water soluble B1 (HCL, Mononitrate etc)

Unless, of course, if you are/were Dr. Costantini who used thiamine hcl exclusively for his thousands of Parkinson's Disease patients. He maintained that thiamine hcl crosses the blood brain barrier just fine so long as the body is flooded with enough of it.

 

[Veritas IV]

Unless, of course, if you are/were Dr. Costantini who used thiamine hcl exclusively for his thousands of Parkinson's Disease patients. He maintained that thiamine hcl crosses the blood brain barrier just fine so long as the body is flooded with enough of it.

Thank you for that correction, i had nearly forgotten about that pretty important detail, lol, but sounds similar to Benfotiamine in that regard. Though i think Benfotiamine is less studied and it took rats approx six months to increase B1 levels in the brain with it.

edit: spelling, etc

 

[mostlylurking]

Thank you for that correction, i had just about forgotten, sounds similar to Benfothiamine in that regard. Though i think Benfothiamine is less studied and it took rats approx six months to increase B1 levels in the brain with it.

I could feel the improvement in my brain via oral thiamine hcl pretty quick. Within 45 minutes of taking 300mg thiamine hcl orally with water, the lactic acidosis went away and my body temperature increased a full degree. I stopped careening into walls early on after the start of taking it. The tremor in my right hand stopped within days too. So from my perspective, thiamine hcl works fine orally and does affect the brain.

It may be of interest that thiamine is needed to maintain the integrity of the blood/brain barrier. So if you're deficient in it perhaps the oral thiamine hcl would have easier access to the brain?

Evidence for early blood-brain barrier breakdown in experimental thiamine deficiency in the mouse - PubMed

In order to assess the involvement of blood-brain barrier (BBB) breakdown in the pathogenesis of thiamine deficiency encephalopathy, autologous albumin immunohistochemistry was performed in mice which were rendered thiamine-deficient by pyrithiamine, a BBB-permeant antagonist of thiamine. In the...

pubmed.ncbi.nlm.nih.gov

https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.12199

"The BBB is formed by endothelial cells that, circumferentially in the capillary, are joined by proteins producing very tight, intercellular junctions; the other component of the BBB is the basement membrane. Montagne et al. described their own studies and those of several others that demonstrated BBB breakdown and dysfunction in AD.56In his studies of rats who were deficient in thiamine, Collins saw abnormalities in the capillary basement membrane, which was widened and had reduced electron density.53 The abnormalities were only seen when an abnormal glial cell was adjacent to a capillary. Using horseradish peroxidase as a marker, Manz and Robertson showed a permeable BBB in thiamine-deficient rats;57 using albumin as a marker of BBB permeation in the brains of mice, Harata and Iwasaki saw massive extravasation of albumin by the 10th day of taking a thiamine-deficient diet.58"

 

[lilsticky]

The Dose was too high is more likely

i thought old people took doses of 500mg