Thiamine Is A Carbonic Anhydrase Inhibitor As Effective As Acetazolamide

[Amazoniac]

1500 at once?

To take? I would compare with the lower dose because it might suffice, or renewing more often. In the experiment it was a single time.

 

[Amazoniac]

I have been posting a lot of stuff based on this guy's work, he synthesizes the information from varied textbooks very well, and deserves a lot more views:

Spoiler: Carbonic Anhydrase (C.A.) Inhibitors | Medicosis Perfectionalis

No idea why the enzyme is placed between H2CO3 and H+/HCO3−.

May be useful:
- "The Primary Sources Of Acidity In The Diet Are Sulfur-containing AAs, Salt, And Phosphoric Acid"

 

[Amazoniac]

..more:

Spoiler: Acute Mountain Sickness (AMS) | Medicosis Perfectionalis

 

[Blue Water]

After findings the studies on synergism between thiamine and acetazolamide, and their combined use in a number of diseases I became intrigued. Then the wild thought just came out of nowhere - what if thiamine was also a carbonic anhydrase inhibitor but at different isoenzymes and with different effectiveness.
It looks like my hunch was correct. Plain old vitamin B1 (thiamine) is not only a carbonic anhydrase inhibitor, but it is about as effective as acetazolamide on average, and more effective at certain isoenzymes of CA. Since thiamine and acetazolamide have about the same effectiveness, this may explain why similar doses of the two substances were used in the studies I posted earlier today.

Inhibition of mammalian carbonic anhydrase isoforms I, II and VI with thiamine and thiamine-like molecules - PubMed
"...Here we determined the in vitro inhibitory effects of 5-(2-hydroxyethyl)-3,4-dimethylthiazolium iodide (1), 3-Benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (2) and thiamine (3) on human erythrocyte carbonic anhydrase I, II isozymes (hCA I and hCA II) and secreted isoenzyme CA VI. K(I) values ranged from 0.38 to 2.27 µM for hCA I, 0.085 to 0.784 µM for hCA II and 0.062 to 0.593 µM for hCA VI, respectively. The compounds displayed relatively strong actions on hCA II, in the same range as the clinically used sulfonamidesethoxzolamide, zonisamide and acetazolamide."

"...the slow cytosolic isozyme hCA I, compound 1 behaves as a moderate inhibitor, with a KI value of 2.27 μM. Compound 2 and thiamine 3 showed better inhibitory activity when compared to the previously mentioned compound 1, with KI values of 1.15 and 0.38 μM (Table 1). Thus, the 4-amino-2-methyl-pyrimidin-5-yl moiety improves hCA I inhibitory activity. AZA is also a strong hCA I inhibitor with this assay and KI of 0.27 μM, whereas thiamine, ZNA and EZA were more powerful inhibitors than AZA (Table 1). A better inhibitory activity has been observed with compounds 2 and 3 for the inhibition of the rapid cytosolic isozyme hCA II (Table 1). Compound 1 showed moderate hCA II inhibitory activity with a KI value of 0.784 μM (Table 1), whereas thiamine was quite an effective hCA II inhibitor, with a KI value of 0.085 μM, (Table 1). Similar to hCA I, 4-amino-2 -methyl-pyrimidin-5-yl moiety strongly influences hCA II inhibitory activity as well. Compounds 1 and 2 were relatively weak inhibitors for hCA VI, whereas, 3, EZA and ZNA were moderate inhibitors of the secreted isozyme, with KI of 0.050–0.095 μM. A better inhibitory activity has been observed with AZA for the inhibition of the secreted isozyme hCA VI (Table 1)."

So, I think this is a pretty important find for several reasons:

1. Thiamine activates pyruvate dehydrogenase and inhibits pyruvate dehydrogenase kinase. This optimizes glucose metabolism into CO2.

2. Thiamine inhibits carbonic anhydrase about as effectively as acetazolamide, which means that not only it stimulates CO2 production but it also inhibits its degradation. I don't know of another drug that does both of these things.

3. In similar doses, thiamine can substitute for acetazolamide in those people that do not have access to acetazolamide or are unwilling to take a prescription drug. In addition, thiamine and acetazolamide are synergistic as mentioned in the studies on mental health I posted earlier today, so in theory one could get away with much lower doses when using both substances together. For instance, there is some data showing that 250mg acetazolamide + 300mg thiamine is as effective as 750mg - 1,000mg acetazolamide in terms of raising CO2.

4. The highest concentration of thiamine is required to inhibit hCA I and it is 380nM/L. This figure from a human study on the pharmacokinetics of thiamine shows that this concentration is achievable using a 1,500mg dose. Th concentration required to inhibit the other isoenzymes of hCA were 85nM and 62nM, which are easily achieved with a thiamine dosage of 300mg - 500mg. In order for acetazolamide to inhibit hCA I, the concentration required is not far off of that for thiamine. This would explain that doses of 2g acetazolamide daily, which given the long half life of the drug will likely reach the concentrations required to inhibit hCA I. But more importantly, a 1,500mg of oral thiamine has been shown to be well tolerated and without any serious side effects. In fact, an human study on Alzheimer treatment with thiamine used 1,500mg doses up to 5 times a day and did not observe any toxicities. But given the synergism of thiamine and acetazolamide, one can probably get the full effects by taking lower doses of both substances together. Alternatively, if only partial inhibition of hCA is OK for your goals then 300mg - 500mg of thiamine should suffice. These lower doses are in line with Peat's recommendations of taking 300mg thiamine every 4 hours if a person has degenerative conditions.

Thoughts?

I wonder if thiamine would work for ulcers and h. pylori similar to famotidine if you think the mechanism of action is the same, or if thiamine or famotidine would interfere with stomach acid and digestion since they inhibit CA.

 

[Amazoniac]

I wonder how futhilamine fares in inhibiting the activity of the other craponic annihilases, such as CA-IIIIIIIII and CA-IIIIIIIIIIII. I think that the following article was posted elsewhere, but couldn't find it:

- Carbonic Anhydrases: Role in pH Control and Cancer

"Of the 15 CA isoforms expressed in humans, only CA IX and CA XII have been implicated in cancer. These enzymes are transmembrane proteins in which their extracellular domain contains the catalytic activity, positioning them in the regulation of the tumor microenvironment. CA IX is of particular interest because of its high expression in solid tumors while exhibiting low expression in normal tissues [3,48,49,50]. Yet, reducing activity of either CA IX/XII activity appears to affect the pH of the tumor microenvironment reducing tumor cell survival and proliferation [33,51]. Taken together, these characteristics make CA IX/XII attractive as anti-cancer targets. Other isoforms may have targeting potential with respect to cancer, but little is known about their specific function even though there is evidence of their expression and upregulation in tumors."

Spoiler

"When tumor cells transition to a hypoxic, or the aerobic glycolytic state, there is a measurable pH difference between the extracellular and intracellular pH (pHe and pHi, respectively). In part, this is postulated to be due to the over production of lactate because of high glycolytic rates and inhibition of pyruvate decarboxylation in the mitochondria. Export of metabolic acids ultimately lowers pHe [76]."

"In most normal cells, a pH differential is maintained between pHi and pHe such that the extracellular space maintains a slightly more basic environment (pHe ≥ 7.3) relative to the intracellular environment (pHi = 7.2) [77,78,79]. This gradient permits the function of normal metabolic, transport, and regulatory processes. In hypoxic tumor cells, however, pHe drops to values ranging from 6.5–7.1 with only a marginal decrease in pHi (≥ 7.2) [77,78,80]. This activates a cascade of events that provide an advantage for tumor cell survival and proliferation. Specifically, the acidic pHe becomes favorable for extracellular matrix (ECM) remodeling, limits HCO3− dependent dynamic buffering, and induces acid activation and expression of proteases, resulting in the facilitation of tumor cell dissemination and invasion. Additionally, the slight decrease in pHe favors tumor cell proliferation, metabolic adaptation, migration pathways, and results in evasion of apoptosis. This ultimately sets up conditions that benefit tumor cell survival and proliferation, resulting in an unfavorable prognosis for cancer patients [67,76,78,81]. The increase in pHi, when compared to the more acidic pHe, favors flux through glycolysis and inhibition of gluconeogenesis (mostly in the liver and pancreas) [82,83]. Specifically, pHi ≥ 7.2 stimulates lactate dehydrogenase (LDH) activity, which has an in vitro pH optimum of ~pH 7.5. This enzyme mediates the conversion of pyruvate to lactate and regenerates NAD+, which is required for continued glycolytic activity [84,85]. Furthermore, the increased pHi increases expression of several glycolytic enzymes, thus contributing to the high rate of observed glycolytic activity within the tumor cell. Alternatively, a lower pHi (<7.2) will reverse these conditions and decrease expression of glycolytic enzymes such as LDH, and transporters like GLUT1 [86,87]."

"The decrease in pHe is caused by the rapid extrusion of lactic acid and free protons from tumor cells, resulting from the upregulation of glycolysis in the cytosolic compartment. It has been postulated that glycolytic enzymes cluster at the inner surface of cell membranes and interact with ion and proton transporters at the cell surface. This allows for a rapid transport of protons both in and out of the cell depending on the shift in metabolic equilibrium achieved within the cellular microenvironment [88,89]. In addition, an acidic pHe establishes a favorable environment for cell metastasis and invasion [90]. Specifically, acidic pHe enhances expression and activities of ECM reorganizational proteases, such as matrix metalloproteinases (MMPs) and cathepsin B [91,92]. In combination with this, an increased pHi ≥ 7.2 creates an environment that favors de novo actin filament formation through the expression and activation of actin-binding proteins such as cofillin, villin, profilin, twinfilin, and talin [93,94,95,96,97,98]. This, in turn, promotes metastatic and invasive tumor cell behavior [93,94,95,96,97,98]."

"This unique pH profile in tumor cells also permits cancer cell proliferation through bypassing cell cycle check points and evasion of apoptotic pathways [99,100]. When pHi ≥ 7.2, there is an increase in the activity of CDKs, specifically CDK1, which increases the efficiency of MAPK pathways [101]. This stimulates the rate of progression through the G2/M phase and into the S phase, where tumor cells become more adapted to proliferation and less sensitive to chemo- and radiation therapies [101]. In addition, the increased pHi suppresses DNA damage checkpoints that would typically slow the progression of a cell through the G2/M phase and restrict proliferation [78]. In combination with this, a pHi ≥ 7.2 favors a suppression of apoptotic pathways [100,102]. In normal cells (where pHi = 7.2), a reduction in pHi to < 7.2 would result in a conformational change in the pro-apoptotic factor, BAX, causing its activation and interaction with the mitochondrial membrane [103]. This interaction causes the release of cytochrome c from the inner mitochondrial membrane and activation of other pro-apoptotic factors such as the caspases [100]. Caspase activity achieves optimal efficiency near pH 6.8 in vitro. When the pHi becomes slightly more alkaline, these pathways are suppressed, allowing the tumor cells to resist apoptosis [100]. In addition, with a pHi ≥ 7.2, which is the case in most tumor cells, there is a high probability that this anti-apoptotic pH level will be maintained, even in cases where there may exist a small influx of protons. Taken together with pH-induced ECM and metabolic transitions, it is clear that the unique pH differential across membranes drives tumor cell proliferation and survival."

 

[Mr Joe]

The reason is probably that acetazolamide is associated with increased levels of ammonia. At least, that the official data. So, in people with bad liver function and inability to convert ammonia to urea this can become an issue. I would like to hear Ray's take on it since he says increased CO2 is the primary way to dispose of ammonia by converting it to urea. This means that if acetazolamide is bad for liver it could be due to something specific that the drug does to the liver and nor its CO2-increasing effects.

https://journals.physiology.org/doi/full/10.1152/ajprenal.00501.2019#:~:text=ACTZ%20causes%20renal%20HCO%203,prevented%20the%20correction%20of%20acidosis.

"ACTZ causes renal HCO 3 − wasting and induces metabolic acidosis but inhibits the upregulation of glutamine transporter and ammoniagenic enzymes and thus suppresses ammonia synthesis and secretion in the proximal tubule, which prevented the correction of acidosis"

Are they saying now that Acetazolamide inhibit Ammonia ?

 

[mostlylurking]

Are they saying now that Acetazolamide inhibit Ammonia ?

High dose thiamine hcl resolves ammonia, so perhaps Acetazolamide does also.

Thiamine Reduces Both Lactate And Ammonia

The study was with humans and also included exercise, which makes thiamine even more interesting to athletes. The type of thiamine used was TTFD, which is the scientific name for allithiamine, and the dose was 10mg/kg. That would mean a total daily dose in the range of 600mg-900mg for most...

raypeatforum.com

 

[AinmAnseo]

I'm liking the thiamine better than acetazolamide. Thanks haidut, such_saturation and aguilaroja for your contributions to this thread.

Blossom, Eight years on, are you still taking high dose thiamine hcl?

 

[Blossom]

Blossom, Eight years on, are you still taking high dose thiamine hcl?

No, I no longer seem need it fortunately.