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Thiamine Is A Carbonic Anhydrase Inhibitor As Effective As Acetazolamide

haidut

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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, though the latter is blood concentration. Since tissue concentrations is 10+ fold higher than blood, achieving those concentrations in cells may be possible with much lower doses. The concentration required to inhibit the other isoenzymes of hCA were 85nM and 62nM, which are easily achieved with a thiamine dosage of 300mg - 500mg, even in blood. 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?
 
Last edited:

haidut

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Such_Saturation said:
http://www.ncbi.nlm.nih.gov/m/pubmed/23389837/

Good find, thanks.
 

aguilaroja

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haidut said:
... Plain old vitamin B1 (thiamine) is not only a carbonic anhydrase inhibitor,...

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. ...

Though only a few pharmaceuticals are currently used as carbonic anhydrase inhibitors (CAI's), the list of substances with CAI action is longer.

It includes sulfonamides, sulfa drugs, coumarins, sildenafil analogs; capsaicin; metronidazole-coumarin conjugates, "complex anions incorporating fluoride, chloride and cyanide"; heavy metal salts of lead, cobalt, & mercury; ethanol; topiramate; antioxidant phenols; salicylic acid derivatives; chalcones, arylamino bisphosphonates; tenoxicam; dexamethasone; famotidine (described in a different haidut post); and more.

Some of these substances are more interesting from a Peat-y viewpoint than others. Some items are dangerous, such as heavy metals. As haidut describes in this and multiple posts, thiamine has many helpful effects. Sulfonamide variant CAI agents are described in many articles.

"Incidentally", there has been concern for over two decades about potential harm where loop diuretics, used to treat congestive heart failure (and high blood pressure or other stuff), deplete thiamine. Some researchers have suggested supplementing thiamine, at least to replace what is lost.
--
http://www.ncbi.nlm.nih.gov/pubmed/25891195

Designing carbonic anhydrase inhibitors for the treatment of breast cancer.
Supuran CT1, Winum JY. Expert Opin Drug Discov. 2015 Jun;10(6):591-7. doi: 10.1517/17460441.2015.1038235. Epub 2015 Apr 20.

"Carbonic anhydrase (CA) IX is one of the proteins that are involved in cancerogenesis in hypoxic breast tumors."

"The most advanced CA IX inhibitors candidates, which demonstrate antimetastatic activity in breast cancer, are the sulfonamides, with one compound (SLC-0111) currently in Phase I clinical development."
---
http://www.ncbi.nlm.nih.gov/pubmed/23910704

Congest Heart Fail. 2013 Jul-Aug;19(4):214-22. doi: 10.1111/chf.12037.
Thiamine supplementation for the treatment of heart failure: a review of the literature.
DiNicolantonio JJ1, Niazi AK, Lavie CJ, O'Keefe JH, Ventura HO.

"...supplementing with thiamine in HF patients has the potential to improve left ventricular ejection fraction. Thiamine deficiency appears to be not uncommon in patients with HF, and supplementation with thiamine has been shown to improve cardiac function, urine output, weight loss, and signs and symptoms of HF."
 

haidut

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aguilaroja said:
haidut said:
... Plain old vitamin B1 (thiamine) is not only a carbonic anhydrase inhibitor,...

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. ...

Though only a few pharmaceuticals are currently used as carbonic anhydrase inhibitors (CAI's), the list of substances with CAI action is longer.

It includes sulfonamides, sulfa drugs, coumarins, sildenafil analogs; capsaicin; metronidazole-coumarin conjugates, "complex anions incorporating fluoride, chloride and cyanide"; heavy metal salts of lead, cobalt, & mercury; ethanol; topiramate; antioxidant phenols; salicylic acid derivatives; chalcones, arylamino bisphosphonates; tenoxicam; dexamethasone; famotidine (described in a different haidut post); and more.

Some of these substances are more interesting from a Peat-y viewpoint than others. Some items are dangerous, such as heavy metals. As haidut describes in this and multiple posts, thiamine has many helpful effects. Sulfonamide variant CAI agents are described in many articles.

"Incidentally", there has been concern for over two decades about potential harm where loop diuretics, used to treat congestive heart failure (and high blood pressure or other stuff), deplete thiamine. Some researchers have suggested supplementing thiamine, at least to replace what is lost.
--
http://www.ncbi.nlm.nih.gov/pubmed/25891195

Designing carbonic anhydrase inhibitors for the treatment of breast cancer.
Supuran CT1, Winum JY. Expert Opin Drug Discov. 2015 Jun;10(6):591-7. doi: 10.1517/17460441.2015.1038235. Epub 2015 Apr 20.

"Carbonic anhydrase (CA) IX is one of the proteins that are involved in cancerogenesis in hypoxic breast tumors."

"The most advanced CA IX inhibitors candidates, which demonstrate antimetastatic activity in breast cancer, are the sulfonamides, with one compound (SLC-0111) currently in Phase I clinical development."
---
http://www.ncbi.nlm.nih.gov/pubmed/23910704

Congest Heart Fail. 2013 Jul-Aug;19(4):214-22. doi: 10.1111/chf.12037.
Thiamine supplementation for the treatment of heart failure: a review of the literature.
DiNicolantonio JJ1, Niazi AK, Lavie CJ, O'Keefe JH, Ventura HO.

"...supplementing with thiamine in HF patients has the potential to improve left ventricular ejection fraction. Thiamine deficiency appears to be not uncommon in patients with HF, and supplementation with thiamine has been shown to improve cardiac function, urine output, weight loss, and signs and symptoms of HF."

Thanks for the clarification. I will see if I can find something interesting about the substances you listed.
My point in the original post is that thiamine packs a double punch. First, it increases CO2 production by stimulating PDH and inhibiting PDHK, and then it boosts these levels of CO2 even more by preventing CO2 degradation through CA inhibition. Do you have a list of other substances that can do both? I'd love to do some research on them. Thanks in advance.
 

aguilaroja

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haidut said:
My point in the original post is that thiamine packs a double punch. First, it increases CO2 production by stimulating PDH and inhibiting PDHK, and then it boosts these levels of CO2 even more by preventing CO2 degradation through CA inhibition. Do you have a list of other substances that can do both?...

The quick answer is no, offhand, I do not know of another single substance that both encourages CO2 release through cellular/TCA cycle respiration while acting as a carbonic anhydrase inhibitor (CAI). It may be interesting to look at salicylic acid, which may "uncouple" mitochondria respiration and act as a CAI (see below). You have posted recently (thank you!) about aspirin, which is much more than the cartoon view of either a COX-2 inhibitor or blood thinner.

Due to your posts, I am re-thinking CAI's and thinking further on Dr. Peat's ideas on beneficial CO2 effect in tissues. I did not recognize how numerous the recent CAI studies were. There seems to be half-recognition that CAI action is found in essential processes, lacking the larger view of CO2 "nutrition" discussed by Dr. Peat.

"Of course", much of the research is lab/tissue study rather than whole organism. How CO2 reaches an array of specific sites involves life's intelligent integration.

http://raypeat.com/articles/articles/co2.shtml
"The local concentration of carbon dioxide in specific tissues and organs can be adjusted by nervous and hormonal activation or inhibition of the carbonic anhydrase enzymes, that accelerate the conversion of CO2 to carbonic acid, H2CO3. The activity of carbonic anhydrase can determine the density and strength of the skeleton, the excitability of nerves, the accumulation of water, and can regulate the structure and function of the tissues and organs."

---
http://raypeat.com/articles/articles/co2.shtml

When mitochondria are “uncoupled,” they produce more carbon dioxide than normal, and the mitochondria produce fewer free radicals. Animals with uncoupled mitochondria live longer than animals with the ordinary, more efficient mitochondria, that produce more reactive oxidative fragments. One effect of the high rate of oxidation of the uncoupled mitochondria is that they can eliminate polyunsatured fatty acids that might otherwise be integrated into tissue structures, or function as inappropriate regulatory signals.

http://raypeat.com/articles/articles/un ... fats.shtml
"...it has become clear that the "uncoupled" mitochondrion, that "wastes oxygen and calories," is protective against free radicals, cancer, and aging. Thyroid hormone and the absence of PUFA are important factors in supporting the "wasteful" mitochondrion."

Bioorg Med Chem. 2008 Aug 1;16(15):7424-8. doi: 10.1016/j.bmc.2008.06.013.
Carbonic anhydrase inhibitors: inhibition of mammalian isoforms I-XIV with a series of substituted phenols including paracetamol and salicylic acid.
Innocenti A1, Vullo D, Scozzafava A, Supuran CT.
"The different mechanisms of inhibition by phenols as compared to sulfonamides, and their diverse inhibition profile for these mammalian isozymes, makes this class of derivatives of great interest...."

http://www.ncbi.nlm.nih.gov/pubmed/15505497
J Cardiovasc Pharmacol. 2004 Nov;44(5):591-5.
Inhibition of cardiac mitochondrial respiration by salicylic acid and acetylsalicylate.
Nulton-Persson AC1, Szweda LI, Sadek HA.

"...treatment of isolated cardiac mitochondria with salicylic acid and to a lesser extent acetylsalicylate resulted in an increase in the rate of uncoupled respiration."
 

haidut

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aguilaroja said:
haidut said:
My point in the original post is that thiamine packs a double punch. First, it increases CO2 production by stimulating PDH and inhibiting PDHK, and then it boosts these levels of CO2 even more by preventing CO2 degradation through CA inhibition. Do you have a list of other substances that can do both?...

The quick answer is no, offhand, I do not know of another single substance that both encourages CO2 release through cellular/TCA cycle respiration while acting as a carbonic anhydrase inhibitor (CAI). It may be interesting to look at salicylic acid, which may "uncouple" mitochondria respiration and act as a CAI (see below). You have posted recently (thank you!) about aspirin, which is much more than the cartoon view of either a COX-2 inhibitor or blood thinner.

Due to your posts, I am re-thinking CAI's and thinking further on Dr. Peat's ideas on beneficial CO2 effect in tissues. I did not recognize how numerous the recent CAI studies were. There seems to be half-recognition that CAI action is found in essential processes, lacking the larger view of CO2 "nutrition" discussed by Dr. Peat.

"Of course", much of the research is lab/tissue study rather than whole organism. How CO2 reaches an array of specific sites involves life's intelligent integration.

http://raypeat.com/articles/articles/co2.shtml
"The local concentration of carbon dioxide in specific tissues and organs can be adjusted by nervous and hormonal activation or inhibition of the carbonic anhydrase enzymes, that accelerate the conversion of CO2 to carbonic acid, H2CO3. The activity of carbonic anhydrase can determine the density and strength of the skeleton, the excitability of nerves, the accumulation of water, and can regulate the structure and function of the tissues and organs."

---
http://raypeat.com/articles/articles/co2.shtml

When mitochondria are “uncoupled,” they produce more carbon dioxide than normal, and the mitochondria produce fewer free radicals. Animals with uncoupled mitochondria live longer than animals with the ordinary, more efficient mitochondria, that produce more reactive oxidative fragments. One effect of the high rate of oxidation of the uncoupled mitochondria is that they can eliminate polyunsatured fatty acids that might otherwise be integrated into tissue structures, or function as inappropriate regulatory signals.

http://raypeat.com/articles/articles/un ... fats.shtml
"...it has become clear that the "uncoupled" mitochondrion, that "wastes oxygen and calories," is protective against free radicals, cancer, and aging. Thyroid hormone and the absence of PUFA are important factors in supporting the "wasteful" mitochondrion."

Bioorg Med Chem. 2008 Aug 1;16(15):7424-8. doi: 10.1016/j.bmc.2008.06.013.
Carbonic anhydrase inhibitors: inhibition of mammalian isoforms I-XIV with a series of substituted phenols including paracetamol and salicylic acid.
Innocenti A1, Vullo D, Scozzafava A, Supuran CT.
"The different mechanisms of inhibition by phenols as compared to sulfonamides, and their diverse inhibition profile for these mammalian isozymes, makes this class of derivatives of great interest...."

http://www.ncbi.nlm.nih.gov/pubmed/15505497
J Cardiovasc Pharmacol. 2004 Nov;44(5):591-5.
Inhibition of cardiac mitochondrial respiration by salicylic acid and acetylsalicylate.
Nulton-Persson AC1, Szweda LI, Sadek HA.

"...treatment of isolated cardiac mitochondria with salicylic acid and to a lesser extent acetylsalicylate resulted in an increase in the rate of uncoupled respiration."

Thanks for the links. It does seem that studies on CO2 are coming out at a greater rate then several years ago. Though I suspect it's due to global warming and people getting hired to publish apocalyptic results on the effects of CO2 on living organisms.
I don't know if you have taken DNP, but I found a way to mimic the effects of taking it pretty closely by using aspirin and MB. Optimal uncoupling occurs with aspirin in concentrations 0.5mM/L. This is achievable with 650mg - 1,000mg aspirin taken every 6-8 hours. With each dose, you can take 5mg MB for additive effect on uncoupling. MB uncouples starting at 0.5uM/L. And finally, you can add 500mg thiamine to each dose to mitigate some of the lactate boosting effects of aspirin and further increase CO2.
Using just the aspirin and MB combo makes me sweaty and hot in a way very close to what I experienced with DNP but without the unpleasant jittery feeling. Adding thiamine made me breath deeper, probably due to the lowered lactate and increased CO2.
 

sweetpeat

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Would taking thiamine at those levels also have a diuretic effect similar to acetazolamide?
 

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viewtopic.php?f=75&t=6825&p=82570&hilit=thiamine+cortisol#p82570
It seems like thiamine in combination with a low dose of acetazolamide (125 daily) is powerfully lowering my cortisol. I had been taking 125mg acetazolamide periodically for edema but after adding thiamine yesterday my face and neck are visibly less puffy which low dose acetazolamide alone did not do! It's probably too soon to say for sure but I certainly have felt more relaxed yesterday and today. Possibly placebo I know, only time will tell.
Hopefully the scientists will weigh in and answer your question with scientific reasoning instead of just anecdotal personal experience sweetpeat.
 

haidut

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sweetpeat said:
Would taking thiamine at those levels also have a diuretic effect similar to acetazolamide?

IF it does indeed inhibit carbonic anhydrase, then yes, it will have diuretic effect. Acetazolamide is a diuretic due to the increase in CO2, which extracts water from the cells and sends to the kidneys to excrete together with bicarbonate.
 

sweetpeat

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Blossom said:
http://www.raypeatforum.com/forum/viewtopic.php?f=75&t=6825&p=82570&hilit=thiamine+cortisol#p82570
It seems like thiamine in combination with a low dose of acetazolamide (125 daily) is powerfully lowering my cortisol. I had been taking 125mg acetazolamide periodically for edema but after adding thiamine yesterday my face and neck are visibly less puffy which low dose acetazolamide alone did not do! It's probably too soon to say for sure but I certainly have felt more relaxed yesterday and today. Possibly placebo I know, only time will tell.
Hopefully the scientists will weigh in and answer your question with scientific reasoning instead of just anecdotal personal experience sweetpeat.

How much thiamine did you take, Blossom?
 

sunmountain

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Does Allithiamine works as well as plain thiamine B-1? If so, what is the equivalent dose?
thanks
 

haidut

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sunmountain said:
Does Allithiamine works as well as plain thiamine B-1? If so, what is the equivalent dose?
thanks

If anything, it should be more effective but since the study was not done with allithiamine I cannot vouch for it. In terms of doses, you can try the same dose and then maybe try lower dose as allithiamine would achieve higher plasma concentrations with lower dose.
 

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sweetpeat said:
Blossom said:
http://www.raypeatforum.com/forum/viewtopic.php?f=75&t=6825&p=82570&hilit=thiamine+cortisol#p82570
It seems like thiamine in combination with a low dose of acetazolamide (125 daily) is powerfully lowering my cortisol. I had been taking 125mg acetazolamide periodically for edema but after adding thiamine yesterday my face and neck are visibly less puffy which low dose acetazolamide alone did not do! It's probably too soon to say for sure but I certainly have felt more relaxed yesterday and today. Possibly placebo I know, only time will tell.
Hopefully the scientists will weigh in and answer your question with scientific reasoning instead of just anecdotal personal experience sweetpeat.

How much thiamine did you take, Blossom?
500mg yesterday and 750mg so far today. I plan on increasing it to the 1500mgs per haidut's post. It seems to make me a bit sleepy or just too relaxed to work so my thought process on this was by increasing it each day I will become accustomed to it and still be able to manage my daily responsibilities. I only based this on my own personal reaction so I don't know if it would effect others the same way.
 

sweetpeat

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haidut said:
sweetpeat said:
Would taking thiamine at those levels also have a diuretic effect similar to acetazolamide?

IF it does indeed inhibit carbonic anhydrase, then yes, it will have diuretic effect. Acetazolamide is a diuretic due to the increase in CO2, which extracts water from the cells and sends to the kidneys to excrete together with bicarbonate.

Gotcha. Thus the need to make sure potassium is covered, I guess? I seem to remember a thiamine/potassium discussion in another thread.
 

sunmountain

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:)

If one takes high doses of thiamine, wouldn't it be necessary to supplement potassium? How do you supplement potassium, Blossom and SweetPeat? Do you take a supplement, and if so, which one and what dosage?
 

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