Do fumarates change into fumaric acid in vivo?

Discuss Tecfidera (BG-12, dimethyl fumarate) as an oral treatment for multiple sclerosis.

Do fumarates change into fumaric acid in vivo?

Postby Anonymoose » Sat Jun 24, 2017 9:08 am

Need brainier folks than I for this one...

Dimethyl fumarate and clemastine fumarate are both alleged to have potential beneficial effects on some pwms for different reasons or unknown reasons. Dimethyl might reduce relapses. Clemastine might contribute to remyelination.

IF fumarates are changed into fumaric acids by our bodies, might it be fumaric acids that are helping?

Fumaric acid is produced in our skin when it is exposed to sunlight. Maybe vitamin d is just the obvious/only tested indicator of deficiency of compounds normally produced by the skin. Maybe it's a fumaric acid deficiency or a deficiency of something else normally produced when skin is exposed to sun that we are missing...

Help me brainiacs. Don't make me try to learn chemistry to quench my curiosity. I'd rather eat bugs!
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Re: Do fumarates change into fumaric acid in vivo?

Postby NHE » Sun Jun 25, 2017 1:09 am

Anonymoose wrote:Need brainier folks than I for this one...

Dimethyl fumarate and clemastine fumarate are both alleged to have potential beneficial effects on some pwms for different reasons or unknown reasons. Dimethyl might reduce relapses. Clemastine might contribute to remyelination.

IF fumarates are changed into fumaric acids by our bodies, might it be fumaric acids that are helping?

Fumaric acid is produced in our skin when it is exposed to sunlight. Maybe vitamin d is just the obvious/only tested indicator of deficiency of compounds normally produced by the skin. Maybe it's a fumaric acid deficiency or a deficiency of something else normally produced when skin is exposed to sun that we are missing...


Here is dimethylfumarate.

Image

It's the methyl ester of fumaric acid. It's a potent oxidizing agent that attacks thiol groups and is thought to act as an Nrf2 activator. There are many molecules in nature that do this. Here's a free review paper that discusses some of them.

Here is clemastine fumarate.

Image

As you can see, it's fumaric acid with a clemastine moiety. It's likely the clemastine that contributes to remyelination. However, I'm not familiar with clemastine. Apparently, it acts as an antihistamine.

https://www.ncbi.nlm.nih.gov/pubmed/8574128
https://www.ncbi.nlm.nih.gov/pubmed/9356796

Anonymoose wrote:Help me brainiacs. Don't make me try to learn chemistry to quench my curiosity. I'd rather eat bugs!


humor-f16/topic19944.html#p191837

Bugs are good. We eat bugs and bug parts all the time. It's nearly impossible for commercial food producers to eliminate all traces of them so there are federal regulations that limit the number of bug parts in food.
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Re: Do fumarates change into fumaric acid in vivo?

Postby Anonymoose » Sun Jun 25, 2017 4:40 am

Thanks, NHE. Why you always gotta use those dumb stick figures on me? ;oP
Does any of that mean fumarates change into or don't change into fumaric acid in our bodies?

I don't think it's certain that DF works via nrf2.
Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2
http://m.pnas.org/content/113/17/4777.short

Like everything else MS, I guess I'll just have to keep wondering about this too.
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Re: Do fumarates change into fumaric acid in vivo?

Postby NHE » Sun Jun 25, 2017 11:09 pm

Anonymoose wrote:I don't think it's certain that DF works via nrf2.
Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2
http://m.pnas.org/content/113/17/4777.short


Schulze-Topphoffa et al. wrote:Significance: Dimethyl fumarate (DMF) (BG-12, Tecfidera), a fumaric acid ester (FAE), is a commonly prescribed oral therapy for multiple sclerosis (MS), a CNS autoimmune inflammatory demyelinating disease that may result in sustained neurologic damage. It is thought that the benefit of DMF in MS therapy is mediated through activation of the antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. However, the role of Nrf2 in the antiinflammatory effects of DMF has not been fully elucidated. Here, we investigated the role of Nrf2 in DMF treatment of the MS model, experimental autoimmune encephalomyelitis (EAE), and demonstrated DMF can modulate T cells, B cells, and antigen-presenting cells, and reduce clinical and histologic EAE, independent of Nrf2.


Yes, We know that Tecfidera depletes and modulates immune cells. That's why patients need to be monitored for PML.

There have been speculations for years that the drug's efficacy in treating MS, as well as psoriasis, may just be due to simple immune suppression.

general-discussion-f1/topic21537.html#p203536
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Re: Do fumarates change into fumaric acid in vivo?

Postby Anonymoose » Mon Jun 26, 2017 10:23 am

The thing that excites me, being one strongly against using immunomodulation as a disease coverup rather than as a treatment for the cause of disease, is that just MAYBE it's the fumaric acid that's at least partially responsible for helping.

Unscientific, accidental study of one...After two extremely stressful, demanding years, my energy crashed again a few months ago. I had labs done and found my iron/ferritin in low end of normal range so I started taking iron and b complex and got some energy back but still wasn't great. My allergies started bugging me so I broke out my stash of clemastine fumarate and started taking one at night with my iron. For the first time in months I woke up with a clear head, ready to go. If I don't take both, I wake up foggy. Yesterday, I was googling fumaric acid some more and found a post on an autism board by a mom who saw improvements in son with succinate and fumarate supplements. Something to do with the Krebs cycle which I know very little about. Since I don't really like taking "medicine," I ordered supplements to test her idea out (ferritin fumarate and e tocopheral succinate). Then I looked at my current iron supplement, ultimate iron. It's form of iron is ferrous succinate. I was already unwittingly using the fumarate/succinate combo and it seems to work for energy and clarity of mind. Will keep playing and see what happens.

Anywho, I'm always thinking out of the box cuz the box that's out there doesn't work and no one, including big pharma or big doctor, has a complete grasp of anything having to do with a living body.

Thanks for helping me bounce things around. :)

Edit to add: I'm tan from taking dogs to dog park 6 hours a week...those trips made no difference in how I felt...'cept they were fun and made me happy. Maybe skin not making fumeric acid when exposed to sun? Too little info to even guess.
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Re: Do fumarates change into fumaric acid in vivo?

Postby Jimpsull » Tue Oct 03, 2017 6:58 pm

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Re: Do fumarates change into fumaric acid in vivo?

Postby Anonymoose » Tue Oct 10, 2017 7:43 am

Just a follow up on status of my goofy idea re: possible fumaric acid deficiency. After a washout, I had an organic acid panel run. My FA levels are perfectly normal...not even at the low end of range. Still low on vitamin d too (random factoid). Another one bites the dust.
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Re: Do fumarates change into fumaric acid in vivo?

Postby sam112233 » Wed Dec 13, 2017 12:23 am

Fumarate is an intermediate in krebs cycle so is important to make ATP along with being able to treat MS, psoriasis, and lots more diseases. At low pH fumaric acid is still protonated- an acid. At blood pH the protons come off, and it becomes fumarate so they are the same thing for the purpose of discussion. The reason a pharma company added ethanol (drinking alcohol), and methanol (wood alcohol) to fumaric acid is so they can get a patent on it. It breaks down to just fumaric acid + the alcohols once in the intestines/blood. Methanol is toxic even in low doses. I have read reports of people taking methyl fumarate for psoriasis getting very bad side effects like kidney/liver problems after 1 year on it, along with diarrhoea, and other GI problems. This is the methanol/wood alcohol doing it not the fumaric acid. This would be another reason they put not just ethanol but methanol with it- to cause bad side effects so someone stops taking it, and settles for a less effective prescription drug.

Fumaric acid can be purchased by itself. On eBay USA someone is selling 454g for 8 AUD$ plus postage. It might be on Amazon too or google "buy fumaric acid (country name)" Food ingredient suppliers sell it also. It is E297. Or Ali Baba if all else fails. I started on 10g today for a suspected mitochondrial disease, and it has had a nice calming, relaxing effect already. It can just be stirred in water, and taken or use a capsule making machine, and make capsules out of it. I made 60 size 000 caps of it today. Each one holds 1.3g which is a good amount. I will take 5-10g a day from today so will let you know how it goes.
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Re: Do fumarates change into fumaric acid in vivo?

Postby NHE » Wed Dec 13, 2017 1:43 am

sam112233 wrote:Fumarate is an intermediate in krebs cycle so is important to make ATP along with being able to treat MS, psoriasis, and lots more diseases. At low pH fumaric acid is still protonated- an acid. At blood pH the protons come off, and it becomes fumarate so they are the same thing for the purpose of discussion. The reason a pharma company added ethanol (drinking alcohol), and methanol (wood alcohol) to fumaric acid is so they can get a patent on it. It breaks down to just fumaric acid + the alcohols once in the intestines/blood. Methanol is toxic even in low doses. I have read reports of people taking methyl fumarate for psoriasis getting very bad side effects like kidney/liver problems after 1 year on it, along with diarrhoea, and other GI problems. This is the methanol/wood alcohol doing it not the fumaric acid. This would be another reason they put not just ethanol but methanol with it- to cause bad side effects so someone stops taking it, and settles for a less effective prescription drug.

Fumaric acid can be purchased by itself. On eBay USA someone is selling 454g for 8 AUD$ plus postage. It might be on Amazon too or google "buy fumaric acid (country name)" Food ingredient suppliers sell it also. It is E297. Or Ali Baba if all else fails. I started on 10g today for a suspected mitochondrial disease, and it has had a nice calming, relaxing effect already. It can just be stirred in water, and taken or use a capsule making machine, and make capsules out of it. I made 60 size 000 caps of it today. Each one holds 1.3g which is a good amount. I will take 5-10g a day from today so will let you know how it goes.


BG-12 and fumaric acid are two different, but related, molecules. BG-12 is dimethyl fumarate. It has the following structure...

    Image

It reacts with thiol groups, -SH, such as those found in glutathione and cysteine residues oxidizing them. Cells sense this oxidative stress and activate the transcription of cell protective genes for antioxidant enzymes.

In contrast, fumaric acid is a dicarboxylic acid where the -CH3 groups are replaced with H.

    Image

It doesn't have the same chemical reactivity with thiols and won't activate the cell protectant genes that dimethyl fumarate activates.

One thing to know is that there are many molecules in nature that have similar functional groups as dimethyl fumarate which gives them similar reactivity with thiols. Here's a free review paper which discusses them.

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Re: Do fumarates change into fumaric acid in vivo?

Postby sam112233 » Wed Dec 13, 2017 1:49 am

Is it the toxic methanol that is the oxidant or is it the naturally occurring fumarate, which is in most cells in the body, is anti cancer, and anti oxidant, that is the oxidant? It is the methanol not the fumarate.

It is not the reactivity with thiols that makes di methyl fumarate good it is the fumarate. The methanol component is bad. Fumaric acid is better than methyl fumarate.

https://www.frontiersin.org/files/Artic ... 5-g001.jpg
https://www.frontiersin.org/articles/10 ... 00085/full

Naturally occurring molecules actually treat disease. There is no need to add functional groups to it (well ethyl fumarate makes it more water soluble- not that it matters. When it gets to pH 5-7 of the intestines it will dissolve properly) other than to create a patentable molecule.
Last edited by sam112233 on Wed Dec 13, 2017 2:33 am, edited 1 time in total.
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Re: Do fumarates change into fumaric acid in vivo?

Postby sam112233 » Wed Dec 13, 2017 1:58 am

I bought this health encylopedia for 95 USD http://hyperhealthencyclopedia.com/order_info.htm
The download link is broken so email them if wanting to buy it

It is really good. It has amino acids, organic acids, minerals, vitamins, food, prescription drugs, and more in there. Here is the page on fumaric acid

Also known as: Allomaleic Acid; Fumarate


Description

Fumaric Acid is an endogenous Organic Acid that is also present in the diet.


Biological Functions and Health Benefits of Fumaric Acid

Immune System

Fumaric Acid may be useful for the treatment of Sarcoidosis. references

Metabolism

Fumaric Acid participates as an intermediate compound in the Krebs Cycle of Energy production within the Mitochondria of Cells - Fumaric Acid is the intermediate Organic Acid between Succinic Acid and Malic Acid within the Krebs Cycle:

- View Fumaric Acid's Role in the Krebs Cycle

- Supplemental Fumaric Acid (3,000 - 6,000 mg per day) facilitates the endogenous production of Energy, alleviates Fatigue and increases Stamina. references

Fumaric Acid is formed as an intermediate product in the Urea Cycle (the process of detoxifying Ammonia to Urea):

- View the Urea Cycle

Nervous System

Fumaric Acid stimulates the activity of Dopamine Beta-Hydroxylase (the enzyme that catalyzes the conversion of Dopamine to Norepinephrine
).

Skin

Fumaric Acid (1% - 3% solution applied topically in conjunction with oral administration of 240 mg - 720 mg per day) may be an effective treatment for many cases of Psoriasis (caution is warranted as this treatment causes some side effects): references

- Psoriasis patients have a metabolic defect that interferes with their natural production of Fumaric Acid and this defect contributes to the development of Psoriasis.

These Substances may Enhance the Function of Fumaric Acid

Enzymes

Fumarate Hydratase (Fumarase) catalyzes the conversion of Fumaric Acid to Malic Acid as part of the Krebs Cycle of Energy production.
Succinate Dehydrogenase catalyzes the conversion of Succinic Acid (Succinate) to Fumaric Acid (Fumarate).

These Substances may Interfere with Fumaric Acid

Organic Acids

Tartaric Acid may interfere with the conversion of Fumaric Acid to Malic Acid within the Krebs Cycle of Energy production (this occurs from Tartaric Acid being an analogue of Malic Acid). references

Dietary Sources of Fumaric Acid note

Herbs: Chives
Vegetables: Beetroot Fennel
Forms of Fumaric Acid

Calcium Fumarate consists of Calcium bound to Fumaric Acid (Fumarate).
Dimethylfumaric Acid (Fumaric Acid Diethylester) is a form of Fumaric Acid used in the treatment of Psoriasis.
Monoethylfumaric Acid (Fumaric Acid Monoethylester; Monoethylfumarate; Monomethylfumatric Acid; Monomethylfumarate) is a form of Fumaric Acid used in the treatment of Psoriasis.

Dosage Recommendations

Metabolism

The usual dosage of Fumaric Acid when used for enhancing Athletic Peformance and Energy is 1,000 mg taken approximately 45 minutes before physical activity.

Skin Ailments

The usual dosage of Fumaric Acid when using the Dimethylfumaric Acid form of Fumaric Acid for the treatment of Psoriasis is 240 mg per day. It is administered orally in conjunction with topical application of a 1% - 3% solution of Fumaric Acid.
The usual dosage of Fumaric Acid when using the Monethylfumaric Acid form of Fumaric Acid for the treatment of Psoriasis is 720 mg per day. It is administered orally in conjunction with topical application of a 1% - 3% solution of Fumaric Acid.

Commercial Availability of Fumaric Acid Supplements

“Singular” Products

Fumaric Acid is available from health food stores and internet-based suppliers in the form of:

- 120 mg capsules

Formulas

Fumaric Acid is an ingredient in some sports formulas available from health food stores and mail order supplement companies. For example:

- powder containing 1,000 mg Fumaric Acid per 17 gram serving.

Chemical Data

Chemical Name

Trans-Butanedioic Acid

Related Topics

Krebs Cycle
Organic Acids
Pycnogenol

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Re: Do fumarates change into fumaric acid in vivo?

Postby NHE » Wed Dec 13, 2017 3:03 am

sam112233 wrote:I bought this health encylopedia for 95 USD http://hyperhealthencyclopedia.com/order_info.htm
The download link is broken so email them if wanting to buy it


From the listed system requirements that program is ~ 20 years old.

    "IBM-compatible PC, 386SX or higher,
    Windows 98 or higher,
    4 MB RAM,
    CD-ROM Drive
    VGA driver in 256 color mode"

I remember 386SXs. Trying to run Win98 with 4 MB ram on one would have been an exercise in futility.

:roll:
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Re: Do fumarates change into fumaric acid in vivo?

Postby sam112233 » Wed Dec 13, 2017 3:11 am

Oh lol. It is actually number 11 not 6. I am using it now. It is really good I would recommend it. It will save someone a lot of time rather than having to search through the literature. They can do a literature search after looking at something in the program if they want to find out more specific information. And it will save someone a lot of time, and money when buying, and trying different nutritional supplements because they can find out really specific things first about what the nutrient does, if it might help them, what bio chemical pathway it is in, what deficiency symptoms are etc.
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Re: Do fumarates change into fumaric acid in vivo?

Postby NHE » Wed Dec 13, 2017 3:16 am

sam112233 wrote:Is it the toxic methanol that is the oxidant or is it the naturally occurring fumarate, which is in most cells in the body, is anti cancer, and anti oxidant, that is the oxidant? It is the methanol not the fumarate.

It is not the reactivity with thiols that makes di methyl fumarate good it is the fumarate. The methanol component is bad. Fumaric acid is better than methyl fumarate.

Naturally occurring molecules actually treat disease. There is no need to add functional groups to it (well ethyl fumarate makes it more water soluble- not that it matters. When it gets to pH 5-7 of the intestines it will dissolve properly) other than to create a patentable molecule.


I suggest that you get out your organic chemistry textbook and review Michael Addition.

Here's a mechanism that illustrates the reaction of a different Nrf2 activator with a thiol group.

Image
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Re: Do fumarates change into fumaric acid in vivo?

Postby sam112233 » Wed Dec 13, 2017 3:56 am

Fumaric acid activates nrf2 itself. Methanol just depletes glutathione making the person sicker. If methanol was so good then alcoholics who drink methylated spirits would be in awesome health but instead they get sicker, and sometimes die after metho binges. It happened to one of my mums old tennants. Once he started on the metho there was no stopping him. He was found dead a few weeks later in the flat.
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