This is the start of a series of posts on Dimethylfumarates.
For long it is yet known that fumarates have a very positive effect on psoriasis and arthritic psoriasis. Still fumarates did not have their breakthrough in medicare. The causes for this will be part of this series.

In the Netherlands the use of fumarates is much more normal than in other countries, there is even a patients organization that promotes the use of a specific form and is busy starting up scientific research to prove that this form is much less toxic with a much better effect than most other medicines.

I do not write this "by my own", the texts are mainly a translation of publications of dr. L.Kunst and dr. Schweckendieck, and I will make references to existing literature on the subject.

Why do I do this?
Well, while speeding around on the different threads of this forum, I found out that there are lots of psoriasis sufferers. None of them are using fumarates, I seem to be the only one. And if I read well, I am also one of the posters that has minor problems with psoriasis, I even have arthritic psoriasis which is very "livable" and relatively under control, with very few extra problems from the medication.
I think it makes sense to share what I know. Maybe some of you will make a try with what I use, and maybe this will help them. The forum on the dutch site shows a lot of people that are very pleased with this medicine.

Below part one of a translation from the site psoriasistherapie dot nl on fumarates. As it is a translation, there may be stupid constructions in the sentences. My mastery of english is quite acceptable, but translating is quite a different job.

First some background information to build up the story.

Energy housekeeping and fumaric acid.

Fumaric aced is a body own substance. Chemically seen it is an unsaturated dicarbon acid. It is formed from cis-butanecarbonic acid (cis-barnstoneacid) under influence of succinatehydrogenasis. This biochemical conversion is a component of the so-called citric acid cycle, and takes place in the mitochondria. Mitochondria are not only the power of our cells, they play an important role in essential metabolic processes and the genetic transfer of a large number of degenerative diseases through specific mitochondrial DNA. A variety of genetic disorders can be attributed to mutations in the mitochondrial DNA, such as defects in the citric acid cycle. The citric acid cycle is a cycle in which oxidation of carbon compounds are oxidized to carbon dioxide. The carbon-containing compounds are derived from fats, sugars and amino acids. The vast majority of fuel is supplied in the form of acetyl-CoA. The citric acid cycle contains except fumaric acid, several intermediate metabolites, such as shown in the accompanying illustration.


The upper portion of pyruvic acid to acetyl-coenzyme A does not actually belong to the citric acid cycle, but it's there to follow up the glycolysis. The reactions involving NAD + conversion to NADH and GDP to GTP and FAD to FADH2 mean that energy is released and that this energy has gone into these compounds formed. This energy is required with all of the biochemical processes in the body.

More to follow in a next post.

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EDIT by Fred:

There is another thread for members conversations about about Dimethylfumarates here: [split] Dimethylfumarates and Psoriasis

You may also be interested in Bill's pure dimethylfumarate thread

And this one explains Fumaderm which is a DMF that you will probably get prescribed in pats of Europe. Fumaderm

Because energy plays such a vital role in our bodies a number of researchers have, including Nobel Laureate Szent Györgyi after the discovery of the citric acid cycle by Hans Krebs in 1937, done research to the cause of various chronic diseases suspected in mitochondrial dysfunction.
Out of that hypothesis, they have done experiments with all possible metabolites of the citric acid cycle in various diseases, without ever having achieved anything.
However, fumaric acid was not investigated, let alone fumaarzuuresters. It was thought at that time, in accordance with the above classical scheme (see previous post), that fumaric acid in the body is easily formed from succinic acid, and therefore, it was not tested separately. Succinic acid has been well studied for efficacy.
Also Schweckendieck, who himself was a psoriasis patient, started from the hypothesis that psoriasis is a mitochondrial disease, and he also performed this type of testing itself.
He did test, fumaric acid and found that this substance, as the only one of all other metabolites of the cycle, both orally and on the skin causes major reactions.
In the meantime, Schweckendieck found out that fumaric acid can only be formed of cis-succinic acid, and not by means of the normal (trans-) succinic acid. In the above schematic model (previous post), this distinction is not made. [For the synthesis of cis-succinic acid the Japanese T. Hara obtained in 1965 a patent].

According to his description fumaric acid caused erythema on his skin, and if taken in sufficient dosage, heat waves in the body (you bet it does....Caroline.). The publication of these interesting properties of fumaric acid by Schweckendiek in 1959, should have shaken the biochemists awake, if only it was for changing the name citric acid cycle into "Fumaric acid cycle".
A second argument is the special position of fumaric acid, because from there are three dicarboxylic acids synthesizable: oxaloacetic acid, malic acid, succinic acid and cis. Citric acid lacks this potential.
However, the name fumaric acid cycle despite the suggestion of Schweckendieck, never established and fumaric acid remained in the background.
Schweckendieck was disappointed that his groundbreaking discovery found no echo, but for him personally, it was obviously the most important thing. He could successfully treat his psoriasis with fumaric acid. There was a drawback in that, to achieve success quite a few grams of fumaric acid, at room temperature a crystalline powder, had to be used. That led to gastrointestinal complaints with Schweckendieck and brought him the idea to attempt the use of fumaarzuuresters as they by their lipophilic pool they easier penetrate the mitochondria than the acid.

Fumaric acid can bind to biochemical alcohols. The main esters which are at issue here concern dimethyl and monoethyl ester, respectively, DMF and MEF. MEF can also make compounds with metals such as K, Na, Mg, Zn, Cu, etc. Schweckendieck expanded his experiments with these esters. This was a hit. The esters worked much stronger, they could be dosed in milligrams and at high doses could even give a rise in temperature upto artificial fever.
Combination of different esters, appeared to be in practice a good choice. This led eventually to the industrial preparate Fumaderm ®, containing DMF plus various salts of MEF.
The additional commercial advantage of this complicated formula is, of course, the idea that imitation by local pharmacists of this unpatentable product, as far as possible is prevented. Fumaderm ® is extensively tested at home and abroad, including Germany and Switzerland and much used over there. Under current legislation, in the Netherlands it can only be prescribed with the aid of a so-called "Medical certificate". Because of that it is many times more expensive than psorinovo. For some years fumaderm is more or less copied and produced by Tiopharma in Oud Beijerland.

In 1985 the first large clinical research with fumarate was publicized in the netherlands by the original author of this post, dr. L. Kunst. This research was an open trial.
He described the positive effect of DMF with 100 psoriasis patients in his practice. By means of several tests he was able to conclude that DMF was the most active component of the combination preparate.
Together with F. Durlinger, pharmacist, he developed the, only DMF containing preparate, psorinovo.
It concerns a dosage form that provides a gradual as possible release of the active substances in the gut and then into the circulation.
In the tablet are DMF and a catalyst to promote biological oxidation. A special coating of the tablet prevents premature disintegration in the stomach.
The generic name of psorinovo is dimethylfumarate enteric coated slow release.
Because from the beginning on there was a difference in opinion on the mechanism of fumarate, the author in 1985 posted the open question on how this mechanism is working.
The last sentence of his article reads:"This aspect can only be studied in a scientific researchcentre, where e.g. are possibilities to observe the mechanism in celcultures." For long time then it remained a little silent on fumaric acid.

Thirteen years later, in 1998 dr Kunst had more than 1500 patients with psoriasis treated with psorinovo. He published his experiences in an article in which he pointed to the above described research of Schweckendieck about generating artificial fever with fumarate (3 Kunst, L., Fumaarzuurtherapie bij psoriasis, Ned Tijdschr Int Geneeskd.1998; 6, 243-251). Dr Kunst concluded that a deficiency of fumaric acid or its inhibition results in an energy deficit, which apart from the onset of psoriasis, also can be expressed in reduced body temperature, fatigue, feel less energetic, etc.
These phenomena are, because they are so general, by physicians often overlooked and not associated with psoriasis. In his practice, dr Kunst has however at dozens of psoriasis patients not only determined their temperature (sometimes morning temperatures of 36.7 ° C and below), but also that the psoriasis began to improve only when the temperature was clearly increased. One example describes M.de Bruijn in his medical history on this website. Treated patients also regularly stated that they were going to feel more energetic as the psorinovotherapie went successful.
Based on the results of temperature measurements and the subjective experiences of patients, dr Kunst concluded that the beneficial effect of fumarate actually has something to do with improving the energy metabolism and the concerned citric acid cycle (fumaarzuurcyclus).
An observation that was necessary because in the apparent contradiction with this, the operation of fumarates, in general, is perceived as an inhibition of autoimmune symptoms. A one-sided view which has important implications for the application of the drug because drugs in this category generally have very undesirable side effects. However, whether the efficacy of fumarate in psoriasis patients is based on such stimulation of the citric acid cyle, in the present state of science this can be answered with certainty only by measuring the basal metabolism before and during the use of this drug. Such research is in the literature so far not yet described and, where dr Kunst is known, also nowhere suggested.

However a study, by Ionescu and Kiehl in 1992, shows this relationship in a completely different way.
They studied skin and blood cells of psorioasispatiënten and found that in psoriasis there is decreased ATP, ADP and cAMP concentrations and abnormal purine nucleotide concentrations in both cell types.
According to these authors the essence of psoriasis is, a run-beaten (de-railed) purine nucleotide metabolism (4).
For the production of RNA and DNA, cells need the necessary mitochondria. The building blocks of RNA and DNA purines and pyrimidines.
The run beaten purine nucleotide metabolism thus apparently refers to a mitochondrial problem.
And because these abnormalities in both blood cells and in the skin cells were found, this study shows unambiguously that psoriasis is not a disease confined to the skin.
That means that Psoriasis is a mitochondrial disease that manifests in different organ systems.
Scientifically speaking, the idea that psoriasis is a skin disease, is outdated, even while the skin manifestations are usually the ones in the foreground.
The creams as first choice, often for years prescribed are in essence only cosmetics that are bad for the skin (see e.g. the case histories of Hans Graves and Vic Asselberghs on this[the dutch] site).
A further substantiation of this view shows the follow-up study of Ionescu and Kiehl.
They incubated the skin and blood cells of psoriasis patients with fumarate. As a result, an increase of the concentration of ATP and the cyclic AMP levels, while at the same time the purine nucleotide synthesis was inhibited.
Both of these effects are in accordance with these authors, characterized by a stimulation of the citric acid cycle, and both effects inhibit the DNA-and protein synthesis, so that the abnormal cell growth (psoriatic uncontrolled cell growth) decreases.
Nibbering et al in 1993 compared with the help of an in vitro study the effect of the MMF (monomethylfumaraat) and DMF at granulocytes (5).
They concluded, as did Litjens 10 years later (6) - that the principle of operation of both compounds is similar, namely that incubation of a granulocytensuspensie leads to increase in cAMP. The concept of "stimulation of the citric acid cycle" not only explains the beneficial effect of fumarate in psoriasis on the skin, but also the flushing, the measured global (body) warming and its effects on rapidly regenerating cells and tissues.
The latter concerns the slight leukopenia, the eosinophilia, lymphopenia and the irritations of the intestinal mucosa (Ionescu and Kiehl). These often unwanted side effects entered phenomena are in fact a sign of proper operation, however it can be too strong and therefore a nasty side.
Significant effect is that these effects being almost always transient and will disappear, which is also recognized by the skeptics.
The more gradual the dosage is increased, the sooner the body is accustomed to the new situation and the sooner the abnormalities in the blood picture are vanished.
If there would be real toxicity, in laboratory detected abnormalities would obviously only increase and persist after cessation of psorinovo-usage.
The reverse appears to be the case shown. Many patients in the practice of dr Kunst, who initially had more or less of these "side effects", but with mutual patience could still be well set up and use for many years now psorinovo in full satisfaction.
Several case histories on the dutch site show this. And on the forum of that site regular new cases of success appear.

Under-temperature may also be due to causes other than an inhibition of the citric acid cycle.
For example, a thyroid hormone deficiency, but of course also other diseases should be excluded or treated.
If with psoriasis patients the lower (under) temperature does not improve, improvement of the skin manifestations will not be achieved. The treatment with fumarates gives, in the case of thyroid hormone deficiency only result when such patients are using T3 and / or T4, of course, under good medical supervision.
Also other internal diseases can block the effect of fumarate. This block must be removed anyway/anyhow. In such cases one speaks of "comorbidity".
A comprehensive, internally directed investigation may be indicated in such cases. The internist Dr.. F.P.L. van Loon thus has already gained much experience.
Physicians (doctors) who limit their diagnostics to viewing of the skin (skin inspection) may therefore miss important diagnoses with the result that the fumarate treatment does not succeed or gives unwanted side effects.

That psoriasis is called an autoimmune disease is already known for decades. We must realize ourselves that that suggests more than it clarifies.
It suggests that we understand the disease as we know both cellular and humoral events in the immune system. These are, however, only reactions, reactions of the immune system, not the cause of disease.
The auto antigens to which the psoriasis-specific T lymphocytes are aimed are still not defined and that isn't different for many autoimmune diseases.
Both for the pathogenesis as for the treatment this knowledge delivers little because it doesn't tell anything about the root cause of this disorder. Of course we can paralyze the immune system with immunosuppressors, but that gives always great risk's. We do not have the immune system, for nothing and the suppression of it can lead to other serious diseases.

Naviaux, director of the Mitochondrial and Metabolic Disease Center at the University of California mentions in The Spectrum of Mitochondrial Disease dozens of degenerative diseases that are wholly or partly based on mitochondrial mutations (6).
Various abnormalities of the citric acid cycle are then listed, but also M Alzheimer, M. Parkinson M.S., SLE, R.A and many others. Some of which are known under the generic name: auto-immune disease.
In 2004 a thesis appears on the above, citing NHR Litjens at Leiden University which deals on the effects of fumarate (7).
In vitro cell cultures were incubated with various components of the citric acid cycle and fumaarzuuresters. The efficacy of MEF (Mono-ethylfumarate) was negligible, DMF was a good second and MMF (monomethylfumarate) was most active. MMF is a substance that is not itself available as a medicament. This substance is formed in the intestine by demethylation of DMF, according to Litjens.
Previously Nieboer et al (8) in a clinical trial already had found that MEF in itself does not have an antipsoriatic effect.
That Schweckendieck healed himself in 1959 of psoriasis with the help of fumaarzuuresters, as in the thesis is stated, is not entirely correct. Schweckendieck accomplished this result with fumaric acid (9). To achieve his goal Schweckendiek had to use doses in grams, with unpleasant gastrointestinal complications. Later he carried on using fumaarzuuresters, stating that the difference between the acid and its esters is gradual, not essential, according to Schweckendiek.
Following the in vitro study, Litjens continued his studies in various groups of healthy volunteers and psoriasis patients over time. It was only aimed at examining the influence of the fumaarzuuresters, in particular of DMF. MMF which results from the hydrolysis of DMF, is intracellular further hydrolysed to fumaric acid, and then ends up in the citric acid cycle "as a fuel".
It follows that the stimulation of the citric acid cycle is that of having a regulatory effect on the immune system, in particular, to certain characteristics of psoriasis cells in the skin (T lymphocytes and dendritic cells) and on the cytokynebalance.
In the next paragraph below titled "DMF versus MEF" is the literal text of the thesis cited, showing that stimulation of the mitochondria according Litjens the purpose of the fumarate treatment.
This is based on the above finding and is also very obvious, but curiously we find nowhere this link back into the summary or in the hypothesis of this thesis.
There the author only repeats the usual classification of psoriasis as an autoimmune disease.
Regarding the side effects of this treatment in the final conclusion is said: "The adverse reaction profile of the fumarate-therapy is usually mild and temporary, the fumarate-herapy can therefore be seen as a safe anti-psoriasis therapy which can be used for a long term."

I have decided after talking with Caroline to split this thread up as it was starting to get a bit messy and sometimes off topic, we all want our readers to be able to find the information and wading through this thread had become a bit difficult.

You're all still welcome to carry on the conversation as I have moved the majority of the posts to a new thread which you can find here: [split] Dimethylfumarates and Psoriasis

I have now locked this thread and Caroline will be the only one who has access to it, she will post only relevant information on the subject Dimethylfumarates that she feels is suitable to give people a better understanding all in one place.

I think this will be better all round as this thread will give all the information in one place, and the conversation can continue without disrupting it.

Any questions please let me know or post on the new Split Thread.

Thank you

Fred.

DMF versus MEF

Although the in vitro research of Litjens has shown that DMF is evidently effective in contrary to MEF, several clinical studies still show, that the combination of DMF/MEF gives a faster result than the treatment with DMF alone.
But concerning the end result there is no difference in the treatment with DMF or the combination DMF/MEF.
Because MEF does not have a result by itself, the explanation of this pharmacodynamic difference can be found in the availability of metal-ions in MEF.
Metals can catalize biochemical reactions, and specifically the reactions in the citric acid cycle. This effect was researched in the Eighties and it was determined which metal-ion was the most effective in combination with DMF, this metal-ion was added to Psorinovo, while removing the MEF. (In the mean time this had disappeared again, there are no metal-ions anymore in the medication).
Strangely enough most studies in the past and present rest on the use of the DMF/MEF cocktail, and this formula is as is produced and prescribed in the Netherlands. Sebok et. al did describe in 1994 an in vitro study showing the working principle of MEF and DMF on hyper proliferative HaCa keratinocytes. They found that the therapeutic width of DMF is larger than that of MEF, which means that MEF in therapeutic doses is more toxic than DMF.
Hagedorn M, et al showed in animal tests that MEF slows the DNA synthesis by preventing the inclusion of 14C thymidine. Also Hohenegger M et al, showed the damaging effect of the monoethylester of fumaric acid very clearly. So this means that there is no good reason to use combinations of MEF and DMF. The product "Fumarate" of Thiofarma, which contains next to DMF also MEF, is however still available on the market. And is prescribed by some dermatologists, and is strangely enough fully paid by the insurances.