[split] Dimethylfumarates and Psoriasis

[Caroline]

At least I have not killed myself. What I dont understand is the assumption that my treatment is inherently bad. Is my disease not controlled? Are there better treatments available for my disease? Have I been forced to take less than ideal treatments by reason of economy? Have I had to wait long periods to access treatment? Is my treatment expensive? Can my treatment be customised to maximise the benefit for me? Have I suffered adverse effects and am I being adequately monitored? Surely outcome is a more important consideration than provenance? Can a medication costing $10 a year not be more effective than a medication costing $2000 a year or $20,000 a year?

ps. I am looking forward to my next dose so I can see if two grams of cysteine taken half an hour before the DMF reduces my side effects. This could be useful information.

Hi Bill,
You did a great job not killing yourself  

• I think nobody thinks your treatment is inherently bad, it certainly is not as DMF is one of the best and most harmless medications working against Psoriasis and PsA.
  
• Your disease is excellently controlled, which does not surprise me as I know that from many others.
  
• Personnaly I do not think that there are better treatments, or it must be the easier one with Psorinovo.  
  
• Economically nobody can and has to force you to other treatments.
  
• Your treatment is immediately available, no hassle with NHS or other insurers or healthcare.
  
• Your treatment is by far the cheapest treatment on Psoriasis ever.
  
• You personally have created the most effective way to use your treatment.
  
• You monitor all important elements of the effects of your treatment yourself and will see changes on a very short notice.
  
• If you mean with provenance that the origin should be a pharmacist, than I immediately agree with you. No need for people to earn money on you.
  
• Certainly a cheap medication can be better than an expensive one, I know that already for years. Only for some strange reason, or plain ignorance, stupidity or bribery, this thought will almost not enter the brain of a dermatologist. Even new medication with DMF, Almiral is on its way, will cost more money than yours and probably more than Psorinovo.
  

Caroline

[Bill]

Caroline, there is research that shows reduced drug efficacy in patients who have developed antibodies for the particular drug. Search "antidrug antibody psoriasis". DMF is probably way too small and breaks down way too fast for such a problem. Once started on DMF, if you can get efficacy without destroying your lymphocytes you can keep going. I apologise for being brief, but generally I dont like rambling on: I would rather be playing with my dogs.

Cheers,

Bill

[Caroline]

Caroline, there is research that shows reduced drug efficacy in patients who have developed antibodies for the particular drug. Search "antidrug antibody psoriasis". DMF is probably way too small and breaks down way too fast for such a problem. Once started on DMF, if you can get efficacy without destroying your lymphocytes you can keep going. I apologise for being brief, but generally I dont like rambling on: I would rather be playing with my dogs.

Cheers,

Bill

Indeed Bill, DMF seems to be in a special position. Still there are mentions of people with whom also the DMF started to fail. Also my doc said to me that it is possible that you body will also finally resist against DMF. He therefore advises the intermittent approach that you are following and he suggests that you sometimes should take a break of a few months and then restart again.

On the one side I know a few people where the DMF stopped working or who needed to have a higher dose, on the other hand I know people who have used it for ten's of years and with whom it it still working excellently.

Cheers,
Caroline.

[Bill]

I've seen numerous cases here that ceased because of the side effects. The 3*240mg daily dosing only took me so far, and although I think that I could improve further on 3*810mg a week, I will have to bide my time on 2*810mg and a bit of sunshine for a while.

Cheers,

Bill

[Caroline]

I've seen numerous cases here that ceased because of the side effects. The 3*240mg daily dosing only took me so far, and although I think that I could improve further on 3*810mg a week, I will have to bide my time on 2*810mg and a bit of sunshine for a while.

Cheers,

Bill

Yes, the side effects. That is a whole other story.
It is the strong point of my medication, the slow release principle, that prevents most of the side effects.
It seems that another pharmacist in Spain, Admiral, is busy with the registration of a similar product based on DMF.

Caroline.

[Bill]

It is more the lymphocyte count, Caroline. The l-cysteine has worked well at mitigating the gastric upset. I am finding benefits from my intense and infrequent regime in line with the views of your specialists.

Cheers,

Bill

[Caroline]

Dimethylfumarate Inhibits Angiogenesis In Vitro and In Vivo: A Possible Role for Its Antipsoriatic Effect?

Quote:

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Received 4 June 2010; Revised 25 October 2010; Accepted 24 November 2010; Published online 3 February 2011.

Abstract
The fumaric acid esters (FAEs) have been used for the oral treatment of psoriasis for some 50 years. Given that a persistent and maintained angiogenesis is associated with several cutaneous diseases, including psoriasis, we sought in our study to gain further insight into their mechanism of action by investigating whether FAEs are able to interfere with angiogenesis mechanisms. Our results demonstrate that dimethylfumarate (DMF) inhibits certain functions of endothelial cells, namely, differentiation, proliferation, and migration. This activity was not exhibited by similar concentrations of monomethylfumarate or fumaric acid. Our data indicate that DMF inhibits the growth of transformed and nontransformed cells in a dose-dependent manner. The growth-inhibitory effect exerted by this compound on proliferating endothelial cells could be due, at least in part, to an induction of apoptosis. Inhibition by DMF of the mentioned essential steps of in vitro angiogenesis is consistent with the observed inhibition of in vivo angiogenesis, substantiated using chick chorioallantoic membrane and live fluorescent zebrafish embryo neovascularization assays. The antiangiogenic activity of DMF may contribute to the antipsoriatic, antitumoral, and antimetastatic activities of this compound and suggests its potential in the treatment of angiogenesis-related malignancies.

Source: Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Málaga


Sorry for Jim. No tests on mice.... only on zebra fish. But very positive against cancer.

[Caroline]

After some consideration I decided to post this information over here, intending to also get a copy in the closed explanation thread Dimethylfumarates and Psoriasis

Some more clarity on the subject of DMF in the form of combination preparation with MEF and DMF.
Nicolle Litjens, is writing in her thesis on page 14: “Monomethylfumarate (MMF) is considered the most active metabolite and is formed in the circulation following the hydrolysis of DMF”. As can be seen under this sentence a schema is following, which shows what hydrolysis means (if you did not know that): and that is that a methyl group (CH3) is replaced by a hydrogen molecule (H).



Everyone who has passed a high school with a little chemistry can conclude from the picture, that from MonoEthylFumarate you can never form MonoMethylFumarate (MMF). Leading doctors, any doctor/dermatologist, should know that, together with the knowledge that the real working factor is MMF, this is the effective molecule. Still doctors are prescribing the combination preparation, of which one component not only does not have any anti-psoriasis effect, but even appears to be toxic.
In the Netherlands this would mean that a even a comparison between the two preparations is senseless as the difference so easily can be seen.

Litjens consciously has examined if there was a difference in activity between the several forms of fumarates concerning their influence on the citric acid cycle. DMF, MMF and MEF were compared. The effect of MEF appeared to be negligible (last line on page 20).



In the rest of the thesis MEF does not play a role anymore. Statements 2 and 3 belonging to the thesis, do speak a clear language (unfortunately I don’t have them). MMF is the most active metabolite (and this can only be originated from DMF). Litjens has written a thesis called: "Immunomodulatory effect of fumarates in psoriasis", and did for this thesis quite some practical research and a lot of theoretical research.

In the mean time science has progressed. The immediate reaction after the reading of the thesis of Litjens would be to prescribe MMF. Unfortunately the law in the Netherlands (after Psorinovo had hit the market) has changed in such a way that it is virtually impossible to get MMF on the market.
The requirements that must be fulfilled for new medicines have been raised so enormously that the development of a new medicine costs billions and that development only is admitted if the research protocol follows a strict and extremely expensive route (Once again people who know nothing block the quality of life of lots of their fellow civilians, only in the sake of utter safety and money). This route can only be followed by a multi national and if the stuff is patentable. MMF is not patentable. So it will only be done if there somehow is a large financial reward. The chance is there, because DMF (in reality MMF) can be used for more and more purposes.
Because  what is happening…..:

Dr. B. Thomas, neuroscientists of the Department of Pharmacology and Toxicology and connected to the Medical College of Georgia (Augusta university) US, has published studies in the Journal of Neuroscience, which show that MMF and DMF stimulate the functioning of the mitochondria (the energy suppliers in every cell [we knew that already, read my thread]), but it appears that DMF initially slows down the working of the mitochondria for a short time, and only in second instance will stimulate, while MMF immediately stimulates the mitochondria.
This inconvenient and disadvantageous difference exists because DMF firstly retracts glutathione (an important anti oxidant) from the mitochondria. So they are working less efficiently and this explains according to dr. Thomas the unwanted side effects of DMF, that are not to be expected with MMF.
After the change of DMF into MMF, the so called hydrolysis, this disadvantage is again compensated and more than that. But this the explanation of the superiority of MMF as a medicine, which also were found by Litjens, without knowing the details.
 
By the way it is this essential effect on the mitochondria, which results in the fact that the body temperature is slightly rising and that people can get a red head (the well know flush), a point that dermatologists never mention, let it even be that they explain the effect on the cytric acid cycle, the biochemical proces that facilitates the production of energy in the mitochondria.
The role of the citric acid cycle I have earlier described in my thread Dimethylfumarates and Psoriasis, which is based on an article in the Dutch Magazine of Integral Medicine and written by my doctor.  

The observed side effects of MEF (a possible detoriation of the kidney function) is based on the same disadvantage that DMF has to a much lesser extent, that is the negative influence on the mitochondria. It is well known that damaging the mitochondrial function in the first place influences the heart, but in the second place the kidneys. This follows in that chronic kidney diseases are mainly based on damaged mitochondria. This is the reason that chronic kidney diseases nowadays are treated with anti oxidants, for example Cysteine ( Bill ! ) , glutamine and glycine  (J Nephrol 2015;42:318-319). MMF seen from this point could be a miracle medicine against heart muscle degradation and kidney degradation, but… also MMF has its lesser sides as it remains immunosuppressive.

By the way, the unwanted side effects of DMF (damaging the mitochondria) can be prevented by eating glutathione rich food and to avoid food with a lot of oxidants. Glutathion is available in raw vegetables and fruit, e.g. Asparagus, avocado and walnuts, fish and meat. You could also use a food supplement wich supplies you with glutathione  250-750 mg per day, depending on your DMF dose.
Schweckendiek prescibed (1981) with the use of fumarates, the anti oxidants cystine and glycine and extensively discussed the mitochondrial functioning in combination with the fumarate treatment.
 
It can be assumed that the dermatologists are too less aware of what is happening in the body. They may be too busy with the outside. The doctors who show the relation between psoriasis, mitochondria, the citric acid cycle and nutrition are not taken seriously.
The dermatologists are not aware what is happening and keep tight to therapies with MEF included. We do not know the effects of the biologicals on the mitochondria yet, but lets not be too negative on that. There is no research findable on that subject.

While neuro scientists have observed that MMF reduces the damage to the neurons with diseases as MS, Parkinson and other neurodegenerative diseases, in England a RCT has been started with Parkinson patients. The purpose is to stop the progress of this disease by this approach, the past has shown that giving anti oxidants to Parkinson patients is of no use.

We must be aware that the use of immunosuppressive medication increases the chance of dangerous infections, although we have seen in the last more than 30 years that this chance is low with the use of fumarates.
If you would want to lower your microbial “load” in order to reduce other immunosuppressive medication than there is another solution for that.
 
Literature.
Metabolite of oral DMF drug for multiple sclerosis appears to slow onset of Parkinson's disease; Medical Science News, June 9, 2016

[Bill]

Thanks, Caroline.

The theory is all fun, but I tend to put more trust into what I observe. Some research I read recently suggested that DMF could bind with several cysteine residue sites on t cells. Good to read that Dr Schweickendiek had looked at cysteine. It really does seem to make my DMF doses far easier to stomach (as does washing it down with skim milk), and I suspect that it might offer some protection for the liver and kidney, at least in the early stages of treatment. There are now several reports of liver toxicity with Tecfidera, so I am curious so see how things are managed.

Cheers,

Bill

[Caroline]

Thanks, Caroline.

The theory is all fun, but I tend to put more trust into what I observe. Some research I read recently suggested that DMF could bind with several cysteine residue sites on t cells. Good to read that Dr Schweickendiek had looked at cysteine. It really does seem to make my DMF doses far easier to stomach (as does washing it down with skim milk), and I suspect that it might offer some protection for the liver and kidney, at least in the early stages of treatment. There are now several reports of liver toxicity with Tecfidera, so I am curious so see how things are managed.

Cheers,

Bill

It's no theory Bill.

Liver toxicity with Tecfidera??? How did they manage to do that?
Should it have something to do with their process of production of DMF?

Cheers,
Caroline