There will be much in the news, especially the financial press, about the new "super drug" coming out from Biogen.
"BG-12"--is a new oral medication for MS.
What is BG-12?
BG 12 is dimethyl fumarate (DMF)- currrently approved as a psoriasis medication called Fumaderm.
BG-12 is a synthetic creation. It is not the same as fumeric acid, which is naturally occurring in our bodies. Chemical companies have created this synthetic "fumeric acid derivitive", so that it can be patented to be used in treatment of psoriasis and now multiple sclerosis.
link to Fumaderm info
link to chemical composition
link to patent for use in multiple sclerosis
A form of this molecule is also used as a fungicide which was applied on upholstered furniture. It was banned in the EU after people had terrible, burn-like allergic reactions to this compound.
link to ban on dimethyl fumarate
This article has pictures of the rashes and burns which caused a huge lawsuit, and got dimethyl fumarate banned as a fungicide.
link
Many of you have heard about this new oral drug in your neurologists' offices or in the news.
I feel it's important for people with MS and those who love them to understand what this drug is, and what it is not.
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Not surprisingly, oral DMF has side effects-
Fumaderm has been linked to 4 cases of PML. The question remains, will prolonged BG 12 use be a risk for PML?
http://multiple-sclerosis-research.blogspot.com/2013/01/pml-and-fumarates.html
In BG 12---
The main side effect that causes a high dropout rate in most clinical trials is gastrointestinal complaints, which occur in up to 60% of patients. Gastrointestinal problems manifest as diarrhoea, nausea and stomach cramps and pains. In addition, flushing occurs in 30% of patients and is worse at the onset of therapy.
Other more serious side effects that have occurred include kidney disturbance and reduced function and white blood cell abnormality. It is essential that kidney function and blood count should be monitored regularly when taking FAEs. These changes appear to be reversible when treatment is stopped and to date there are no reports of severe long-term toxicity.
Very small molecules such as BG-12 (molecular weight = 144) are notoriously tough to use as drugs: they hit lots of enzymatic targets, not just the intended ones, and tend to have unpredictable side effects.
more must-read info on BG-12 and MS
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How does it work?
BG-12 is an Nrf2 activator.
The Nrf2 signaling pathway (nuclear factor erythroid 2-related factor) is how your body defends and protects itself against damaging proteins, toxins, oxidative stress and inflammation. Nrf2 activators are actually PRO-oxidant....meaning they introduce an oxidizer, so that your body will turn on its own antioxidant protection.
link
Nrf2 activator means that this compound turns on or activates the enzymes in your own cells to fight oxidative stress in your body. These enzymes then protect your oligodendrocytes (myelin forming cells), and keep them from dying during an attack of oxidative stress. BG-12 acheives this by modifying and depleting glutathione in your body.
For those who love science and want to dig deeper:
link to Nrf2 signaling paper
Mechanism of Action of BG-12
BG-12 activates the Nrf2 signaling pathway, a new MS therapy target central to cellular defenses against toxic, metabolic, and inflammation-associated stress.
The Method of Action (MOA) of fumeric acid esters in MS is not completely understood. It appears to cause a drop in lymphocytes, or mute the immune system. It may be that activating the Nrf2 pathway affects immune cells.
Despite numerous in vitro and ex vivo studies, the mechanism of action of FAE is not fully understood. A convenient hypothesis is based on the idea that DMF interferes with the cellular redox system by modulating intracellular thiols and thereby increasing the level of reduced glutathione [14]. These increased glutathione levels may finally lead to an inhibition of the translocation of NF-?B into the nucleus. Altering the NF-?B pathway results in a decreased expression of NF-?B dependent genes that regulate the expression of a cascade of inflammatory cytokines, chemokines, and adhesion molecules [25]. This affects different types of cells in the immune system (Table 11) and their counterparts like the endothelium. However, at higher concentrations, DMF may induce apoptosis in all cell types.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724664/
This new MS drug is using the oxidative stress pathway, which affects different cells in the immune system and the endothelium.
Much like the Endothelial Health program--a lifestyle and nutrition program I created for Jeff four years ago, and give away for free. Please note that oxidative stress is the number 1 target in this program.
link to Endothelial Health program
Here is what a biotech and pharmaceutical researcher, Dr. David Cavalla, with 27 years of experience in pharma, says about the questionable development of BG 12 for MS.
Oddly enough---BG 12 for MS does not have a specific mechanistic target in the immune system...but that doesn't mean Biogen won't try to find a link and put forth a hypothesis.
Various hypotheses have been advanced for DMF’s mechanism of action, including modulation of the intracellular redox system resulting in consequential effects on nuclear factor kappa B, TNF-alpha, interleukin (IL)-8 and IL-1b. From then, we see effects on anti-inflammatory cytokines such as IL-10 and IL-1RA; decreased expression of adhesion molecules such as ICAM-1, VCAM-1 and E-selectin; stimulation of TH1 and down-regulation of TH2 T-cell subtypes; and induction of apoptosis in antigen-presenting cells and induction in anti-inflammatory stress protein heme oxygenase 1.
But no precise mechanistic target: so is this a deficiency in the regulatory package that Biogen-Idec will submit to the FDA; or if not, how will it address this question?
link
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Are there other products that are like BG-12?
Yes.
Here is a study, presented at ECTRIMS last year, that shows how a natural supplement, made up of plants and called "protandim," did better than BG-12 at activating the antioxidant cells. What's really funny to me, is that Biogen paid for this study....and it shows another product is better.
Nrf2 activators are able to protect oligodendrocytes against ROS-induced cytotoxicity. Conclusions: Our findings indicate that several Nrf2 activators are able to significantly increase antioxidant enzyme production in oligodendrocytes. Interestingly, protandim, a dietary supplement consisting of herbal ingredients, was the most potent inducer and therefore may be the most suited as a therapeutic strategy. Importantly, Nrf2-mediated antioxidant enzyme expression in oligodendrocytes resulted in enhanced oligodendrocyte survival during an oxidative attack.
link to abstract presented at ECTRIMS
Now, before you get all excited and go and buy protandim from Montel WIlliams....
STOP! Please, give me five minutes to explain. The active ingredients in protandim are plants.
The dietary supplement (675 mg) Protandim (LifeVantage Corp.,Littleton, CO, USA) consists of ?ve ingredients:
150 mg W. somnifera powder (ashwagandha),
150 mg B. monniera (45% bacosides),
225 mg S. marianum (70-80% silymarin),
75 mg Ca. sinesis (greentea, 98% polyphenols and 45% (epigallocatechin-3-gallate),
75 mg curcumin (95%) from turmeric (Cu. longa).
Three of the plants I have recommended, that have published research as Nrf2 activators-
Curcumin--the golden plant that gives Indian curry its color, also called tumeric.
link to research on tumeric
Silymarin--or milk thistle, know to protect liver cells and produce glutathione
link to research on silymarin
and EGCG, or green tea. Known for its antioxidizing and metal chelating effects.
link to research on EGCG
Readers on this page will know I've been recommending plants for a while now.
Here's the link where I learned about protandim's ingredients.
(For those who are interested in learning more about this science, read the whole paper.
It is illuminating.)
link to protandim ingredients
Here is Dr. Perlmutter's Nrf2 activator supplement. It contains tumeric, EGCG and broccoli seed.
link
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What does this mean?
It means that companies will continue to look for ways to make money off of chronic illness. That's their job. Some salesmen will be wearing white coats. Some salesmen will be dressed in designer suits and have TV shows. But I believe the truth should be free. And the truth is, there are plants that can help you be healthier. The companies will tell you only they have the special, proprietary blend. They will use incredibly confusing scientific language to make you believe only they understand this. That they have formulated this, it has cost them millions, and they deserve to patent it. If you feel better purchasing from these people and can afford to, go ahead :) But I would like to save you some money. I would also like this medicalese to be understood in the vernacular--the language of the people.
Print this info out and bring it to your doctor, functional doctor, naturopath. They can help you.
There are many other nutritional and lifestyle changes Jeff and I suggest.
Remember, it's not just one pill. THERE IS NO ONE MIRACLE PILL.
It's a new lifestyle. Read the whole Endothelial Health program for this lifestyle.
And always talk to your own doctor before beginning a new nutritional or exercise regimen.
link to Endothelial Health
Keep asking the big questions.
Why is oxidative stress a problem in MS in the first place?
Why did Biogen decide to pursue this area of research?
How does this fit in with Dr. Zamboni's discovery of CCSVI?
Answer:
Slowed cerebral blood flow (hypoperfusion) creates oxidative stress.
link to research on oxidative stress caused by hypoprfusion
Hope that explains some of the science of Nrf2 activators---if there are more specific questions, please ask below.
Also, remember, I'm not a doctor---so ALWAYS discuss any nutritional supplements with your own naturopaths, doctors and medical team.
be well (and save your $)
Joan
