I was initially very excited by this new treatment for multiple sclerosis, but as I researched I became less so.
Fumarate, as fumaric acid, is a member of the Krebs cycle in the body. The Krebs cycle is the breakdown of carbohydrates, proteins, and fats in the body. It’s a naturally occurring compound that in large scale studies seems to prevent the worsening of remitting-relapsing multiple sclerosis.
It can also be taken orally, an improvement on the injectables.
But all is not well in the world of dimethyl fumarate. It is used as a desiccant in the sachets of furniture and in shoe boxes. There are wide spread reports of allergic responses and dimethyl fumarate is classed as an extremely potent irritant. But this is the same compound that is helping MS patients?
How exactly is an irritant working within the body? The compound had previously been used to treat psoriasis, but at that time they were unsure of the method of action. Nothing recent has been shown about its mechanism of action, but a recent trial of dimethyl fumarate showed that when it came in contact with infected cells, it allowed viral infection to spread more rapidly.
Given its effect on the surface of the skin, it seems likely that dimethyl fumarate is acting internally as an irritant that is suppressing/distracting the immune system from other activity. While in no way does this invalidate the slowing of the plaque formation, it indicates that the long-term effects of the compound will be more in line with other suppressive agents with the corresponding side effects. In simplest terms, it has a unique method of action but may still end up with a steroid-like side effect picture.
Int J Dermatol. 2012 Jan;51(1):42-5. doi: 10.1111/j.1365-4632.2011.04916.x. Epub 2011 Sep 14.
D’Erme AM, Bassi A, Lotti T, Gola
Dimethyl fumarate (DMF) has been recognized as an extremely potent irritant and sensitizer found in sachets inside furniture. The first skin manifestations were correlated to contact with sofas, chairs, and other furniture. In these last years, some papers have reported a development of allergic contact dermatitis on the foot caused by DMF present in high concentration in shoes made in China.
We report the case of a 37-year-old woman who presented with severe eczema on the foot shortly after having bought a new pair of shoes. The diagnosis was performed by patch tests with DMF in several dilutions, with pieces of internal and external parts of the shoes, and by chemical analysis of the shoes.
In the last three years, goods containing DMF increased diffusely despite the augmentation on global preventive measures by Europe.
Therefore, new cases of contact dermatitis could be dependent on DMF, and it is of note that this allergen is not included in most series for patch testing.
© 2011 The International Society of Dermatology.
J Invest Dermatol. 2011 Jun;131(6):1189-91.
Fumarate esters as angiogenesis inhibitors: key to action in psoriasis?
Fumarate esters–an oral therapy for psoriasis–are used primarily in Europe, but not at all in the United States. Given that biological therapies are exceedingly expensive and pose an increased risk for infections and malignancy, the need for safer and less expensive therapies for psoriasis is compelling. Nonbiological therapies for psoriasis, including methotrexate and systemic retinoids, carry potentially severe side effects and relatively high cost. Fumarate, a natural product that is generated internally in humans during the Krebs cycle, is an attractive alternative to these therapies. However, the mechanism for fumarate’s activity in psoriasis remains unknown.
J Invest Dermatol. 2011 Jun;131(6):1356-64.
J Invest Dermatol. 2011 Jun;131(6):1347-55.
Int MS J. 2008 Mar;15(1):12-8.
Spotlight on fumarates.
Lee DH, Linker RA, Gold R.
Department of Neurology at St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.
The recent years have witnessed great efforts in establishing new therapeutic options for multiple sclerosis (MS). There is a clear need for more effective, safe and at the same time orally available treatment options. Here we review the potential of fumaric acid esters (FAE) as a new therapeutic option for MS. FAE have been claimed to possess immunomodulatory properties and are already in clinical use as second-line therapy for severe systemic psoriasis. They also displayed beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model mimicking many aspects of MS. In addition, FAE may also act on the blood-brain barrier and exert neuroprotective properties via activation of anti-oxidative pathways. A first magnetic resonance imaging (MRI) based Phase II study in relapsing-remitting MS (RRMS) revealed a dose-dependent, significant reduction of brain lesion activity for BG-12, a dimethyl FAE compound. Currently, two multicentre, Phase III studies for testing clinical efficacy in RRMS are initiated. In view of their profile, FAE compounds may have the potential to add to our therapeutic options in RRMS in the future.
J Allergy (Cairo). 2011;2011:457169. Epub 2011 Oct 24.
Effects of β(2) Agonists, Corticosteroids, and Novel Therapies on Rhinovirus-Induced Cytokine Release and Rhinovirus Replication in Primary Airway Fibroblasts.
Van Ly D, King NJ, Moir LM, Burgess JK, Black JL, Oliver BG.
Respiratory Research Group, Discipline of Pharmacology, The University of Sydney, Sydney, NSW 2006, Australia.
Rhinovirus-(RV-) induced asthma exacerbations account for high asthma-related health costs and morbidity in Australia. The cellular mechanism underlying this pathology is likely the result of RV-induced nuclear-factor-kappa-B-(NF-κB-) dependent inflammation. NF-κB may also be important in RV replication as inhibition of NF-κB inhibits replication of other viruses such as human immunodeficiency virus and cytomegalovirus. To establish the role of NF-κB inhibitors in RV-induced IL- 6 and IL-8 and RV replication, we used pharmacological inhibitors of NF-κB, and steroids and/or β(2) agonists were used for comparison. Primary human lung fibroblasts were infected with RV-16 in the presence of NF-κB inhibitors: BAY-117085 and dimethyl fumarate; β(2) agonist: salmeterol; and/or corticosteroids: dexamethasone; fluticasone. RV-induced IL-6 and IL-8 and RV replication were assessed using ELISAs and virus titration assays. RV replicated and increased IL-6 and IL-8 release. Salmeterol increased, while dexamethasone and fluticasone decreased RV-induced IL-6 and IL-8 (P<0.05). The NF-κB inhibitor BAY-117085 inhibited only RV-induced IL-6 (P<0.05) and dimethyl fumarate did not alter RV-induced IL-6 and IL-8. Dimethylfumarate increased RV replication whilst other drugs did not alter RV replication. These data suggest that inhibition of NF-κB alone is unlikely to be an effective treatment compared to current asthma therapeutics.
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