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   DIR Return to: TECFIDERA (dimethyl fumarate, BG-12, Fumaderm)
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       #Post#: 240--------------------------------------------------
       How Tecfidera works explained
       By: agate Date: April 4, 2014, 3:20 pm
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       From Medical News Today, April 3, 2014:
       [quote]Research may lead to development of novel therapeutic
       agents for multiple sclerosis
       Just a few short weeks ago, dimethyl fumarate was approved in
       Europe as a basic therapy for multiple sclerosis. Although its
       efficacy has been established in clinical studies, its
       underlying mode of action was still unknown, but scientists from
       Bad Nauheim's Max Planck Institute for Heart and Lung Research
       and the University of Lubeck have now managed to decode it. They
       hope that this knowledge will help them develop more effective
       therapeutic agents.
       ...
       Basic MS therapy to date generally involved beta interferons or
       the active substance glatiramer acetate. In both cases, the drug
       was administered by injections under the skin or into the
       muscle, which is a cause of considerable discomfort and
       annoyance to many patients.
       By contrast, the active substance dimethyl fumarate (DMF),
       approved in Europe for MS treatment only a few weeks ago, brings
       a ray of hope to those affected since it can be taken in tablet
       form. The efficacy of DMF in clinical studies was at least
       comparable to that of the more established substances, while its
       side effects were moderate by comparison.
       DMF has been in use for some twenty years as a successful
       treatment for psoriasis, but little was known about how it
       influences immune function. Scientists from Nina Wettschureck's
       research groups at the Max Planck Institute for Heart and Lung
       Research in Bad Nauheim and Markus Schwaninger from the
       Institute of Experimental and Clinical Pharmacology and
       Toxicology at the University of Lübeck have explained
       significant aspects of how DMF works.
       In their study, the researchers used a standardised mouse model
       of multiple sclerosis, whereby drugs trigger an autoimmune
       response, leading to characteristic reactions within days. In
       this way, they induced neurological deficits comparable to those
       observed in MS. "In the group we treated with DMF, the problems
       with motor function were considerably lower than in the control
       group," says Wettschureck.
       The researchers uncovered the mode of action by treating
       genetically modified mice in the same way. "In mice that don't
       have the gene for the receptor called HCA2, DMF was unable to
       prevent the signs of paralysis," explains Schwaninger. This
       means that the HCA2 receptor must mediate the therapeutic effect
       of DMF. HCA2 is a so-called G protein-coupled membrane receptor
       which occurs, among other places, on a certain type of white
       blood cells, neutrophil granulocytes. "In animals treated with
       DMF, the number of granulocytes that infiltrated the nervous
       system was much lower than in untreated animals. In animals
       without the HCA2 receptor, the number of invasive granulocytes
       remained equally high despite treatment with DMF," stated
       Wettschureck.
       In other experiments involving cell cultures, the scientists
       found that activation of the HCA2 receptor is responsible for
       infiltration of the central nervous system by white blood cells.
       DMF blocks this infiltration, thereby preventing the associated
       inflammation. "Our study has enabled us to provide the first
       evidence that DMF's protective effect is due to the HCA2
       receptor. However, we are not ruling out the possibility that
       there may also be other mechanisms," observed Wettschureck.
       As a next step, the scientists want to find out why patients
       respond differently to treatment with DMF. "It may be that
       individual genetic differences influence the efficacy of DMF,"
       states Schwaninger. Consequently, future therapies could be
       specifically designed for individual patients, an approach known
       as personalised medicine.
       The researchers also intend to search for additional substances
       that bind to the HCA2 receptor. "Ideally, we would find a
       substance of comparable or even greater efficacy, but with fewer
       side effects," says Wettschureck. The colleagues in Bad Nauheim
       and Lübeck hope this will lead to the development of novel
       therapeutic agents for MS with an improved profile in terms of
       efficacy and adverse effects.
       [/quote]
       [quote]Original publication:
       Hui Chen, Julian C. Assmann, Antje Krenz, Mahbubur Rahman,
       Myriam Grimm, Christian M. Karsten, Jörg Köhl, Stefan
       Offermanns, Nina Wettschureck, Markus Schwaninger
       Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate’s
       protective effect in EAE. The Journal of Clinical Investigation,
       2 April 2014 (doi:10.1172/JCI72151)
       Max-Planck-Gesellschaft[/quote]
       The entire article can be seen here
  HTML http://www.medicalnewstoday.com/releases/274939.php?tw.
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