Tuesday, 5 February 2013

Amiloride a new treatment for progressive MS

#MSBlog Amiloride for progressive MS. Does it work?

Arun et al. Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. Brain. 2013 136:106-15.

Background: Neurodegeneration is the main cause for permanent disability in MS. The effect of current immunomodulatory treatments on neurodegeneration is insufficient. Therefore, direct neuroprotection and myeloprotection remain an important therapeutic goal. Targeting acid-sensing ion channel 1 (encoded by the ASIC1 gene), which contributes to the excessive intracellular accumulation of injurious Na(+) and Ca(2+) and is over-expressed in acute multiple sclerosis lesions, appears to be a viable strategy to limit cellular injury that is the substrate of neurodegeneration. While blockade of ASIC1 through amiloride, a potassium sparing diuretic that is currently licensed for hypertension and congestive cardiac failure, showed neuroprotective and myeloprotective effects in experimental models of multiple sclerosis, this strategy remains untested in MSers.

Methods: In this translational study, they tested the neuroprotective effects of amiloride in MSers with primary progressive multiple sclerosis (PPMS). First, they assessed ASIC1 expression in chronic brain lesions from post-mortem of MSers with progressive multiple sclerosis to identify the target process for neuroprotection. Second, they tested the neuroprotective effect of amiloride in a cohort of 14 MSers with primary progressive MS using MRI markers of neurodegeneration as outcome measures of neuroprotection. MSers with PPMS underwent serial MRI scans before (pretreatment phase) and during (treatment phase) amiloride treatment for a period of 3 years. Whole-brain volume and tissue integrity were measured with high-resolution T(1)-weighted and diffusion tensor imaging. 


Results: In chronic brain lesions of MSers with progressive MS, we demonstrate an increased expression of ASIC1 in axons and an association with injury markers within chronic inactive lesions. In MSers with PPMS, they observed a significant reduction in normalized annual rate of whole-brain volume during the treatment phase, compared with the pretreatment phase (P = 0.018, corrected). Consistent with this reduction, they showed that changes in diffusion indices of tissue damage within major clinically relevant white matter (corpus callosum and corticospinal tract) and deep grey matter (thalamus) structures were significantly reduced during the treatment phase (P = 0.02, corrected). 

Corpus callosum = the white matter structure joining the two hemispheres

Corticopsinal tract = the motor pathway from the cortex to the spinal cord

Thalamus = deep gray matter structure in the brain


Conclusion: Their results extend evidence of the contribution of ASIC1 to neurodegeneration in MS and suggest that amiloride may exert neuroprotective effects in MSers with progressive MS. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in MSers. 



"Amiloride works on ASIC channels which is an acid sensing ion channel. Blockage of this stops neurodegenertion in EAE. This is a translational study in humans."

"There is already advanced plans for a clinical trial in progressive MS as part of the SMART study and another trial in  optic neuritis is happening. These were discussed by Drs Toosey and Dr Chataway at our research day and will be on this blog for you to see in ~2-3 weeks time."

"This is good news for MSers with progressive MS in that this study supports another therapeutic target for treating progressive MS. Again the problem will arise if the next two studies are positive is how do you get amiloride through phase 3 and licensed. Amirloride is off patent and it will be very difficult  to get Big Pharma involved. Another reason why we need to launch the Big Pharma Alternative or BPA."

9 comments:

  1. Where are the trials listed? I couldnt find them on clinicaltrials.gov.

    What dosage they used?

    Wouldnt it be great if antiviral + blood pressure drug would made change in MS treatment?

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    1. The trials are in late stages and will be happening soon and then details will be released there will no doubt be press releases, some have been in the planning for over 5 years. The optic neurits trial was sponsored by the UK Ms Society so if you check out their website to see what they have funded then it will be there.

      It would be great if we can get drugs to alter the course of MS

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  2. We have seen that the mechanism by which Amiloride and Simvastatin protect neurons is different (both being neuroprotective but not targeting the cause for progression upstream. Do you think combining neuroprotective therapies would have a synergistic effect or it would be much more efficient to combine anti-viral (Charcot Project) + neuroprotective therapies?

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    Replies
    1. Definitely. I would think that if you combine drugs that hit different targets in the neurodegenerative pathway you should get at least additive effects if not synergistic ones. This should be combined with DMTs too as early as possible in the course of disease. Anti-virals may be shown to be of use too.

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  3. Replies
    1. It means experimental results are translated into clinical results.

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  4. My OH has PPMS, so this study of interest to us. To ask a blunt question, did the 14 PPMS'ers experience a stability of symptoms? Did that downward spiral to more ill health etc stop while these patients were on this product?

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  5. if the fda cant tax it we wont get it.they don't care about ms. they care about money. its the American way

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