Amiloride

A board to discuss future MS therapies in early stage (Phase I or II) trials.

Amiloride

Postby Liberation » Sat Feb 02, 2013 7:45 am

Anyone tried Amiloride? Any experience with i? As it is already a cheap prescription drug with safe track record and with great potential for progressive patients, I would have assumed that some doctors might have prescribed it or someone tried it.

Amiloride study in Multiple Sclerosis wins national award

This week the Multiple Sclerosis (MS) research team at University of Oxford was awarded the prestigious MS Research Project of the Year award. The award was announced at the 2012 MS Society awards ceremony in “recognition of world class research projects, based in the UK, working hard to beat MS”.

The research led by Professor Lars Fugger in collaboration with Dr Matt Craner identified a target, the acid sensing ion channel (ASIC), which when blocked by the drug amiloride prevented nerves and myelin from being damaged in laboratory models of MS. This early stage research published in Brain in 2011 extended the initial observations of a role of targeting ASIC as a neuroprotective therapy in MS (Nature Medicine, 2007). The combined evidence of these studies demonstrating a protective benefit of amiloride offers the potential to rapidly translate to patients with MS and through protecting nerve and myelin cells it is hoped this could lead to a treatment that halts disability progression.

Professor Lars Fugger’s approach of identifying novel pathways which may contribute to neuro-axonal injury, and to target them with drugs that are already in clinical practice and have a well-identified safety profile, forms a research platform which enables “fast-track neuroprotective therapies” to be brought into play within the therapeutic arena in MS. As part of a University of Oxford translational MS research programme these findings have formed the basis of a phase II clinical trial of amiloride led by Dr Matt Craner, which is being funded by the MS Society and due to start soon.

http://www.imm.ox.ac.uk/wimm-research/m ... onal-award
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Re: Amiloride

Postby Anonymoose » Sat Feb 02, 2013 8:30 am

I haven't tried it but it looks interesting. I wonder if it would have the same effect on muscle tension that clonidine does. This seems to fit with the osmotic demyelination idea.

http://hyper.ahajournals.org/content/43/5/952.short
Human Endothelium: Target for Aldosterone
Hans Oberleithner, Thomas Ludwig, Christoph Riethmüller, Uta Hillebrand, Lars Albermann, Claudia Schäfer, Victor Shahin, Hermann Schillers
+ Author Affiliations

From the Institute of Physiology II, Nanolab, University Münster, Germany.
Correspondence to Dr Hans Oberleithner, Institut für Physiologie, Robert-Koch-Str 27a, 48149 Münster, Germany. E-mail oberlei@uni-muenster.de
Abstract

Aldosterone has long been known to control water and electrolyte balance by acting on mineralocorticoid receptors in kidney. However, recent studies demonstrated the presence of these receptors in nonclassical locations, including the cardiovascular system. We tested the hypothesis whether endothelial cells respond to aldosterone with changes in cell volume, a measure for ion-mediated water movement across the cell membrane. By means of atomic force microscopy in fluid, we measured volume of adherent human umbilical venous endothelial cells exposed for 72 hours to 10 nmol/L aldosterone. Over this period of time, cells swell by ≈18%. Aldosterone-induced swelling is prevented by 100 nmol/L of the mineralocorticoid receptor antagonist spironolactone, added to the primary endothelial cell culture. Aldosterone-treated cells dramatically shrink when 1 μmol/L of the diuretic amiloride is applied. Cells deprived of aldosterone do not respond to amiloride. Our conclusions are: (1) aldosterone leads to sustained cell swelling inhibited by administration of spironolactone or the sodium channel blocker amiloride; (2) cells respond to amiloride after aldosterone exposure; (3) renal diuretics act on endothelial cells; and (4) both amiloride and spironolactone could be useful for medical applications to prevent aldosterone-mediated endothelial dysfunction.
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Re: Amiloride

Postby CureOrBust » Sat Feb 02, 2013 3:49 pm

I's be interested if it has the same effect on humans that it has on mice, so will be reading carefully if someone wants to try it?
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Re: Amiloride

Postby Liberation » Sun Feb 03, 2013 2:45 am

I got into contact with the research team and they confirmed that there is an ongoing study with ppms patients. The results of the preliminary study were published in the Brain journal. They think the results are encouriging. However, as the drug is off patent it will be hard to find funding for clinical trials. So, it is upto your doctor/neuro to prescribe it if sufficient supporting data emerge. I think the situation could be similar to HSCT where the treatment was approved for a different indication, but the doctors used it successfully for MS as well. Only, insurance did not cover it. With amiloride money is not a problem as it costs only a few bucks.

I am just wondering if any neuro follows this research and will use it.

Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride
Tarunya Arun1,2,*, Valentina Tomassini1,2,3,*, Emilia Sbardella1,2,4, Michiel B. de Ruiter2,5, Lucy Matthews1,2, Maria Isabel Leite1, Rose Gelineau-Morel6, Ana Cavey1, Sandra Vergo1,7, Matt Craner1,7, Lars Fugger1,7, Alex Rovira8, Mark Jenkinson2 and Jacqueline Palace1
+ Author Affiliations
1 Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, UK
2 Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
3 School of Medicine, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, UK
4 Department of Psychology, Sapienza University, Rome, Italy
5 Department of Radiology, Academic Medical Centre, University of Amsterdam, The Netherlands
6 School of Medicine, Baylor College of Medicine, Houston, TX, USA
7 MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
8 Magnetic Resonance Unit, Department of Radiology, Hospital Universitari Vall d'Hebron, Barcelona, Spain
Correspondence to: Jacqueline Palace, Division of Clinical Neurology, Department of Clinical Neurosciences, Oxford University Hospitals Trust, OX3 9DU Oxford, UK, E-mail: jacqueline.palace@clneuro.ox.ac.uk
Received July 4, 2012.
Revision received October 9, 2012.
Accepted October 20, 2012.
Summary
Neurodegeneration is the main cause for permanent disability in multiple sclerosis. 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 Ca2+ 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 patients with multiple sclerosis. In this translational study, we tested the neuroprotective effects of amiloride in patients with primary progressive multiple sclerosis. First, we assessed ASIC1 expression in chronic brain lesions from post-mortem of patients with progressive multiple sclerosis to identify the target process for neuroprotection. Second, we tested the neuroprotective effect of amiloride in a cohort of 14 patients with primary progressive multiple sclerosis using magnetic resonance imaging markers of neurodegeneration as outcome measures of neuroprotection. Patients with primary progressive multiple sclerosis underwent serial magnetic resonance imaging 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 T1-weighted and diffusion tensor imaging. In chronic brain lesions of patients with progressive multiple sclerosis, we demonstrate an increased expression of ASIC1 in axons and an association with injury markers within chronic inactive lesions. In patients with primary progressive multiple sclerosis, we 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, we 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). Our results extend evidence of the contribution of ASIC1 to neurodegeneration in multiple sclerosis and suggest that amiloride may exert neuroprotective effects in patients with progressive multiple sclerosis. This pilot study is the first translational study on neuroprotection targeting ASIC1 and supports future randomized controlled trials measuring neuroprotection with amiloride in patients with multiple sclerosis.

http://brain.oxfordjournals.org/content/136/1/106.short
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Re: Amiloride

Postby CureOrBust » Sun Feb 03, 2013 7:19 am

OK, now I will look into it a little more.

My GP is very understanding with me trying off label medication that he has prescribed before and is comfortable with its safety.
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Re: Amiloride

Postby Liberation » Mon Jun 17, 2013 8:36 am

CureOrBust wrote:OK, now I will look into it a little more.

My GP is very understanding with me trying off label medication that he has prescribed before and is comfortable with its safety.


Hi Cure,
have you followed up on Amiloride? Any experience so far?
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Re: Amiloride

Postby CureOrBust » Tue Jun 18, 2013 2:59 am

:oops: nope...
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Re: Amiloride

Postby CureOrBust » Tue Jun 25, 2013 3:56 am

But giggledygook has tried this. regimens-f22/topic9664-90.html#p210715
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Re: Amiloride

Postby gibbledygook » Wed Jun 26, 2013 8:33 am

As this is a sodium channel blocker it inhibits nerve conduction. I started taking this at the same time as switching to Gabapentin for night spasms. Both made my walking temporarily worse. I'm now going back on the baclofen so may resume amiloride as I'd love to block sodium and acid sensing channels...
3 years antibiotics, 06/09 bilateral jug stents at C1, 05/11 ballooning of both jug valves, 07/12 stenting of renal vein, azygos & jug valve ballooning,
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Re: Amiloride

Postby LR1234 » Wed Jun 26, 2013 10:58 am

Neuro is writing letter for me this week to request script from gp.......gonna give it a go, will keep u posted.
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Re: Amiloride

Postby LR1234 » Mon Jul 15, 2013 11:23 am

Started this today 10mg dose.

Left eye affected by neuropathy still fairly bad about 80% vision. I can see but reading is hard as there are white stripes through everything and black shadows over faces:(
Other than a slight muscle issue in that eye, ongoing numbness and some cog fog from cognitive relapse abd fatigue attacks I am ok.
Will keep u posted x
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Re: Amiloride

Postby Liberation » Tue Jul 16, 2013 9:05 am

LR1234 wrote:Started this today 10mg dose.

Left eye affected by neuropathy still fairly bad about 80% vision. I can see but reading is hard as there are white stripes through everything and black shadows over faces:(
Other than a slight muscle issue in that eye, ongoing numbness and some cog fog from cognitive relapse abd fatigue attacks I am ok.
Will keep u posted x


thanks for reporting. I root for you. :)

I inferred from the studies that slowing of the disease can be expected rather than improvement. With progressive disease, even that would be a great thing. Halting would be super. It would be worth taking MRIs in every half a year to see changes. Probably that much time would be needed to have a good basis for you for comparision.

"Amiloride was given to 12 people with primary progressive MS over one year in the form of a single daily 10mg oral dose. The participants were tracked using magnetic resonance imaging that incorporated scans taken during the year before the treatment period began and throughout the treatment phase. The MRIs were analysed to see if markers of neurodegeneration, such as brain volume and tissue damage, were improved on amiloride.

The MRI scans showed that the rates of neurodegeneration and tissue damage were reduced during the amiloride treatment phase when compared to the year prior to treatment. The participants also showed higher rates of disability change on the expanded disability severity score, in the period before treatment when compared with the treatment phase – although since the trial only included a very small group this finding will have to be confirmed.

Even though the trial was small, these are encouraging results and further clinical trials are warranted. ‘This is the first translational study on neuroprotection to target ASIC1,’ said the authors, ‘and supports future randomised controlled trials measuring neuroprotection with amiloride in patients with MS’. Since amiloride has already been approved for other conditions, the clinical trial process may be shortened, and provide a much needed treatment option for disability in MS."
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Re: Amiloride

Postby LR1234 » Tue Jul 16, 2013 2:04 pm

Well I took 10mg yesterday and it messed up my tummy big time!! I also felt a bit dizzy.
I am ultra sensitive to meds though and have lowered to 5mg for the time being.
Last edited by LR1234 on Fri Sep 20, 2013 1:12 am, edited 2 times in total.
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Re: Amiloride trial

Postby reallyreally » Wed Jul 17, 2013 7:08 pm

A clinical trial is starting in UK also.

Now, after reviewing published data on drug treatments that might help protect nerves in the brain, UK researchers are focusing on three drugs that are licensed for other conditions.

From BBC News
"MS hope from 'off-the-shelf' drugs"

About 500 people with late-stage MS are to enroll in clinical trials in England and Scotland to see if three common drugs can slow disease progression.The three drugs are amiloride - currently licensed to treat heart disease and high blood pressure; ibudilast - an asthma drug used in Japan - ; and riluzole, the sole treatment for motor neurone disease.

http://www.bbc.co.uk/news/health-23327835
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Re: Amiloride

Postby LR1234 » Thu Jul 18, 2013 10:02 am

I think that's why the neuros here are prescribing it
I'm on 5mg now and no issues:)
Last edited by LR1234 on Fri Sep 20, 2013 1:10 am, edited 1 time in total.
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