Saturday, 17 October 2015

Glaterimer acetate and Spasticity...what next?

Meca-Lallana JE, Hernández-Clares R, Carreón-Guarnizo E.Spasticity in multiple sclerosis and role of glatiramer acetate treatment. Brain Behav. 2015 ;5(9):e00367. doi: 10.1002/brb3.367. Epub 2015 Jul 14.

INTRODUCTION:Spasticity is one of the most disabling and difficult-to-treat symptoms shown by patients with multiple sclerosis, who often show a suboptimal and unsatisfactory response to classic treatment and new available nonpharmacological alternatives. Due to the progressive nature of this condition, the early management should be essential to improve long-term outcomes.
METHODS:We performed a narrative literature review of the contribution of spasticity to the burden of multiple sclerosis and the potential role of classic disease-modifying drugs.
RESULTS:Added to the underlying pathophysiology of spasticity, certain external factors and drugs such as interferon may exacerbate the existing condition, hence their awareness is crucial as part of an effective management of spasticity. Furthermore, the evidence for the effectiveness of glatiramer acetate in preventing spasticity in naïve patients and in those switching from interferon should not be ignored.
CONCLUSIONS:This literature review proposes the examination of spasticity and the influence of classic disease-modifying agents on the level of existing condition among the variables to be considered when deciding on therapy for multiple sclerosis in clinical practice.

You know we like to post on the different actions of glatermirer acetate...but now the attention is drawn to spasticity....Come one what's next? 


Glaterimer is a group of amino acids...are they going to get into the brain to stop spasticity...unlikely but could GA inhibit spasticity , unlikely but could it block the disease process that leads to nerve damage then yes because it blocks relapses which are damaging and by accumulating less damage you are less likely to develop spasticity....What do I know and no doubt you may put me right with your experiences.

However what next GA and bladder, GA and continenence, GA and vision, GA and ....In the words of a Golch Advert..,Schtop!
However, the point is if you convert to GA then your chances of developing spasticity may be less that if you took interferon beta. I am sure if you take a more effective DMT then your chances of spasticity will be lower too

CoI We are developing a potential spasticity treatment.

Ehling R, Di Pauli F, Lackner P, Rainer C, Kraus V, Hegen H, Lutterotti A, Kuenz B, De Zordo T, Schocke M, Glatzl S, Löscher WN, Deisenhammer F, Reindl M, Berger T.Ehling R, Di Pauli F, Lackner P, Rainer C, Kraus V, Hegen H, Lutterotti A, Kuenz B, De Zordo T, Schocke M, Glatzl S, Löscher WN, Deisenhammer F, Reindl M, Berger T. 

Data from in vitro and animal studies support a neuroprotective role of glatiramer acetate (GA) in multiple sclerosis (MS). We investigated prospectively whether treatment with GA leads to clinical and paraclinical changes associated with neuroprotection in patients with relapsing-remitting (RR) MS. Primary aim of this clinical study was to determine serum BDNF levels in RR-MS patients who were started on GA as compared to patients who remained therapy-naive throughout 24months. Secondary outcomes included relapses and EDSS, cognition, quality of life, fatigue and depression, BDNF expression levels on peripheral immune cells (FACS, RT-PCR), serum anti-myelin basic peptide (MBP) antibody status, evoked potential and cerebral MRI studies. While GA treatment did not alter serum levels or expression levels on peripheral immune cells of BDNF over time it resulted in a transient increase of serum IgG antibody response to MBP, mainly due to subtype IgG1 (p<0.05), after 3months. However, no significant differences were found between GA treated and therapy-naive patients with regard to serum BDNF and intracellular BDNF expression levels, nerve conduction (including median and tibial nerve somatosensory, pattern-shift visual and upper and lower limb motor evoked potentials) or MRI (including volume of hyperintense lesions, volume of hypointense lesions after CE, mean diffusivity and fractional anisotropy) outcome parameters. In conclusion, our findings do not support a major impact of GA treatment on paraclinical markers of neuroprotection in human RR-MS.

In this study they did not find evidence to support an effect on neuroprotection and it failed to influence primary progressive disease so this conclusion may have been expected

15 comments:

  1. The Beta Interferons could exacerbate eg spasticity due to their own immunogenic character? ... I say this why my first DMT was the 44th Rebif, and I could only stand it for almost 4 months since I felt the worsening of my symptoms related to MS (tingling throughout the body) and spasticity in his left leg. I passed for Copaxone, who I'm already there 01 years and 03 months felt an absurd better ...

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    1. I am not sure why beta interferon would directly affect spasticity, which is a product of damage. Maybe you felt worsening of symptoms becuase the drug was not working

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    2. I do not know ... I only know that at the time had a high fever when he wore (even flu-like symptoms), came to take 03 Ibuprofen or Acetaminophen to achieve cease these symptoms, and feel a sense (which was not in accordance with Lhermitte my neuros) column and left leg (where I had lost strength), the one symptom and did not even when he was recovering from wrist. I did the wrist and a week later I started with Rebif. When I interrupted Rebif and Copaxone started this feeling ceased, so whatever I thought of it is a reaction of "defense" of my body to Interferons and not that it was something of MS even ...

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    3. MD
      The manufacturer's own info sheet which came in the packet with my Rebif states the following in relation to potential side effects (in a font size of about 5pt on an A3 sized sheet of paper)
      "Nervous System: Seizures (see Precautions: General).
      Transient neurological symptoms (i.e.,hypoesthesia, muscle spasm, paresthesia, difficulty walking, musculoskeletal stiffness) that mimic MS exacerbations of limited duration, temporally related to the injections and most prominent at the initiation of
      therapy. In some cases, these symptoms were associated with flu-like syndrome."

      Unfortunately "temporarily related to injections" is a problem when you have to inject 3x a week - there is insufficient time for the impacts to wear off before you inject again.

      Another abbreviated "plain English" patient info sheet for Rebif also notes the following as a side effect:
      "Muscle stiffness or spasms, weakness, difficulty walking"

      So the horse's mouth (manufacturer) acknowledges that their own product can cause these problems for people.

      My foot and leg spasms stopped in a less than a week after stopping Rebif and have almost completely stayed away. My walking coordination also improved, as did fatigue and depression (both side effects acknowledged by the manufacturer, with severe depression recorded at 25% incident rate).

      It's a bit hard when the drug that's supposed to help the MS has side effects which mimic or worsen MS symptoms - makes it bloody difficult to tell whether it's your MS playing up or it's caused by the treatment. Even harder if the symptom did exist in a mild or sporadic form before starting the drug (which my foot spasms did, but not the leg spasms), and the only way to find out is to stop the drug.

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    4. OK thaks,...I stand corrected. I am not a clinician and do not read these fact sheets,

      I am not clear of the mechanism of this, maybe some one can enlighten me. Maybe it has something to do with cytokines maybe it affects TNF whic appears to inhibit conduction

      Depression is a well known side effect and early studies were associated with suicide

      As you say some drugs can inhibit one thing good for MS but also be on the other side and do things good. It is because biology uses the same pathway too do different things.

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    5. Increased spasticity is a well-known adverse effect of beta-interferons, and I usually explain this to pwMS as well as myself as part of Uhthoff's phenomenon triggered by the drug. Beta-IFN causes temperature to rise as part of the flu-like syndrome, that unmasks or exacerbates pre-existing symptoms. Some pwMS don't have fever and yet get increased spasticity, perhaps cytokine release does not reach the threshold to cause temperature but is sufficient to exacerbate symptom, I don't know, may be others do. It may well depend on the degree of damage to motor fibres due to MS and the severity of spasticity. In people who whilst taking b-IFN developed SPMS the experience of stopping the drug is often a relief with lesser spasticity playing a key role. To suggest Glatiramer is actively improving spasticity is more difficult to prove beyond reasonable doubt, and in my view is has not. There are obviously sponsored papers trying to suggest there is an effect of Drug C whilst it is actually stopping Drug B that explains the difference.

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    6. I suppose what MD is getting at is you can make the case for your drug to improve each MS symptom individually, or say here is effective disease modification, which will - hopefully - affect the disease process as a whole, and as a result each of your symptoms - some more, some less. As long as you are NEDA on Glatiramer then fair play stick to it.

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  2. Actually, if you use the logic involved in the tweaked Rituximab for patentability trial, Copaxone is the first drug shown to have any effect on a true PPMS subpopulation:

    http://www.ncbi.nlm.nih.gov/pubmed/19426995

    These results were not obtained by stacking the deck with PRMS or newly diagnosed PPMSer with enhancing lesions, found through a post-hoc analysis of previous Rituxmab failures.

    This is "p-haccking" in Team G's eyes yet it is perfectly acceptable when designing a trial for Ocrelizumab which has great profit potential that no doubt some of the Team G'ers will get a slice of. So if a trial was re-done for male PPMers with no restriction and had positive effect, how would team G act?

    For a male MSer with RRMS the evidence is clear to me that Copaxone is the right choice for me after looking at the data fully. What is amazing to me about this is that it has on impact on progrssion without imposing any sort of immunosuppressive function that is a hallmark of the "highly effective" drugs marketed by Team G.

    So again it makes you wonder where Team G's motives are comming from? This is particularly clear when a threat is presented that shows a treatment effect that has a potential to diminish the popularity of Mouse's soon to be spacicity drug.

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    1. Nice response. It is what is expected from someone of your caliber.

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    2. It is a nonsense to suggest that we are financially gaining personally from the ocrelizumab studies.

      The trial of copaxone was I believe terminated early because the arguement goes that the placebo group was not progressing at a fast enough rate, and the cynic would suggest because the trial was failing.

      You cite the suggestion that the trial was positive in males however if the trial was positive then copaxone would be available for PPMS...it isn't.

      So the trial failed and to get a positive response you have to do another trial with a defined target as an endpoint. You cannot go cherry picking trials with unplanned analysis for this very reason. Otherwise pharma would be saying this trial was positive and that trial is positive so yes it is p hacking and for human trials you cannot do this. These are the rules. If a trial was done in males PPMSers and it worked I would say great. However I would expect the licence for use would be restricted to males only. Likewise if the trial showed a compound only worked in active PPMSers then I would predict that this is what the licence would be too.

      It is amazing to you...that it does this. Yes it may be but unless the study is repeated it is meaningless and you should put no faith in the result. There are a myriad of studies that do not repeat.

      TeamG motives.....if you are asking this it frankly depresses me.

      If a treatment is good enough it will stop disease in its tracks and many symptoms due to damage will not develop including spasticity, I can live with this and there are many MSers with spasticity, however if there was no MS spasticity we could live with that too there are many of other conditions where spasticity develop...and unfortunately we are not going to stop spinal cord injuries from occurring and there are thousands of these every year all over the world every year around the world, between 250 000 and 500 000 people suffer a spinal cord injury (SCI).


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    3. As for calibre.... at the moment I would select 44 :-) Dirty Harry:-)

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    4. You should probably read the latest Cochrane review before you start spouting whit is and what isn't highly effective:
      sis
      Background

      Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants, and biologics. Although there is consensus that these therapies may reduce the frequency of relapses, their relative benefit (effectiveness compared to each other) in delaying new relapses or disability worsening remains unclear due to the limited number of direct comparison studies (i.e. studies comparing two or more active agents with each other).

      Objectives

      We aimed to assess and rank the benefit from and the extent of adverse events associated with 15 drugs, i.e. interferon beta-1b, interferon beta-1a (Avonex, Rebif), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, and immunoglobulins.

      Study characteristics

      We included 39 studies up to September 2014 in this review, comprising a total of 25,113 participants suffering from RRMS. The majority of the included studies were short-term, with a median duration of 24 months.

      "Key results and quality of the evidence

      For preventing relapses, alemtuzumab, natalizumab, and fingolimod are more effective than the other drugs, based on moderate to high quality evidence.

      For preventing irreversible disability worsening, insufficient evidence is currently available.

      It is worth noting the following:

      - The benefit of all of these treatments beyond two years is uncertain and this is a very relevant issue for people with a lifelong disease such as multiple sclerosis, who will possibly need long-term treatments.

      - Safety data from these short-term studies are scanty, poorly reported and cannot provide enough evidence for us to obtain a reliable risk profile of the treatments included in this review.

      - Most of the included studies were sponsored by pharmaceutical companies and this is a known potential source of bias."

      http://www.cochrane.org/CD011381/MS_immunomodulators-and-immunosuppressants-relapsing-remitting-multiple-sclerosis-network-meta-analysis

      The best you can say is some drugs are "highly effective" at reducing relapses in a two year trial. This does not automatically translate into longterm effectiveness.

      Also, Just because a drug is not pursued for a given subpopulation does not negate the results of data gathered using double blind, placebo controlled, multi-centered trial outcomes whether they were derived via post hoc analysis or pre-stated as primary endpoints. I don't give a damn what pharma thinks is unfair or not. If the results from a gold standard trial shows an effect you can be confident the effect is real.

      So if you believe that the only way a drug is proven effective is if it has been approved by the FDA then you must conclude that Clabradine is useless. But I don't think you beleive this, you just like to twist the data to fit your views. But the reason for this is unclear. Maybe you have no financial gains from your biases but your behavior is sending a different message.

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    5. Anon 8:47: Suppose that we have 20 random variables, X_i ~ N(0,1). We have 20 corresponding null hypotheses: H_i = X_i is drawn from N(0,1). We draw samples for each X_i, and test each hypothesis H_i using a z-test. What is the probability of a false positive, i.e. that we reject at least one H_i?

      If you understand null hypothesis testing, then this is trivial to answer.

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  3. IFN B-1A made all of my symptoms much worse. A bit under a year ago I gave up on Rebif after persevering with it for about ten months and nearly all symptoms improved within a couple of weeks (especially depression). No regrets so far, and I feel a lot better without Rebif. Last two MRIs have basically been "no real changes evident", and I'm only taking LDN now.

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