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MouseDoctor

52 comments

  • How long usually takes drug from EMA approval until it will get to patients? When people can expect Lemtrada?

    • Typically 3 months on mainland Europe; in the UK it takes about 14-17 months on average post the EMA decision to become available in the UK. This is called rationing by delay.

  • I believe NICE will assess this in the later part of this year, the haggle will be about cost effectiveness and depending on how greedy Sanofi/Genzyme is will I suspect depend on the length of time taken for the rest of Europe G can probablt answer

  • NICE will drag its feet on this issue. It is hindered by the economic pressures affecting the nation. I do think that the notion of needing to have two relapses within a 12 month period will still be a requisite.

  • I had read an article a few months ago in medscape where there was a debate between if multiple sclerosis was primarily an autoimmune or degenerative disease, what caught my attention was the conclusion where a doctor Robert Herndon, MD, professor, neurology, University of Mississippi Medical Center was quoted as saying there has been a "dramatic" decrease over the years in the proportion of patients with relapsing-remitting disease who go on to secondary progressive MS.

    "It used to be, before we had treatments, that you could anticipate that after 20 years or so, close to 90% of relapsing-remitting patients would develop secondary progression, but long-term follow-up on patients taking Copaxone [glatiramer acetate; Teva Pharmaceuticals] showed that rate is now about 49%," Dr. Herdon pointed out. "This is very evident in clinics."…

    Have these results been replicated in any of the other DMD that are already known? Do you agree that these are evident based on clinical data out there?

    • I had read an article a few months ago in medscape
      this was the study of peter stys I believe

      In relaton of decrease in conversion to SPMS the problem of using historical data is that there has been a change in the demographic of people in trials. About fifteen years ago the relapse rate was about 1.5 but now it is about 0,5 so less active MSers are being examined. This may be because the highly active Msers are being put on treatment and are not entering trials. But if the people being examined are less active the rate of conversion to SPMS may be expected tobe less.

    • I don'tknow about the conversion rate this is Gs domain and are you being cynical about trial design? :-).

      From a marketeer point of view you are right

  • Thank you Mousedoctor, I was curious about the claim because I hadn't found any mentions of decrease of SPMS before, and when I read that thought there would have been more of a buzz about something like that.

    • Dear Andy
      There are a few papers on NLRP3 inflammasome and how this relates to the function of macrophages. How this relates to MS and diabetes type II or I would just be speculation I am afraid. Prof G and I talked about it really were not convinced we would any thing usefulto say at this point.

      As to your other question we were not sure there was any real link other than cahnce

      Sokolovska A, Becker CE, Ip WK, Rathinam VA, Brudner M, Paquette N, Tanne A, Vanaja SK, Moore KJ, Fitzgerald KA, Lacy-Hulbert A, Stuart LM.

      Activation of caspase-1 by the NLRP3 inflammasome regulates the NADPH oxidase NOX2 to control phagosome function.

      Phagocytosis is a fundamental cellular process that is pivotal for immunity as it coordinates microbial killing, innate immune activation and antigen presentation. An essential step in this process is phagosome acidification, which regulates many functions of these organelles that allow phagosomes to participate in processes that are essential to both innate and adaptive immunity. Here we report that acidification of phagosomes containing Gram-positive bacteria is regulated by the NLRP3 inflammasome and caspase-1. Active caspase-1 accumulates on phagosomes and acts locally to control the pH by modulating buffering by the NADPH oxidase NOX2. These data provide insight into a mechanism by which innate immune signals can modify cellular defenses and establish a new function for the NLRP3 inflammasome and caspase-1 in host defense. Nat Immunol. 2013 Jun;14(6):543-53. doi: 10.1038/ni.2595. Epub 2013 May 5.

      Frederick J Sheedy, Alena Grebe, Katey J Rayner, Parisa Kalantari, Bhama Ramkhelawon, Susan B Carpenter, Christine E Becker, Hasini N Ediriweera, Adam E Mullick, Douglas T Golenbock, Lynda M Stuart, Eicke Latz, Katherine A Fitzgerald & Kathryn J Moore CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nature Immunology (2013) doi:10.1038/ni.2639

      Particulate ligands, including cholesterol crystals and amyloid fibrils, induce production of interleukin 1β (IL-1β) dependent on the cytoplasmic sensor NLRP3 in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands, including oxidized low-density lipoprotein (LDL), amyloid-β and amylin peptides, accumulate in such diseases. Here we identify an endocytic pathway mediated by the pattern-recognition receptor CD36 that coordinated the intracellular conversion of those soluble ligands into crystals or fibrils, which resulted in lysosomal disruption and activation of the NLRP3 inflammasome. Consequently, macrophages that lacked CD36 failed to elicit IL-1β production in response to those ligands, and targeting CD36 in atherosclerotic mice resulted in lower serum concentrations of IL-1β and accumulation of cholesterol crystals in plaques. Collectively, our findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation.

    • Thanks for the reply, I will read and try and digest. I will keep pursuing the'Amateur Sleuth' role, it keeps me busy and out of trouble. (for the most part 😉
      I like maths, so the chance conundrum will have my 'Detective's Nose' twitching for some time.

      Regards as always.

  • Do you have any thoughts about the antiviral drug being developed that is called DRACO? They say if this medicine works, it could be the cure for virtually all viral disease. If this drug can really detect if a cell is infected with a virus and then tell the cell to commit suicide, could it also cure a virally caused MS?

    • Sounds interesting but it will have to be shown to be safe in clinical trials. it's been shown to be effective in mice but my caveat is that lab mice are essentially virus-free and will only be infected with the virus to be studied. In humans we catch lots of viruses many of which will have no consequence so if this drug deletes all virally infected cells, there may not be many left after the therapy, which would be a huge problem.
      We need to proceed with caution but as you say if MS IS caused by a virus this could be of huge benefit.
      Personally I'd be pushing for an anti EBV vaccine, again with the caveat that it would take 30 years or so before we knew if this was the answer or not!

    • That didn't sound well..
      I hope you get whatever is bothering you sorted out. It's has really been a nice experience for me to come over and meet you all, I really appreciate your hard work.
      Best wishes
      /Swedish Sara

  • This study shows that Vitamin D3 improves myelination and recovery after nerve injury.

    PLoS One. 2013 May 31;8(5):e65034. doi: 10.1371/journal.pone.0065034. Print 2013.

    http://www.ncbi.nlm.nih.gov/pubmed/23741446

    Cholecalciferol (vitamin d3) improves myelination and recovery after nerve injury.

    Chabas JF, Stephan D, Marqueste T, Garcia S, Lavaut MN, Nguyen C, Legre R,
    Khrestchatisky M, Decherchi P, Feron F.

    Aix Marseille Université, CNRS, NICN UMR 7259, Marseille, France ; APHM, Hôpital de la Conception, Services de Chirurgie de la Main, Chirurgie Plastique et Réparatrice des Membres, Marseille, France.

    Previously, we demonstrated
    i) that ergocalciferol (vitamin D2) increases axon diameter and potentiates nerve regeneration in a rat model of transected peripheral nerve
    and
    ii) that cholecalciferol (vitamin D3) improves breathing and hyper-reflexia in a rat model of paraplegia.

    However, before bringing this molecule to the clinic, it was of prime importance
    i) to assess which form – ergocalciferol versus cholecalciferol – and which dose were the most efficient
    and
    ii) to identify the molecular pathways activated by this pleiotropic molecule.

    The rat left peroneal nerve was cut out on a length of 10 mm and autografted in an inverted position. Animals were treated with either cholecalciferol or ergocalciferol, at the dose of 100 or 500 IU/kg/day, or excipient (Vehicle), and compared to unlesioned rats (Control).

    Functional recovery of hindlimb was measured weekly, during 12 weeks, using the peroneal functional index. Ventilatory, motor and sensitive responses of the regenerated axons were recorded and histological analysis was performed. In parallel, to identify the genes regulated by vitamin D in dorsal root ganglia and/or Schwann cells, we performed an in vitro transcriptome study.

    We observed that cholecalciferol is more efficient than ergocalciferol and, when delivered at a high dose (500 IU/kg/day), cholecalciferol induces a significant locomotor and electrophysiological recovery.

    We also demonstrated that cholecalciferol increases
    i) the number of preserved or newly formed axons in the proximal end,
    ii) the mean axon diameter in the distal end, and
    iii) neurite myelination in both distal and proximal ends.

    Finally, we found a modified expression of several genes involved in axogenesis and myelination, after 24 hours of vitamin supplementation. Our study is the first to demonstrate that vitamin D acts on myelination via the activation of several myelin-associated genes.

    It paves the way for future randomised controlled clinical trials for peripheral nerve or spinal cord repair.

    PMCID: PMC3669361
    PMID: 23741446 [PubMed – in process]

    • OK so you have pasted the abstract thanks.
      So if you are atking your 5000IU/day that is about 100IU/kg/day so you will get bone health and maybe some remyelination potential also.

      There are studies in the netherlands planned to look at optic neuritis, so with by monitoring visual evoked potentials this may occur

  • Prof G, I just wanted to mention that following the various threads about access to highly effective DMDs in the UK, I wrote to Lord Dubs. This morning, I received a really knowledgeable and positive reply which leaves me with no doubts whatsoever about his understanding and commitment to our cause. P.

    • Your are lucky made you have the right line of communication I wrote to him about the BPA…..and not a sausage.

  • I never expect any of your team to reply to comments (although hugely pleased when you do) but can we expect that you routinely read them through (say) the day they are posted? (Or is it hit-and-miss?).

    • When you last asked this question I believe there was a response.

      Do comments get read…yes…we have to remove the rubbish that sometimes gets posted.

      Do they get read daily…I would say the answer is generally Yes….someone from Team G will generally read the posts every day.

      ProfG gets an email when anyone posts…no wonder he has about 1500 emails in his in box.
      MD generally reads them at least once every day but if workpressures dictate then they are read when time prevails.
      MD2 is abit stone age and doesn't do the internet at the weekendor in the evening.

      Will they get an answer always…No

      some posts have no question, if someone answers the question in an adequate way we do not need to add more, are they clinical questions then MD and MD2 probably won't answer them either no knowledge or no insurance. These are the ones you want answers to but ProfG or other neuro needs to answer them.

      Are the questions leading…then we can't answer them e.g. Prof G cannot give a consultation, or a market opinion.

      Sometimes he is just too busy to answer them..sorry

    • In my opinion no.

      Prof G may want to defend the pharma position I don't however he is being sent away for a relax.

      It is an effective cartel with a prce war that just makes MS drugs go higher and higher.

    • In addition in the current structure of posting comments are hard to track. We have a reply to a post so recent posts get lost in amongst a load of older ones. Sometimes they get lost in this and don't get answered. Prog G prefers this style and he is the boss. I prefer the chronological list so the recent post is always at the bottom and so easy to see

  • This blog seems to have an emphasis on drug trials and treatments. Is there much research for the cause of MS? Is it true that RRMS usually becomes SSPMS after approx 15 years with or without treatment? Also, when candidates are chosen for trials, is lifestyle considered in the findings?

    • I think it is an extension to people in the original trial.

      I can't say what this means G will know but it is not our job to supply news from Novartis, we can report it.

      You wouldn't want to extend a trial if it was dangerous

  • Well my favourite example of Australian 'brain shred' was just awarded the prestigious Australian Academy of Science Medal – 14 years on from diagnosis. He is 57 years of age. Perhaps a study of persons who have MS >10 years and are 'productive' might be worth studying to tease out issues such as level of disability, lesion load, brain volume loss from diagnosis to long term follow up – and an add an examination of lifestyle factors, education-cognitive reserve etc. Are such persons really benign – does the definition of benign need to change? Are DMD's are contributing to a better disease and health profile? Does the latitude advantage contribute? Lots of tasty research questions!

    http://www.science.org.au/news/media/2mediarelease22072013.html

  • Is there any docummented evidence of spontaneous axon repair ( not myelin) ? or is there evidence of the brain compensating for damage and re routing.

    Regards as always

    • Axon repair in MS. Yes, there is so called axonal plasticity when new sodium channels are inserted in the demyelinated segment to restore conduction. These channels are aberrant and can fire spontaneously which is one of the mechanisms behind pain in MS. There is also evidence of axonal sprouting and new synapse formation in MS and animal models. However, these processes are believed to limited in the adult central nervous system.

    • Thank you, So natures way of compensating,but with side effects ? nevertheless something to work on, if maybe decades away.

      Regards as always

  • What is the likelihood of a XXMD3 – a Mousepenny perhaps joining team G? Given the gender bias of MS, an XXMD might be able to shed some light on matters sensitively female.

  • we have XXMD3 on the team already. Will they comment?

    i always thought MD2 was in touch with their inner feel

  • ings
    Ffor one xx after her first post some of you were so rude she never came back.

    sensitivity is a two way street

  • Glad to know about an XX on the team. Can't comment about MD2, he would know best about that. Unfortunate that XX was treated rudely – I thought the English were quintessential representatives of the mannered classes? Us 'convicts', we know how to mind our 'P's and 'Q's.

  • Agreed, unfortunate that XX was treated rudely. As to the English being polite, we don't have a monopoly 🙂

    People who are unnecesarily rude really don't do anyone any favours, including themselves. What's the point? It just shows ignorance and lack of consideration. I'm really sorry XX was put off posting again.

  • Just sharing a bit of research from 'down under' …..it's a long flight for the carrier pidgeons. I don't know the 'interconnections' of the research world in terms of sharing MS research. Two links from MSRA here, relate to EBV, ignore the references to the peer reviewed journals, see link to project funded by MSRA led by Prof Allan Kermode:

    http://www.msra.org.au/new-research-strengthens-link-EBV-infection-and-ms

    and to a lesser extent, Dr Wilson's post doc fellowship:

    http://www.msra.org.au/studying-role-common-environmental-and-behavioural-risk-factors-onset-and-clinical-course-ms-0

    And may I ask out of curiosity, are the funding amounts for similar projects comparable to similar endeavours in the UK?

  • Often when I hear new 'world first' discovery my brain goes into extrapolation mode and endeavours to connect the findings to MS. So here's a newspaper report of such a small study of exercise on unconscious patients to establish whether exercise improves recovery rates. Specialised US exercise machines were obtained similar to the FES system where the exercise, – cycling in this instance, was conducted by machine generated nerve stimulation to muscles and moved to patient initiated program upon regaining consciousness. Compared with peers, trial participants had faster recovery, earlier standing and walking, reduced delirium and earlier return to home.

    I wonder where I would place this in the MS framework? As part of hospitilised relapse recovery program? Would a review of the parameters and timing of FES training be useful? Of course there is also a clear equity issue with access to FES based equipment given it's hefty price tag. Whilst this is only a small study, the results were encouraging and the study expanded to include more participants. Any thoughts?

    http://www.theage.com.au/victoria/unconscious-patients-get-legup-with-cycling-20130819-2s7fx.html

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