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Thread: Jerry Silver and Other Discussion from ChinaSCINet Update

  1. #441
    Senior Member lynnifer's Avatar
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    Quote Originally Posted by crabbyshark View Post
    There is no possible way, post-hoc, to gauge if ibuprofen had anything to do with your improvements or not. It should be studied in a clinical trial.
    *sigh* I took the Motrin many years AFTER the patchiness feeling came back as I aged from pushing myself in a chair plus pain from menstruation .. in my 28th year now. Therefore, I can say with assurance that Motrin had nothing to do with it. I've since graduated to Oxy when needed - which isn't often.

    Go support Dr Young in that other thread.

    Fampyra is totally the result of my lower back sensation/muscles returning which I started taking in late June 2012.
    Roses are red. Tacos are enjoyable. Don't blame immigrants, because you're unemployable.

    T-11 Flaccid Paraplegic due to TM July 1985 @ age 12

  2. #442
    Quote Originally Posted by NowhereMan View Post
    "The results here reveal that axonal sprouting and neuroprotection are likely to be the primary mechanisms of ibuprofen’s action in spinal contusion. In contrast, the corticospinal regeneration highlighted by a previous study (Fu et al., 2007) was not observed here. We find that ibuprofen dependent axonal regeneration is confined to a small subset of raphespinal fibers after complete transection." (Wang, et al, 2009).
    NowhereMan,

    Thanks for posting this.

    Wang, et al. 2009 studied the effects of ibuprofen on the spinal cord contusion model. The contusion model probably require combination therapies that address multiple obstacles to generation. Many other therapies, such as chondroitinase, nogo antibodies, and PTEN deletion are not effective as single therapies of contusion model. On the other hand, Wang, et al. did show that ibuprofen increased axonal sprouting and had neuroprotective effects in the contusion model.

    The discovery that ibuprofen shuts off RhoA is important because it gives us another tool to explore the role of RhoA in preventing axonal regeneration. If Ibuprofen really does not have any beneficial effects on recovery of function in chronic spinal cord injury, this may be because other obstacles to regeneration are present at the injury site besides axonal growth inhibitors (including Nogo and CSPG) that work on receptors based on RhoA.

    Wise.
    Last edited by Wise Young; 02-10-2013 at 10:38 AM.

  3. #443
    Quote Originally Posted by Fly_Pelican_Fly View Post
    I didn't dismiss anything as being bogus. But I do question the rationale to take this to human trials without compelling evidence in a clinically relevant animal injury model. The fact that human trials are incredibly expensive to execute and difficult to recruit for should mean that the selection criteria of therapies for human trials should be very carefully and efficiently thought out.

    Obviously the goal of Cure is important, but equally important is the critical path to goal with the resources available to the clinical community. Cash is king, and the custodians of the cash need to take a balanced approach in selecting therapies during frugal times. You always want the "biggest Bang for your Buck". A scattergun approach raises the probability of failure - and impacts the argument that investing in science to reduce healthcare costs diminishes - especially when governments are making huge cutbacks.
    Pelican,

    Thanks for your comments. I don't think that I said that Ibuprofen should be taken to clinical trial without further study. Admittedly, you did not use the word bogus and I apologize for suggesting that you did. On the other hand, the tone of the discussion is that ibuprofen should be dismissed as a potential therapy for spinal cord injury because this is a common drug and people have been taking this drug for years without showing improvement.

    It is important that people understand the implications of the Fu, et al. study. They have found that Ibuprofen and Indomethacin, two common and inexpensive drugs, are more effective than Cethrin in blocking RhoA. RhoA is of course the intracellular messenger that mediates the effects of most of the axonal growth inhibitors, including Nogo and myelin-based axon growth inhibitors, chondroitin-6-sulfate proteoglycans (CSPG), and other extracellular matrix proteins.

    If an effective RhoA blocker has no beneficial effect on chronic spinal cord injury, it would argue strongly against drugs such as nogo antibody, soluble nogo receptor, chondroitinase and CSPG receptor blockers working as well. It is an important tool and should not be dismissed as a potential candidate therapy.

    Wise.
    Last edited by Wise Young; 02-10-2013 at 10:38 AM.

  4. #444
    Quote Originally Posted by Fly_Pelican_Fly View Post
    Based on the very nature of its financial resources, a non-commercial clinical trial (network) should be taking less risk than a commercial clinical trial run by a large biotech or pharmaceutical when selecting a therapeutic target. Larger entities can afford the odd failure. Non-commercial trials cannot afford failure when money is so hard to come by. All the more reason for demonstrating compelling evidence in the translational stage in a clinically relevant chronic animal model before moving forward with any trial. Dont you think?
    Pelican, before we go forward on this discussion, perhaps you should suggest some other therapies that you think should be tested. We are really quite open to suggestions and we are currently considering the next set of therapies that we would test in ChinaSCINet.

    If you would like, we can start a discussion on what constitutes risk in clinical trials and what animal models can do. I have spent most of my career on these two issues and suggest that the situation is not as simple as you are suggesting.

    Wise.

  5. #445
    Quote Originally Posted by Wise Young View Post
    Pelican, before we go forward on this discussion, perhaps you should suggest some other therapies that you think should be tested. We are really quite open to suggestions and we are currently considering the next set of therapies that we would test in ChinaSCINet.

    If you would like, we can start a discussion on what constitutes risk in clinical trials and what animal models can do. I have spent most of my career on these two issues and suggest that the situation is not as simple as you are suggesting.

    Wise.
    My comment was a generic point that clinical trials funded by donor money should be even more responsible when managing risk than a commercial entity due to finite resources.

    I wont suggest therapies as I am not a scientist. I'll leave that to the numerous scientific advisory boards that exist out there.

    However, I am an investor. Whether that is by donating funds, buying stock in an entity (not that I do this) or by investing time and money advocating for Cure for chronic spinal cord injury. So my definition of risk is not dissimilar to that of a venture capitalist ie the chance that an investment's return will not be as expected. My return may not be financial, but rather additional voluntary function

    btw I'm a fan of SCINetChina. I believe clinical trials must be executed in India and China in order to accelerate Cure. However, I hope the network does not become a "catch all" for therapies that have not been translated appropriately. What constitutes "translated appropriately" is perhaps the discussion we need to hear?

  6. #446
    Quote Originally Posted by Fly_Pelican_Fly View Post
    My comment was a generic point that clinical trials funded by donor money should be even more responsible when managing risk than a commercial entity due to finite resources.

    I wont suggest therapies as I am not a scientist. I'll leave that to the numerous scientific advisory boards that exist out there.

    However, I am an investor. Whether that is by donating funds, buying stock in an entity (not that I do this) or by investing time and money advocating for Cure for chronic spinal cord injury. So my definition of risk is not dissimilar to that of a venture capitalist ie the chance that an investment's return will not be as expected. My return may not be financial, but rather additional voluntary function

    btw I'm a fan of SCINetChina. I believe clinical trials must be executed in India and China in order to accelerate Cure. However, I hope the network does not become a "catch all" for therapies that have not been translated appropriately. What constitutes "translated appropriately" is perhaps the discussion we need to hear?
    Pelican,

    I ask your opinion because I would like to know what you would consider to be a reasonably de-risked therapy that should go to trial. I respect your opinion as an investor. By the way, most spinal cord injury scientific advisors have never designed, organized, or participated in clinical trials, so I am not sure that their opinions are necessarily any more valid than yours. You (and others) have expressed the view here that any therapy that has not yet been tested in appropriate chronic spinal cord injury models should not be taken to clinical trial. There have been several groups that have been trying to say that clinical trials should be done only when specified criteria are met.

    I disagree that a therapy should meet some specified efficacy criteria before going to trial. It is already difficult enough to get therapies into clinical trials without some committee (usually a self-appointed committee with little or no experience with clinical trials) stopping therapies from going into clinical trial because somebody on the committee believes that a therapy does not work, that certain spinal cord injury models are not good, or other scientific politics. Yes, as I hope you and others here should have gathered, there is substantial scientific politics going on in spinal cord injury. There are many scientists pushing their own agenda, their theory, their treatment, and their model. They are competing with each other and they often have a lot at stake, including their reputation and funding.

    To get a therapy into trial, particularly in a non-profit network, one must convince literally hundreds of scientists, clinicians, investors, and patients that the therapy is worthwhile testing in preclinical studies, pursuade companies to donate the therapies, raise millions from skeptical organizations and donors, get regulatory approval from the FDA in the U.S. and regulatory authorities in other countries, get ethical and clinical approval from institutional review boards, and apply to dozens of funding agencies. Believe me, these are not trivial tasks and I don't think adding scientific politics to that burden is a good idea.

    Regarding clinical trials and risk, you are probably referring to risk of therapy proving to be not beneficial. I think of failure as a clinical trial that fails to provide credible data. For example, if ChinaSCINet shows definitively that umbilical cord blood mononuclear cells and lithium are not beneficial in chronic spinal cord injury, I would consider the trial a success. It means that we can close the door on umbilical cord blood mononuclear cell transplantation, which is already being practiced by clinics catering to medical tourists around the world. If the trial shows that umbilical cord blood mononuclear cells are beneficial, the trial would be even more successful. The only failure is if the trial were so poorly designed and conducted that we don't get a reliable answer one way or another.

    A review of how ChinaSCINet chose its trials illustrates that the situation is not as simple as you have suggested. In 2006, when we started the current series of trials for ChinaSCINet, the investigators of ChinaSCINet considered all the therapies that were available. We had several objectives:
    1. We wanted to prove to the world that we have a network that can carry out rigorous clinical trials rapidly and efficiently.
    2. We wanted to gain experience with testing of combination therapies in clinical trials.
    3. We wanted to test a cell therapy that is safe, readily available to the world if the treatment is effective, and that is already being used.
    4. We wanted a therapy that was safe. A trial that has to be stopped because of a safety issue means that we would have to start all over again.
    5. Of course, we wanted to have a therapy that would cure spinal cord injury.


    After reviewing all available therapies in 2006, we chose umbilical cord blood mononuclear cells and lithium because we thought these were the most promising, safe, and feasible therapies. Please note that neither of these therapies were discovered in my laboratory or "my" therapies in any sense of the word. My laboratory did not do the preclinical studies. As it is turning out, the choice of umbilical cord blood and lithium was a good one because phase II trials showed that the therapies are safe and have yielded interesting results that the group has decided to pursue. First, lithium seems to reduce severe neuropathic pain in people with chronic spinal cord injury and we are doing a phase III trial to confirm this unexpected finding. Second, umbilical cord blood mononuclear cells appear to stimulate growth of fiber bundles across the injury site of people with chronic spinal cord injury. Third, a surprising number of people are recovering locomotor function, albeit without early motor and sensory score changes. A phase III trial will confirm and convince the world that the treatment does or not does not have these effects. We could have also decided that the data that we have collected so far is not worthwhile following up and that we should start testing other therapies. Because it takes time to prepare therapies for trials, we are now seriously considering what therapy to test next after the planned Phase III trial is done. Believe me, there is no perfect therapy out there that is ready to go to trial. Should we wait? If so, how long?

    Wise.
    Last edited by Wise Young; 02-10-2013 at 02:32 PM.

  7. #447
    Quote Originally Posted by lynnifer View Post
    *sigh* I took the Motrin many years AFTER the patchiness feeling came back as I aged from pushing myself in a chair plus pain from menstruation .. in my 28th year now. Therefore, I can say with assurance that Motrin had nothing to do with it. I've since graduated to Oxy when needed - which isn't often.
    Quote Originally Posted by lynnifer View Post
    lol - I have taken hundreds of bottles of Motrin over the years for PMS, pain, headaches, etc.
    You've flippantly blown off the idea that ibuprofen could somehow help you despite scientific evidence suggesting that ibuprofen inhibits RhoA and your own admission that you've had return over the years while taking hundreds of bottles of Motrin. Correlation does not equal causation (which is why there are clinical trials) but I would think you'd be more considerate than that.

    You said you have transverse myelitis. I'm not really familiar with TM. The suffix "-itis" tells me it's an inflammation of some kind. In addition to inhibiting RhoA, ibuprofen is also an anti-inflammatory. Perhaps any beneficial effects of ibuprofen would be even greater for someone dealing with transverse myelitis.

    Quote Originally Posted by lynnifer View Post
    Go support Dr Young in that other thread.
    This statement represents most of what's wrong with the cure forum and maybe spinal cord injury research in general. Science being treated like sports.

    Wise Young is a boss not because of UCBMC or Cethrin or MUSE cells. Wise Young is a boss because he's created an f-ing clinical trial network to test therapies that could make us better. A clinical trial to treat chronic SCI in humans, maybe the first ever, is happening right now.

    Quote Originally Posted by lynnifer View Post
    Go support Dr Young in that other thread.
    Wise Young works tirelessly on our behalf. Do you listen to his talks? "When I was in Pittsburgh last month" "I was in Detroit last week" "The investigators I met in Oslo were very enthusiastic" "ChinaSCINet would not exist if not for direct flights from Newark to Hong Kong" (I looked those flights up, they are 15 hours long) "I was in Verona" "Recently I returned after spending Christmas and the New Year in China"

    During his time spent traveling he makes time to log in to the forum that he created for the people he is trying to help to communicate with the people he is trying to help and sees comments like this:
    Quote Originally Posted by lynnifer View Post
    Go support Dr Young in that other thread.
    Amazing.
    Last edited by crabbyshark; 02-10-2013 at 10:10 PM.

  8. #448
    Quote Originally Posted by Wise Young View Post
    NowhereMan,

    Thanks for posting this.

    Wang, et al. 2009 studied the effects of ibuprofen on the spinal cord contusion model. The contusion model probably require combination therapies that address multiple obstacles to generation. Many other therapies, such as chondroitinase, nogo antibodies, and PTEN deletion are not effective as single therapies of contusion model. On the other hand, Wang, et al. did show that ibuprofen increased axonal sprouting and had neuroprotective effects in the contusion model.

    The discovery that ibuprofen shuts off RhoA is important because it gives us another tool to explore the role of RhoA in preventing axonal regeneration. If Ibuprofen really does not have any beneficial effects on recovery of function in chronic spinal cord injury, this may be because other obstacles to regeneration are present at the injury site besides axonal growth inhibitors (including Nogo and CSPG) that work on receptors based on RhoA.

    Wise.
    Wise,

    if I understand you correctly here above you agree that the "lesion environment" in chronic SCI is still a major problem.

    If there is one thing that disturbs me deeply in SCI research is the fact that the "lesion environment" (the scar) in chronic SCI hasn't been studied deeply by more labs yet. We could be much closer to a cure if we knew precisely what molecules, cells etc. are present in the "lesion environment" in chronic SCI.

    Paolo
    In God we trust; all others bring data. - Edwards Deming

  9. #449
    Quote Originally Posted by Wise Young View Post
    ..
    To get a therapy into trial, particularly in a non-profit network, one must convince literally hundreds of scientists, clinicians, investors, and patients that the therapy is worthwhile testing in preclinical studies, pursuade companies to donate the therapies, raise millions from skeptical organizations and donors, get regulatory approval from the FDA in the U.S. and regulatory authorities in other countries, get ethical and clinical approval from institutional review boards, and apply to dozens of funding agencies.
    ...
    Wise.
    Wise,

    all these tasks above should become much easier if you have at least one animal study (in chronic SCI) that show efficacy of the therapy you want to bring to clinical trial, so I believe that to have a positive animal study is essential (but maybe not enough) to raise the money needed for a clinical trial.

    BTW I am an investor too since, as you know, I am putting time and money to help finding a cure for chronic SCI.

    Paolo
    In God we trust; all others bring data. - Edwards Deming

  10. #450
    Quote Originally Posted by paolocipolla View Post
    Wise,

    if I understand you correctly here above you agree that the "lesion environment" in chronic SCI is still a major problem.

    If there is one thing that disturbs me deeply in SCI research is the fact that the "lesion environment" (the scar) in chronic SCI hasn't been studied deeply by more labs yet. Paolo
    So, just how would you propose this be done on live humans?

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