RL648_81: Synthesis and Evaluation of Potent KCNQ2/3-specific Channel Activators

Discussion in 'Research News' started by attheedgeofscience, Mar 29, 2016.

    1. Bobby B
      Fine

      Bobby B Member Benefactor

      Tinnitus Since:
      11/2015
      Cause of Tinnitus:
      long term NIHL and recent acoustic trauma
      We know the FDA and the medical community isn't taking tinnitus suffering seriously.

      There is no reason to side with the FDA on that one - they will make sure the process takes a very long times and costs so much that most investors will be reluctant to pour money unless they are sure to recoup their investment.

      And the other risk here, if during this long time another better epilepsy drug is discovered, with a mode of action not affecting T, we can probably kiss this "official" RL_81 goodbye for good.

      Professor T - great name for this btw - spent all this time working on his new molecules.. it would be very sad that this ends up nowhere for all the many reasons that have nothing to do with how it works.

      Then we will are back to "live with it" and try those snake-oily sound or T re-training techniques...
       
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    2. AUTHOR
      AUTHOR
      attheedgeofscience
      No Mood

      attheedgeofscience Member Mighty Benefactor Hall of Fame

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      Denmark
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      Resolved since 2016
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      See information page
      To be (very) honest, I don't think that would change much. "Zooming out" and seeing the big picture, I would like to mention that - on average - 22 US veterans commit suicide. Every day. There is even a specific home page on FB for that (Mission 22):

      www.facebook.com/Mi22ion

      With such staggering numbers, you would think that a lot would get done to alter that statistic. For sure some of these veterans are - and were - suffering from tinnitus (being the #1 disability suffered by veterans). But even that seems not to get the attention of decision makers. I personally corresponded with the WWP - the most powerful NGO for veterans (and +3M followers on Facebook) and they were not interested in sharing anything related to tinnitus and research on their Facebook page. In fact, tinnitus wasn't even mentioned in their latest survey from members (see attachment).

      In retrospect, and with the setbacks seen in terms of clinical trials and long delays with time-to-market, I cannot help but think that my stem cell treatments were the best decision I could ever have made - because the cavalry didn't come to rescue me back in 2013 (and not anytime soon thereafter either).

      I should, however, point out that Auris Medical is still a player in the game, and also one dedicated and well managed pharma company (and helpful staff). At some point their AM-102 is due to enter clinical trials (provided all goes well). Indeed, a news feed post was shared on that a little while back:



      It remains to be seen which category of patients will be in scope for the trial. But at least, there is potentially one additional drug coming our way.

      While the embedded FB-post (on RL-81) I shared in the first message here on this thread now has +200 ratings (all-in-all), the one from Auris Medical, above, has far less. It would be better if the tinnitus community had ensured that the ratings were the other way around.
       

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    3. Mithrandir
      Ape-like

      Mithrandir Member

      Tinnitus Since:
      10/2015
      Cause of Tinnitus:
      Acoustic Shock Disorder (TTTS)
      @attheedgeofscience Thanks for your information about Mission 22, that's a sad moment for USA. This country doesn't help those brave guys who worked for it...so sad story ! Disability of vets like T must be one of the most important act from US Army for the guys...

      After all your tinnitus journey (through the hell) and with all the knowledges you provide us. Definitely you consider stem cell like the best think you've ever done ? Is it your main advice for T sufferers ? (of course if people have money to go to Asia)
       
    4. Alue
      No Mood

      Alue Member

      Tinnitus Since:
      01/2016
      Cause of Tinnitus:
      Acoustic Trauma
      It seems they adopt the "just ignore it, pretend it doesn't exist, and hope it goes away" mantra with tinnitus.

      The WWP is a pretty disgraceful NGO when you take a closer look at their spending.

      Although I haven't seen the results I had hoped for with AM101 (could be the placebo), the trails have been a positive experience for me, and at least at my site everything has been very professional. I really hope Auris is successful! Even if AM101 doesn't help chronic sufferers, a successful drug coming to market would be huge for the future of tinnitus research.

      If AM102 targets more chronic tinnitus, do you think patients that participated in AM101 would still be eligible to sign up for the AM102 trials?
       
    5. Bertman
      No Mood

      Bertman Member Benefactor

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      That's what I assumed this thread was all about. Kind of like how people are trialling trobalt on their own but with an experimental drug instead. It's for personal benefit, not to create scientific data; that's what scientists, doctors and researchers are for. More of a try it and see if it works for you kind of thing. If it does then great, if not then keep on keeping on like we are now. As I said earlier though, it is too risky for me at the moment, but who knows, in the future if people say it works then I may have to reconsider. It'd be nice to know if something out there works and have the option of trying it before/if it makes it to market.
       
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    6. linearb
      Psychedelic

      linearb Member Benefactor Hall of Fame

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      A misunderstood statistic: 22 military veteran suicides a day (LA Times)

      http://www.forbes.com/sites/timwors...c-of-suicide-in-the-us-military/#69acb6641769
      On the other hand, veterans certainly do have tinnitus at much higher rates than the general population, to the tune of $1 billion a year in disability costs.
       
    7. Bertman
      No Mood

      Bertman Member Benefactor

      Location:
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      I agree with you, but I also understand why it's the way it is. Although we don't know the specifics on whether or not it will work for us chronic T folk, it's easy to associate it with am-101 which doesn't seem to have hope for us longer term T people. So the majority of people on here will likely dismiss it as something with less value to us than it really has. This drug on the other hand seems like it would be able to help chronic T more than an injection into the ear would. (I know this is a very long shot and we shouldn't get too excited over preliminary data like this yet, but that's just the way it appears)
       
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    8. AUTHOR
      AUTHOR
      attheedgeofscience
      No Mood

      attheedgeofscience Member Mighty Benefactor Hall of Fame

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      I would have absolutely no opinion on such matters. I would say such a question would either be answered via the inclusion/exclusion criteria when/if the trial of AM-102 commences. Alternatively, there may also be an opportunity to set up a Q&A-session with Auris Medical at some point in the future (they have already done that - very generously - twice in the past). As it happens, I set up the first one back in January/February last year:

      https://www.tinnitustalk.com/threads/auris-medical-q-a.8201

      If members of this board would like me to investigate that, then, as a minimum, I require the news feed post of AM-102 that I shared earlier on in this thread to reach a minimum of 250 ratings combined (likes/shares/comments).

      Alternatively, I know @Michael2013 is looking for ways to become more of an asset with the tinnitus community - so perhaps this could be his first task as an apprentice (i.e. setting up a Q&A-session).
       
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    9. Leo1994
      Suicidal

      Leo1994 Member

      Location:
      Sweden
      Tinnitus Since:
      2005
      Researchers at the University of Pittsburgh School of Medicine and Arts & Sciences have designed a more effective version of an FDA-approved epilepsy drug with the potential for fewer side effects, according to a study published on March 22 in Molecular Pharmacology. The experimental agent also could prove to be a treatment for tinnitus and other disorders caused by volatile neural signaling.

      Epilepsy, in which erratic firing of nerve signals causes seizures, affects about 1 percent of people worldwide, said senior investigator Thanos Tzounopoulos, Ph.D., Endowed Chair in Auditory Physiology, associate professor of otolaryngology and member of the Auditory Research Group, University of Pittsburgh School of Medicine. Drugs to treat the disorder primarily work by influencing the transport of sodium, potassium and chloride ions across the nerve cell membrane to try to reduce the excitability of the brain cells.

      "Unfortunately, these drugs don't work well in nearly a third of patients and there is a great need for better treatments," Dr. Tzounopoulos said. "We have been able to refine an existing medication so that it acts selectively on certain nerve cell membrane transport channels, which should make it more effective."

      The available drug is called retigabine, and while it has improved symptoms for some patients, it can also lead to troublesome side effects, including retinal abnormalities, urinary retention and skin discoloration. Dr. Tzounopoulos was part of a study team that evaluated an earlier modification of retigabine, dubbed SF0034, which is being further developed by SciFluor Life Sciences LLC in Cambridge, Mass.

      For the current project, Dr. Tzounopoulos and Peter Wipf, Ph.D., Distinguished University Professor of Chemistry at Pitt, rationally redesigned several structural components of retigabine to further increase its potency. Retigabine works by activating all five types of potassium transport channels in the KCNQ category, but only two of the potassium channels, KCNQ2/3, are important for stabilizing the cell membrane of brain cells involved in hyperexcitability-related disorders, such as epilepsy and tinnitus, Dr. Tzounopoulos explained. The new compound, known as RL648_81 ("RL-81"), targets just those channels.

      When the researchers compared the three drugs head-to-head in lab tests, they found RL-81 was 15 times more potent than retigabine and three times more potent than SF0034. Because of its specificity, RL-81 also should have fewer side effects.

      The experimental compound could also help people with tinnitus by preventing hyper-excitation of nerve cells in auditory pathways, Dr. Tzounopoulos noted.

      "At this point, the new compound is ready to be studied further in animal models of epilepsy and tinnitus and for other preclinical assessments," Dr. Wipf said. "RL-81 appears to have great potential for the treatment of these challenging neurological conditions."

      https://www.sciencedaily.com/releases/2016/03/160330102848.htm
       
    10. Beste
      Disappointed

      Beste Member

      Tinnitus Since:
      02/16/2016
      Cause of Tinnitus:
      Benzo/Clonazepam, Stress
      I think we need to start a petition as TT and help the team behid this study to finish it before 2020! Most of us will be chronic by then and this drugs will not work for us most probably.
       
    11. Bobby B
      Fine

      Bobby B Member Benefactor

      Tinnitus Since:
      11/2015
      Cause of Tinnitus:
      long term NIHL and recent acoustic trauma
      Yeah petition will work ! Maybe the starving children in Africa should also start a petition on the Internet to draw attention .

      No one wants to take the risk trying that drug on themselves and no one is willing to pay for tests etc... So you will have to wait until 2020 and beyond
       
    12. Beste
      Disappointed

      Beste Member

      Tinnitus Since:
      02/16/2016
      Cause of Tinnitus:
      Benzo/Clonazepam, Stress
      Bobby, you know this world is cruel place. Since no one will gain money by helping African children they just refuse to pay more attention to them. It sucks but this is what it is.

      This is something different. I read somewhere that Professor said the progress is slow due to financial situations. I think that means if we help the team of retigabine they may finish their works earlier. I think our situation is not as desperate as African children.
       
    13. Danny Boy
      Cheerful

      Danny Boy Member Benefactor Hall of Fame

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      This drug isn't for tinnitus first, it's for epilepsy first. Therefore, we won't be able to obtain the drug for quite a long time, as it's not even in trials yet. They are trying to find a pharmaceutical company who wants the drug.

      Also, people who are on the verge of suicide, because of their tinnitus would beg to differ. If you have super loud tinnitus coupled with hyperacusis and reactive tinnitus, yeah...It's horrible.

      Additionally, I would think it's useful to know if the drug actually works for tinnitus on humans, as people are jealous of these mice getting rid of their tinnitus and we can't.
       
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    14. Beste
      Disappointed

      Beste Member

      Tinnitus Since:
      02/16/2016
      Cause of Tinnitus:
      Benzo/Clonazepam, Stress
      Yes. I'm one of those people.
       
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    15. gotyoubynuts

      gotyoubynuts Member

      Tinnitus Since:
      10/1990
      Cause of Tinnitus:
      Concert
      You now have hyperacusis and reactive tinnitus as well? What's next?
       
    16. Beste
      Disappointed

      Beste Member

      Tinnitus Since:
      02/16/2016
      Cause of Tinnitus:
      Benzo/Clonazepam, Stress
      I always had hyperacusis and reactive tinnitus. Please first read my old posts! They just used to be mild.
       
    17. jacob21
      Amazed

      jacob21 Member Benefactor

      Tinnitus Since:
      2008 > 2009 "cured" >2nd onset June 2016
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      Noise Induce ( loud music )
      Hi

      I read this tread very interesting
      Hope Dr Tzounopoulus will find something very soon

      I have a question , what is RTG ? is it a drug ?
       
    18. DebInAustralia
      Fine

      DebInAustralia Member Benefactor Advocate

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      Rtg = retigabine
       
    19. lambos

      lambos Member

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      May 5 2013
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      unsure
    20. valeri

      valeri Member Benefactor Hall of Fame

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      At best this drug is at least 10 years away!
       
    21. lambos

      lambos Member

      Tinnitus Since:
      May 5 2013
      Cause of Tinnitus:
      unsure
      I sure hope sooner than that but you might be right valeri as its such a slow process with animal and then human testing and lastly the hope of FDA approval...i would love to be part of the human testing of this drug however having said that maybe stem cell is the way to go or another epilepsy drug perhaps.
       
    22. Jim51042

      Jim51042 Member

      Tinnitus Since:
      3/28/16
      Cause of Tinnitus:
      Headphone use
      Its been over a year since this RL-81 thread was created. I was wondering if anyone has heard any updates? Any updates in the animal research? Is 2020 still the target date for human clinic trials? Thanks.
       
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    23. Jim51042

      Jim51042 Member

      Tinnitus Since:
      3/28/16
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      Here is a supplier and price of the RL-81. Note I'm not suggesting you try. I've just emailed Prof T to get an update on his progress. If what I've interpreted from the prior posts conversions with Prof T are correct and he is no longer developing this drug then maybe someone on this site knows a university/drug maker who can take up the baton.

      http://www.sigmaaldrich.com/catalog/product/sigma/sml1738?lang=en&region=US
       
    24. Kratos
      Dreaming

      Kratos Member

      Location:
      Spain
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      October 2016
      Cause of Tinnitus:
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    25. Jim51042

      Jim51042 Member

      Tinnitus Since:
      3/28/16
      Cause of Tinnitus:
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      That answered my question. Thanks.
       
    26. Tigo

      Tigo Member

      Tinnitus Since:
      2 years
      Cause of Tinnitus:
      genetic hearing loss
      Can you buy this stuff? Is it for T?
       
    27. ReyKalinic

      ReyKalinic Member

      Location:
      Roma
      Tinnitus Since:
      2000
      Cause of Tinnitus:
      Triggered by TN 2004/05
      No one knows. I'm going back to pre forum level. It Made me loopy.
       
    28. Jim51042

      Jim51042 Member

      Tinnitus Since:
      3/28/16
      Cause of Tinnitus:
      Headphone use
      I want to update my earlier post. I have received an email reply from Prof T. He is still working on RL648-81 with the goal of doing clinic studies on people.
       
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    29. acufenero
      Starving

      acufenero Member

      Tinnitus Since:
      August 2014
      Cause of Tinnitus:
      Acoustic trauma
      Good news. I've been on Retigabine some months ago (I still have a full box of 300 mg). It definitely worked for me as it lowers my T for a few hours, but it has too many serious side effects.
       
    30. Jim51042

      Jim51042 Member

      Tinnitus Since:
      3/28/16
      Cause of Tinnitus:
      Headphone use
      @acufenero how much say from at (8/10 to a 4/10) did RTG reduce your T?
       

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