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

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

    1. acufenero
      Starving

      acufenero Member

      Tinnitus Since:
      August 2014
      Cause of Tinnitus:
      Acoustic trauma
      From 6 or 7/10 to almost no tinnitus, unperceivable even in a quiet room with my fingers on my ears. It lasts for a few hours, while T comes back gradually.
       
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    2. Jim51042

      Jim51042 Member

      Tinnitus Since:
      3/28/16
      Cause of Tinnitus:
      Headphone use
    3. Jim51042

      Jim51042 Member

      Tinnitus Since:
      3/28/16
      Cause of Tinnitus:
      Headphone use
      Did you develop a tolerance to Trobalt and if so how long did it to get a tolerance?
       
    4. acufenero
      Starving

      acufenero Member

      Tinnitus Since:
      August 2014
      Cause of Tinnitus:
      Acoustic trauma
      First time I took 3x300mg for like 3 months, give or take. I do think I developed some tolerance as it didn't lower my T anymore (It's difficult to measure T, you know), so I stopped because of this and side effects (it messes so much with your eyes. Luckily, all gone now). A couple of months later I started again with the same conclusions: lowered my T for a few months, then stopped because of tolerance and side effects.
       
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    5. ReyKalinic

      ReyKalinic Member

      Location:
      Roma
      Tinnitus Since:
      2000
      Cause of Tinnitus:
      Triggered by TN 2004/05
      Tolerance to retigabine in few months..... :whistle:! who know how to do people with epilepsy! years and years without tolerance....:whistle:
       
    6. Marlino
      Cowboy

      Marlino Member

      Location:
      Germany
      Tinnitus Since:
      02/2016
      Cause of Tinnitus:
      unknown
      Was it effective from the first pill on or did you need to take it for a while before it helped?
       
    7. acufenero
      Starving

      acufenero Member

      Tinnitus Since:
      August 2014
      Cause of Tinnitus:
      Acoustic trauma
      From the very first one.
       
    8. Marlino
      Cowboy

      Marlino Member

      Location:
      Germany
      Tinnitus Since:
      02/2016
      Cause of Tinnitus:
      unknown
      Thanks. Thats interesting. I have some trobalt in my drawer but didn't try it yet. Anecdotes of permanent floaters freaked me out.
      Currently I try pregabalin but when I finish I will give trobalt a short try.
      Not so much to get relief, but just to know if it works for me like it does for you.
      If it does it would probably convince me that my t originates from the nerves and not from my left ear hair cells. Not that it matters but since my onset I kept wondering and wondering and wondering...
       
    9. DoNotGoGentle

      DoNotGoGentle Member Benefactor

      Tinnitus Since:
      10/15 got worse 11/16
      Cause of Tinnitus:
      Earbuds, inner ear infection NHL and high frequency loss
      I am little worried about medication to treat this condition. Sure it sounds novel but your body might get used to it pretty fast and your messing with your brain. Hey I am all for it if no side-effects. What do others think?
       
    10. Paulmanlike

      Paulmanlike Member Hall of Fame

      Tinnitus Since:
      2008
      Cause of Tinnitus:
      Noise
      Not worth it until something comes to the market without any risky side effects.

      Trobalt can turn your blue and milky man boobs
       
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    11. Alue
      No Mood

      Alue Member

      Tinnitus Since:
      01/2016
      Cause of Tinnitus:
      Acoustic Trauma
      LOL what?
       
    12. Paulmanlike

      Paulmanlike Member Hall of Fame

      Tinnitus Since:
      2008
      Cause of Tinnitus:
      Noise
      Trobalt what people were taking for tinnitus this and seizure drug, the side effects turned them blue and gave them a set of knockers, regardless to say, I haven't left the house since because I'm blue, but I've had a whale of a time playing with my new moobs
       
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    13. NatureHiker
      Angelic

      NatureHiker Member

      Any new news on RL-81?
       
    14. DoNotGoGentle

      DoNotGoGentle Member Benefactor

      Tinnitus Since:
      10/15 got worse 11/16
      Cause of Tinnitus:
      Earbuds, inner ear infection NHL and high frequency loss
      We appreciate your interest in this compound and for your message. We have
      not begun human testing for the compound yet. We are not able to provide
      any forecast about when or if we will test this for tinnitus sufferers.
      We have a corporate policy that precludes us from sharing such information
      on an individual basis. I apologize but I cannot share more than that at
      this time. We wish you the best in your pursuits.
      Kind regards,
      Bethany Worrell
      --
      Bethany Worrell

      SciFluor Life Sciences LLC

      300 Technology Square

      Cambridge, MA 02139

      bethany.worrell@scifluor.com

      (w) 617-684-4748


      Emailed them. Not sure if SF0043 is the same not much to say
       
    15. acufenero
      Starving

      acufenero Member

      Tinnitus Since:
      August 2014
      Cause of Tinnitus:
      Acoustic trauma
      What a coincidence. I too emailed them last week and got the very same answer.
       
    16. Mic
      Buzzed

      Mic Member

      Tinnitus Since:
      -
      Status update for RL648_81:

      Screenshot_20170813-103529.jpg
       
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    17. Paulmanlike

      Paulmanlike Member Hall of Fame

      Tinnitus Since:
      2008
      Cause of Tinnitus:
      Noise
    18. Paulmanlike

      Paulmanlike Member Hall of Fame

      Tinnitus Since:
      2008
      Cause of Tinnitus:
      Noise
      Does this mean they will test it for tinnitus? Unclear
       
    19. AUTHOR
      AUTHOR
      attheedgeofscience
      No Mood

      attheedgeofscience Member Mighty Benefactor Hall of Fame

      Location:
      Denmark
      Tinnitus Since:
      Resolved since 2016
      Cause of Tinnitus:
      See information page
      The intention is certainly to test RL-81 (a series of compounds) for efficacy vs. tinnitus. The problem tinnitus research is facing is that no pharma company is especially eager to take on a clinical trial pipeline related to tinnitus: the risk of failure (incl. false negative outcome) is too high.
       
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    20. Mic
      Buzzed

      Mic Member

      Tinnitus Since:
      -
      Who knows... from a logical point of view one could expect that the pre-clinical study probably only focused on the neurochemical regulation of kv7.2-7.3 channels on cellular level.

      Next step is to proof safety for use as a medicine (hence the analogs) and test it's efficacy on different conditions. This could be tinnitus (as Tzanoupolous theoritisized) or epilepsy (as a safer alternative for retigabine). It depends on which pharma corp gets the licence (and their projection of returning their investment).
       
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    21. jer

      jer Member

      Tinnitus Since:
      06/2015
      Cause of Tinnitus:
      Acoustic trauma
      @attheedgeofscience Is there something that we as a community can do to expedite this process? I am so sick of inaction, and If pharmaceutical companies won't help us, then we must revert to helping ourselves right?

      How much does taking a medicine all the way though clinical testing cost? I know this is a big question and probably unrealistic. But maybe it's a discussion we need to have on here to form something?
       
    22. Paulmanlike

      Paulmanlike Member Hall of Fame

      Tinnitus Since:
      2008
      Cause of Tinnitus:
      Noise
      Suppose with any investment

      Higher risk = Higher reward

      Lower risk = lower reward
       
    23. AUTHOR
      AUTHOR
      attheedgeofscience
      No Mood

      attheedgeofscience Member Mighty Benefactor Hall of Fame

      Location:
      Denmark
      Tinnitus Since:
      Resolved since 2016
      Cause of Tinnitus:
      See information page
      If you are thinking of directly influencing the timeline of the clinical trial itself, then I don't believe there is anything that can be done considering:
      • The willingness to contribute (or lack thereof) from the worldwide tinnitus community
      • The monetary power (or lack thereof) from the worldwide tinnitus community
      If anything could be done, it would probably be reduced to using the social media and/or contacting interest groups like the ATA. But, it is a fairly hopeless enterprise - been there, done that.

      However, as it happens, almost a year ago, I did relay specific information that had come to my attention about RL-81 to a pharma company (and which is one of the four that have been approached about carrying the in vivo clinical research forward; at that point only in vitro studies had been done). Of course, this is kind of old news by now, but something I had not shared before (in public). For the same reasons, I can also confirm that Allergan is not one of the pharma entities in question (unlike what is suggested here recently):
      It is fully understandable that slow progress can be frustrating. But finding effective treatments for medical conditions is not limited to tinnitus: there are many maladies that don't don't have good therapies. Tinnitus is but one of them...

      The answer to how much it costs is:
      1. "It depends" (on the structure, screening, medical procedures involved, as well as the size of the clinical trial).
      2. "Lots of money".
      As an example, when Auris Medical extended their TACTT3 trial in Europe (with 60+60 participants), the added cost was of the order of "a couple of million dollars". Given that even professional organisations like the ATA operate with a budget of about one million dollars per year (before overhead expenses are covered), you can be sure that informal collections via online forums can at best collect anything from a few hundred dollars to a few thousand dollars. So trying to influence any outcome with regards to RL-81 has about the same chance of success as you being able to sell sand in the Sahara Desert or ice on the North Pole. That's just the way it is...
       
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    24. AUTHOR
      AUTHOR
      attheedgeofscience
      No Mood

      attheedgeofscience Member Mighty Benefactor Hall of Fame

      Location:
      Denmark
      Tinnitus Since:
      Resolved since 2016
      Cause of Tinnitus:
      See information page
      Yes: generally, an investor buying a "standard" investment e.g. one that you can invest in via a financial institution would ask for a higher return on investment (ROI) if it carries a higher risk. But investing in a clinical trial product candidate isn't a standard investment. And higher risk doesn't necessarily carry a higher reward (in this regard) because that would depend on the medical need and market cost (which determine the market value). Put another way: there are many other diseases (than tinnitus) that are worth pursuing therapies for and which at the same time would also be a good investment (due to high medical need). So from the investor point-of-view: why take a chance on finding a cure for tinnitus when there are so many other areas of interest that could be considered?
       
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    25. Paulmanlike

      Paulmanlike Member Hall of Fame

      Tinnitus Since:
      2008
      Cause of Tinnitus:
      Noise
      Exactly. I was always planning to watch Auris closely if they succeeded, and to buy shares in them. Not anymore though unfortunately.
       
    26. acufenero
      Starving

      acufenero Member

      Tinnitus Since:
      August 2014
      Cause of Tinnitus:
      Acoustic trauma
      Unlike what you're implying here, I didn't make anything up. Couldn't you read the press release that I linked?
       
    27. AUTHOR
      AUTHOR
      attheedgeofscience
      No Mood

      attheedgeofscience Member Mighty Benefactor Hall of Fame

      Location:
      Denmark
      Tinnitus Since:
      Resolved since 2016
      Cause of Tinnitus:
      See information page
      Sure, I can read it: I have just now and also when it was released about a year ago. However, here is what you wrote:

      upload_2017-8-14_20-34-9.png

      And all I am saying is that RL-81 is not backed by big pharma and specifically not Allergan. In the press release, the material about potassium channels was unrelated to Allergan. SF0034 is backed by "small pharma" (not big pharma). A development for SF0034 (which sits with SciFluor) is scheduled later this year (but I will not bet anything on that pipeline before I see it "in action" - just as with Frequency Therapeutics...).
       
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    28. jer

      jer Member

      Tinnitus Since:
      06/2015
      Cause of Tinnitus:
      Acoustic trauma
      And what about trobalt / retigabine. Where those two medicines not backed by big pharma? And if that was so, why not back a redesigned drug that should work a lot better than the ones that they already backed? Was that just because the first two medicines weren't sold enough, and they see they might not be able to recoup their financial investment?
       
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    29. Pleasure_Paulie

      Pleasure_Paulie Member

      Location:
      Australia
      Tinnitus Since:
      06/2016
      Cause of Tinnitus:
      Noise or maybe... unicorns!
      That compound was developed Glaxosmithkline (very very big pharma) and while I can't be sure, I would suspect that was removed due to poor performance in the market and an already oversaturated market for epilepsy pharmaceuticals. You can see their R&D pipeline here https://www.gsk.com/en-gb/investors/product-pipeline/
       
    30. lymebite
      Vegged out

      lymebite Member Benefactor

      Location:
      United States
      Tinnitus Since:
      2013
      Cause of Tinnitus:
      Unknown
      Perhaps there is a cilantro cure for tinnitus? Turns out cilantro is a natural KCNQ2/3 activator.

      Cilantro leaf harbors a potent potassium channel–activating anticonvulsant

      Published 16 July 2019

      Rian Manville and Geoffrey Abbott


      Abstract
      Herbs have a long history of use as folk medicine anticonvulsants, yet the underlying mechanisms often remain unknown. Neuronal voltage-gated potassium channel subfamily Q (KCNQ) dysfunction can cause severe epileptic encephalopathies that are resistant to modern anticonvulsants. Here we report that cilantro (Coriandrum sativum), a widely used culinary herb that also exhibits antiepileptic and other therapeutic activities, is a highly potent KCNQ channel activator. Screening of cilantro leaf metabolites revealed that one, the long-chain fatty aldehyde (E)-2-dodecenal, activates multiple KCNQs, including the predominant neuronal isoform, KCNQ2/KCNQ3 [half maximal effective concentration (EC50), 60 ± 20 nM], and the predominant cardiac isoform, KCNQ1 in complexes with the type I transmembrane ancillary subunit (KCNE1) (EC50, 260 ± 100 nM). (E)-2-dodecenal also recapitulated the anticonvulsant action of cilantro, delaying pentylene tetrazole-induced seizures. In silico docking and mutagenesis studies identified the (E)-2-dodecenal binding site, juxtaposed between residues on the KCNQ S5 transmembrane segment and S4-5 linker. The results provide a molecular basis for the therapeutic actions of cilantro and indicate that this ubiquitous culinary herb is surprisingly influential upon clinically important KCNQ channels.

      https://www.fasebj.org/doi/10.1096/fj.201900485R
       
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