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

[linearb]

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

Cilantro is a natural chelator of some metals, so I went through a phase where I ate TONS of the stuff. Zero impact on tinnitus, but now I know how to make really good salsa and guac.

 

[Tigo]

What happened to RL-81 made by SciFluor Life Sciences? Their website is offline...
Is this again a dead end for a hopeful tinnitus treatment?

 

[Christiaan]

What happened to RL-81 made by SciFluor Life Sciences? Their website is offline...
Is this again a dead end for a hopeful tinnitus treatment?

It's too early to tell. Many people have mailed Dr. Tzounopoulos and he wrote them that the pre-clinical trials (on animals) have proven promising so far. And we know that they have the necessary financial backing to proceed to phase 1. Thus, there's no reason to think that there's a dead end at this early stage. Maybe they are updating the website for all we know.

 

[frpp]

Since these are epilepsy drug,s I wonder if they'll be able to stop spasms in the ear?

 

[Croaker]

Since these are epilepsy drug,s I wonder if they'll be able to stop spasms in the ear?

I think TTTS comes from the same signals that cause pain in hyperacusis, so I bet it will help.

Very eager to see if anyone on here is able to get their hands on XEN-496 in the near future. I would warn anyone considering this that it is the same active molecule as in Trobalt. XEN-1101 is reformulated for fewer side effects but it won't finish phase 2b testing until June 2022, although we can expect topline results in June 2021.

 

[Born To Slay]

I think TTTS comes from the same signals that cause pain in hyperacusis, so I bet it will help.

Very eager to see if anyone on here is able to get their hands on XEN-496 in the near future. I would warn anyone considering this that it is the same active molecule as in Trobalt. XEN-1101 is reformulated for fewer side effects but it won't finish phase 2b testing until June 2022, although we can expect topline results in June 2021.

So XEN-496 isn't different from Trobalt at all?

 

[weab00]

I think TTTS comes from the same signals that cause pain in hyperacusis, so I bet it will help.

Very eager to see if anyone on here is able to get their hands on XEN-496 in the near future. I would warn anyone considering this that it is the same active molecule as in Trobalt. XEN-1101 is reformulated for fewer side effects but it won't finish phase 2b testing until June 2022, although we can expect topline results in June 2021.

Am wondering the same thing about side effects. I know that Trobalt caused visual snow syndrome in a number of people. Hopefully the negative side effects can be reduced. But we wouldn't know the long-term side effects until decades down the line. Although I'd gladly trade 5-10 years of lifespan for a tinnitus and hyperacusis-free life.

 

[GBB]

Do you need to take Trobalt continuously? I've definitely seen stories on here where people have mentioned cessation or permanent improvement of their tinnitus from a "round" of Trobalt, so I've never been clear on that aspect.

 

[Croaker]

Do you need to take Trobalt continuously? I've definitely seen stories on here where people have mentioned cessation or permanent improvement of their tinnitus from a "round" of Trobalt, so I've never been clear on that aspect.

Most of the anecdotes I've seen mentioned that relief was temporary.

This makes sense if something is forcing the type II fibers or the bushy cells Dr. Shore mentioned to be sensitized. Regulating potassium channels doesn't solve the fundamental problem.

 

[weab00]

Most of the anecdotes I've seen mentioned that relief was temporary.

This makes sense if something is forcing the type II fibers or the bushy cells Dr. Shore mentioned to be sensitized. Regulating potassium channels doesn't solve the fundamental problem.

Wonder what this means with regards to setbacks and spikes. If you experienced an acoustic trauma while on a kV modulator would you experience pain/burning as long as you stayed on the medication? Guess it comes down to whether setbacks are physical damage or neuropathic pain.

 

[Croaker]

Wonder what this means with regards to setbacks and spikes. If you experienced an acoustic trauma while on a kV modulator would you experience pain/burning as long as you stayed on the medication? Guess it comes down to whether setbacks are physical damage or neuropathic pain.

I expect it would block most symptoms. It depends on how much more effective XEN-1101 is than Trobalt. I don't think most setbacks are from physical damage.

 

[dan]

Do you need to take Trobalt continuously? I've definitely seen stories on here where people have mentioned cessation or permanent improvement of their tinnitus from a "round" of Trobalt, so I've never been clear on that aspect.

Yes continuously, which causes irreversible organ damage/sudden death syndrome eventually.

Why do you want to try it?

 

[weab00]

Yes continuously, which causes irreversible organ damage/sudden death syndrome eventually.

Why do you want to try it?

Are you implying that's why @Danny Boy died?

 

[GBB]

Yes continuously, which causes irreversible organ damage/sudden death syndrome eventually.

Why do you want to try it?

It would be more appealing if the effects could be cemented from a temporary regimen.

 

[dan]

Are you implying that's why @Danny Boy died?

Very perceptive of you.... good news though, Prof. Thanos is addressing this issue with RL-81, he told me this himself. It's being tweaked.

 

[dan]

It would be more appealing if the effects could be cemented from a temporary regimen.

Sorry for being so obtuse, I don't get it...

 

[GBB]

Sorry for being so obtuse, I don't get it...

I was answering honestly - you asked if I was considering it - I said it would be more attractive if I didn't need to take if forever. Anything that has wiped out tinnitus deserves to be considered imo.

 

[weab00]

I was answering honestly - you asked if I was considering it - I said it would be more attractive if I didn't need to take if forever. Anything that has wiped out tinnitus deserves to be considered imo.

I too am wary of taking a novel seizure medication for life. But if it offers temporary relief I'd be all over it. I have a feeling regenerative medicine will be out before potassium channel modulators anyway, so hopefully we won't wind up needing it. Always good to have a second line of treatment though.

 

[tommyd87]

I was answering honestly - you asked if I was considering it - I said it would be more attractive if I didn't need to take if forever. Anything that has wiped out tinnitus deserves to be considered imo.

Taking something once is of course going to be much more attractive and also much more beneficial in terms of safety. See this is why I think that the cochlear regeneration treatments are going to be better because you only need to take a small number of doses to complete the course and do not actually have to take it repeatedly to get and also actually maintain a benefit.

 

[attheedgeofscience]

This thread was created more than five years ago (by yours truly) with no developments since then (as far as I know). However, earlier this year, an in vivo-study was released on RL-81 suggesting that the channel activator is effective at the preclinical stage. It would seem, therefore, that the timeframe between the in vitro- and in vivo- study has been some five years...

The "non specific KCNQ channel activator" that is alluded to in the abstract is probably Trobalt.

The above is not much. But, I thought I'd share it for those of you with an inclination for science updates. And given the lack of progress elsewhere in the pharma landscape, the above is perhaps worthwhile keeping an eye on. Contacting either Prof. Wipf or Prof. Tzounopoulos should be feasible (in order to understand next steps...).

 

[serendipity1996]

This thread was created more than five years ago (by yours truly) with no developments since then (as far as I know). However, earlier this year, an in vivo-study was released on RL-81 suggesting that the channel activator is effective at the preclinical stage. It would seem, therefore, that the timeframe between the in vitro- and in vivo- study has been some five years...

The "non specific KCNQ channel activator" that is alluded to in the abstract is probably Trobalt.

The above is not much. But, I thought I'd share it for those of you with an inclination for science updates. And given the lack of progress elsewhere in the pharma landscape, the above is perhaps worthwhile keeping an eye on. Contacting either Prof. Wipf or Prof. Tzounopoulos should be feasible (in order to understand next steps...).

Most of the discussion has been on Xenon Pharmaceuticals, which has developed a reformulated version of Retigabine with improved potency, safety, and selectivity. They already have two drug candidates in Phase 2b and Phase 3 of clinical trials.

 

[Matchbox]

Most of the discussion has been on Xenon Pharmaceuticals, which has developed a reformulated version of Retigabine with improved potency, safety, and selectivity. They already have two drug candidates in Phase 2b and Phase 3 of clinical trials.

I agree. XEN1101 is the winning horse right now even if it wasn't meant for tinnitus / hyperacusis.

 

[NewLionel]

Where/when do I get my hands on this stuff?

 

[AfroSnowman]

Is this a pill or injection?

 

[Gb3]

Is this a pill or injection?

IV I think.

 

[Travis Henry]

How come no-one has tried RL-81? What would be the dosage of RL-81 if one were to try it, hypothetically?

IV I think.

I believe it's powder so pill form.

I agree. XEN1101 is the winning horse right now even if it wasn't meant for tinnitus / hyperacusis.

But unlike RL-81, XEN1101 is not made for tinnitus.