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

[acufenero]

@acufenero how much say from at (8/10 to a 4/10) did RTG reduce your T?

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 tinnitus comes back gradually.

 

[Jim51042]

@acufenero what dosage were you taking?

 

[Jim51042]

Did you develop a tolerance to Trobalt and if so how long did it to get a tolerance?

 

[acufenero]

@acufenero what dosage were you taking?

Did you develop a tolerance to Trobalt and if so how long did it to get a tolerance?

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 tinnitus anymore (it's difficult to measure tinnitus, 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 tinnitus for a few months, then stopped because of tolerance and side effects.

 

[ReyKalinic]

Tolerance to retigabine in few months..... ! who know how to do people with epilepsy! years and years without tolerance....

 

[Marlino]

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 Ttinnituscomes back gradually.

Was it effective from the first pill on or did you need to take it for a while before it helped?

 

[acufenero]

Was it effective from the first pill on or did you need to take it for a while before it helped?

From the very first one.

 

[Marlino]

From the very first one

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...

 

[DoNotGoGentle]

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?

 

[Paulmanlike]

Not worth it until something comes to the market without any risky side effects.

Trobalt can turn your blue and milky man boobs

 

[Alue]

Not worth it until something comes to the market without any risky side effects.

Trobalt can turn your blue and milky man boobs

LOL what?

 

[Paulmanlike]

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

 

[NatureHiker]

Any new news on RL-81?

 

[DoNotGoGentle]

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

 

[acufenero]

What a coincidence. I too emailed them last week and got the very same answer.

 

[Mic]

Status update for RL648_81:

 

[Paulmanlike]

http://molpharm.aspetjournals.org/content/89/6/667.long

 

[Paulmanlike]

Status update for RL648_81:

View attachment 13472

Does this mean they will test it for tinnitus? Unclear

 

[attheedgeofscience]

Does this mean they will test it for tinnitus? Unclear

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.

 

[Mic]

Does this mean they will test it for tinnitus? Unclear

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).

 

[jer]

@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?

 

[Paulmanlike]

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.

Suppose with any investment

Higher risk = Higher reward

Lower risk = lower reward

 

[attheedgeofscience]

@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?

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):

Isn't Allergan backing the research as stated in the pr?

By the way, do you think that these kind of approaches can "cure" tinnitus (that is, shut the ringing down) after taking the drug for some time? Or are they more likely to be taken on a daily basis?

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...

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?

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...

 

[attheedgeofscience]

Suppose with any investment

Higher risk = Higher reward

Lower risk = lower reward

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?

 

[Paulmanlike]

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?

Exactly. I was always planning to watch Auris closely if they succeeded, and to buy shares in them. Not anymore though unfortunately.

 

[acufenero]

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):

Unlike what you're implying here, I didn't make anything up. Couldn't you read the press release that I linked?

 

[attheedgeofscience]

Unlike what you're implying here, I didn't make anything up. Couldn't you read the press release that I linked?

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:

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...).

 

[jer]

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?

 

[Pleasure_Paulie]

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?

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/

 

[lymebite]

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