Prof. Thanos Tzounopoulos Receives $2 Million Grant

[StoneInFocus]

He is taking forever. Are we still in pre-clinical with the RL drug? Why? He is really risking becoming redundant to some off-label use of the Xenon drugs. I hope things start moving at some point because we have been talking and following this thread for years and people died in the meantime. It's always the same story, none of these guys seems to get the urgency for people who are on the brink. I think, realistically, our only option are the Xenon drugs. Maybe this guy will be able to help the next generations, which is a good thing, but we should emotionally disinvest from his work, it's too far away and moving too slowly on the clinical side.

I wonder how RL648_81 entering the clinical phase would affect its supply. I mean, the synthesize instructions are freely available, and there are multiple chemical vendors selling the stuff already. In a paper published last year the Prof said that "further toxicology assessments and a transition to early clinical evaluation are therefore in progress."

I don't know how much of that is true but let's suppose for a minute the toxicology profile of RL648_81 turns out to be relatively "good" (whatever that implicates precisely). Would more online vendors start selling it? Chinese or Indian chemical factories start producing it in bulk? Maybe more research teams start doing experiments with it? I don't really know but maybe the more 'open source' nature of RL648_81 gives it an edge over Xenon's products.

By the way, have you ever considered taking Flupirtine?

 

[DebInAustralia]

This would something important to figure out, would we have to take his drug for a lifetime, or just for a couple of months?

On another note, I recently stumbled upon the supplement Quercetin and its supposed Kv7 modulation properties:

"Quercetin potentiated KCNQ1/KCNE1, KCNQ2/3 and KCNQ4 currents but, unusually, not KCNQ5. Strikingly, quercetin augmented both activation and inactivation of KCNQ1, via a unique KCNQ activation mechanism involving sites atop the voltage sensor and in the pore. The findings uncover a novel potential molecular basis for therapeutic effects of quercetin-rich foods and a new chemical space for atypical modes of KCNQ channel modulation" (source).

I really want to understand if and how the mechanisms of Quercetin differ from those of Retigabine and similar anticonvulsant drugs. Could Quercetin help in a similar way with tinnitus and hyperacusis? Only a few people on this forum have actually taken this supplement.

I have found several anecdotal reports of Quercetin reducing/eliminating tinnitus for some (not on here). If it weren't for a link to a study I stumbled on here suggesting Quercetin is ototoxic, I would be tempted to try it again.

 

[Padraigh Griffin]

I have found several anecdotal reports of Quercetin reducing/eliminating tinnitus for some (not on here). If it weren't for a link to a study I stumbled on here suggesting Quercetin is ototoxic, I would be tempted to try it again.

Apologies for not getting back to you yet Deb but mojo is low.

From my research Quercetin hits the Kv 7.1 channel, not the Kv 7.2 channel.

Hope you are well.

 

[StoneInFocus]

So I've done some quick searches on Google and apparently cannabidiol (CBD) is a Kv2/7.3 channel opener too. A paper published in February 2022 reads that:

Cannabidiol activates neuronal Kv7 channels... The potent enhancement of Kv2/7.3 channels by CBD may contribute to its effectiveness as an antiepileptic drug by reducing neuronal hyperexcitability... Our results suggest that the clinical efficacy of CBD could result at least in part by the enhancement of the Kv7-mediated M-current in central neurons... Further development of Kv7.2/7.3 enhancers for treating epilepsy and other neuronal disorders seems promising, especially because retigabine has been withdrawn from clinical use because of a number of off-target side effects. Compared to other compounds recently found to enhance Kv7.2/7.3 channels, CBD has the distinction of having already been successfully used in multiple epilepsy clinical trials. However, CBD is far from a perfect drug as it requires large dosages and has a complex pharmacokinetic profile that limit its effective oral administration. Improved knowledge of CBD's most important molecular targets should allow for the design of novel compounds that retain its key molecular actions but with improved pharmacokinetics and reduced off-target effects.

Now I'm not a neuroscientist by any means, I'm just copying some interesting remarks from the study so I have no idea about how its 'pharmacokinetic profile' compares to other Kv7 channel openers such as Retigabine, Flupirtine, XEN1101 etc. The potential of CBD oil in treating tinnitus is well known on this forum, as there are numerous threads about people being cured by its administration. I've quickly glanced over some of these threads, the results of people trying CBD oil are very mixed (see some of the comments and the very scientific poll on this thread). I haven't really analyzed these threads in details, so I don't know the cause of this variety in CBD response is yet. One of the causes of the adverse effects of taking CBD oil could be attributed to the purity of the product that is consumed, or in other words, they could be attributed to the THC residue in some of these oils, but that is total speculation on my part

The thread on Retigabine also reported mixed results, but I don't know how they compare to those of CBD oil. Considering hyperacusis, @Willpowered claimed CBD oil gave him temporary relief for an estimated 5-6 hours, but he did say that "[relief] can be maintained with more oil and I think it builds up in your system." @Willpowered hasn't been seen since 2018.

In conclusion, I think this article (see PDF) is a potential bombshell for anyone interested in the works of Tzounopoulos and Xenon Pharmaceuticals. As far as I know the connection between potassium channel activation and cannabidiol hasn't been made on this forum as of yet. CBD could be a promising Kv7-based treatment for tinnitus and noxacusis that is available over the counter (if it's legal in your country).

As you may have read, my experiments with Flupirtine were a total disaster, but I attribute that to its psychoactive properties. Theoretically, CBD is not psychoactive so it should cause less adverse effects in that particular area. I think the Kv7.2/7.3 channel modulation properties of CBD are an important discovery for anyone waiting for the release of XEN1101 and RL-81, particularly those with pain hyperacusis.

Love to hear what y'all think.

 

[InNeedOfHelp]

A role for KCNQ channels on cell-type-specific plasticity in mouse auditory cortex after peripheral damage

A new paper by Prof. Tzounopoulos. It seems to point towards KCNQ potassium channels as a potential pharmaceutical target as has been stated before.

 

[KoolKat]

A role for KCNQ channels on cell-type-specific plasticity in mouse auditory cortex after peripheral damage

A new paper by Prof. Tzounopoulos. It seems to point towards KCNQ potassium channels as a potential pharmaceutical target as has been stated before.

Why does all this progress take so goddamn long.

 

[AnthonyMcDonald]

Why does all this progress take so goddamn long.

$$$.

Just kidding. He's probably working on multiple projects at the same time. He recently released a paper about different versions of RL-81. So he's doing something.

 

[Hazel]

Here is a little update from my discussion with Thanos at the ARO conference.

 

[Amv]

Thanos Tzounopoulos is a great guy. I really hope he can find the molecule and is successful in his trials. I would be grateful to think of him as the guy who relieved my tinnitus. Of course, also Dr. Susan Shore. They both represent ethical and the bright side of science.

 

[AnthonyMcDonald]

Thanos Tzounopoulos is a great guy. I really hope he can find the molecule and is successful in his trials. I would be grateful to think of him as the guy who relieved my tinnitus. Of course, also Dr. Susan Shore. They both represent ethical and the bright side of science.

I believe XEN1101 will come to market significantly faster (2-3 years) than any of his versions. But we'll have to wait and see.

 

[awake 44]

I believe XEN1101 will come to market significantly faster (2-3 years) than any of his versions. But we'll have to wait and see.

Totally agree. The latest update by @Hazel made me believe that. It is not bad news. XEN1101 is developed by big company and is advanced in trials. I think it will he easier for them to deal with FDA and commercialization than it is for Thanos. I will have no issues with taking it off-label. After some years off-label usage by all of us, it will lead to official tinnitus related approval.

I'm very optimistic for Dr. Shore/XEN1101 combo. I do not know how to get my life back while waiting for this combo to come out though. I miss music, miss being able to relax and focus.

 

[KoolKat]

I believe XEN1101 will come to market significantly faster (2-3 years) than any of his versions. But we'll have to wait and see.

If you were a betting man, do you think XEN1101 is it? From all you've heard and seen, do you think this is the one?

 

[ploughna]

Keep an eye also on Biohaven - BHV7000/7010. They are moving aggressively in this space with an expedited trial schedule, a product they claim is better than XEN1101 and have indicated the possibility of trialing it for other conditions later.

See the BHV7000 thread for more information.

 

[AnthonyMcDonald]

If you were a betting man, do you think XEN1101 is it? From all you've heard and seen, do you think this is the one?

I don't know. We won't know for certain unless people try it. It's not free of side effects, either. Visual snow is a dangerous potential side effect of potassium channel openers.

 

[Pivot10]

I don't know. We won't know for certain unless people try it. It's not free of side effects, either. Visual snow is a dangerous potential side effect of potassium channel openers.

Curious why a majority of people with visual snow also have tinnitus - 60% I believe. Not sure about the relationship, but a major factor that is not fully understood.

 

[DimLeb]

Curious why a majority of people with visual snow also have tinnitus - 60% I believe. Not sure about the relationship, but a major factor that is not fully understood.

And also floaters. I myself developed visual snow and started noticing a big increase in floaters (from 2-3 I always had, to around 10-15) in a few weeks since tinnitus onset.

 

[StoneInFocus]

A role for KCNQ channels on cell-type-specific plasticity in mouse auditory cortex after peripheral damage

A new paper by Prof. Tzounopoulos. It seems to point towards KCNQ potassium channels as a potential pharmaceutical target as has been stated before.

The paper reads:

We found an increase in KCNQ potassium channel activity in L2/L3 Parvalbumin expressing neurons of the auditory cortex one day after noise exposure, associated with a hyperpolarizing shift in the minimal voltage activity of KNCQ channels.

I'm a bit confused whether Tzounopoulos refers to all the KCNQ channels in this case rather than just the Kv7.2/7.3 channels specifically. After noise exposure, has the minimal voltage activity of KNCQ channels decreased in all the channels or just 2 and 3? If I understand it correctly, these L2/L3 'layers' refer to specific anatomical divisions of the auditory cortex and are not related to potassium channels Kv7.2/7.3 in particular. Moreover, in his experiments on mice he uses Retigabine to open potassium channels 2,3,4 and 5, instead of a drug that just activates channels 2 and 3, like his own RL648_81.

Previously, Tzounopoulos stated that "the channels that were identified by us that play a role in tinnitus are the channels KC and Q2 and 3, but this Retigabine drug opens KC and Q2, 3, 4 and 5 so already there was a lack of specificity."

Reviving Retigabine for Tinnitus — Thanos Tzounopoulos, PhD

I'm wondering whether Tzounopoulos still thinks that only channels Kv7.2/7.3 play a role in tinnitus and hyperacusis, or that other channels are involved as well?

 

[star-affinity]

Curious why a majority of people with visual snow also have tinnitus - 60% I believe. Not sure about the relationship, but a major factor that is not fully understood.

Seems I'm joining the club.

I've been noticing a kind of shimmering over the entire visual field, visual snow and a couple of floaters for a few days now. I've had low frequency drone/hum tinnitus in my head since December 2020, and a high pitch "cicada stuck at one frequency" (that sometimes oscillates a bit up in pitch and then back) since May 2021.

Not too surprising the brain freaks out since it constantly feels like a laser is running through the head and I have constant brainfog and a "sensation" of something running in the head (due to the hum).

So head/ear tinnitus, eye "tinnitus" and since one year lower back "tinnitus" (pain that won't fully go away even though exercise helps).

Thanks life. At least my sense of smell and taste is still intact. For now...

 

[Nick47]

Seems I'm joining the club.

I've been noticing a kind of shimmering over the entire visual field, visual snow and a couple of floaters for a few days now. I've had low frequency drone/hum tinnitus in my head since December 2020, and a high pitch "cicada stuck at one frequency" (that sometimes oscillates a bit up in pitch and then back) since May 2021.

Not too surprising the brain freaks out since it constantly feels like a laser is running through the head and I have constant brainfog and a "sensation" of something running in the head (due to the hum).

So head/ear tinnitus, eye "tinnitus" and since one year lower back "tinnitus" (pain that won't fully go away even though exercise helps).

Thanks life. At least my sense of smell and taste is still intact. For now...

I thought you were providing an update to Prof. Tzounopoulos' research?

 

[star-affinity]

I thought you were providing an update to Prof. Tzounopoulos' research?

Sorry. I was looking for posts about "visual snow" and found the one I quoted. I'll be quiet.

 

[haha ear go eeee]

I don't know. We won't know for certain unless people try it. It's not free of side effects, either. Visual snow is a dangerous potential side effect of potassium channel openers.

I'm wondering if XEN1101 would cause visual snow or not, since it only opens Kv7.2 and Kv7.3? I'm not sure if it could worsen visual snow. Maybe it wouldn't cause it since it doesn't open Kv7.5? I'm speculating that opening Kv7.5 may be causing visual snow in some, since Gabapentin opens that one along with Kv7.2 and Kv7.3 and had visual snow as a side effect.

 

[Josh59]

Hello @Hazel,

I've just re-read the discussion you had with Prof. Thanos Tzounopoulos at the 46th annual MidWinter meeting of the Association for Research in Otolaryngology.

Was he able to give you any information about the future of his research? For example, where might he be between now and 2024?

During this discussion, did you feel confident about possible positive results on animals and future clinical trials on humans?

Has Prof. Thanos Tzounopoulos ever spoken to Dr. Susan Shore, for example? I assume so. Why don't researchers pool their skills and work together to further research?

 

[TheDarius]

I believe XEN1101 will come to market significantly faster (2-3 years) than any of his versions. But we'll have to wait and see.

Reading stuff like this gives me hope. I miss the comfort of silence.

 

[ErikaS]

Because I live in the Pittsburgh area, I emailed Professor Thanos just to ask for any update on his work. This response was on October 10th:

Dear Erika,
Very sorry to learn of your tinnitus and hope you feel better soon. We are continuing preclinical development (safety, etc) of the KV7 modulators. When clinical trials start, it will be posted in the phrc.pitt.edu.

Best,
Thanos

I emailed him back and asked if there was any guess on timeframe for human clinical trials, and asked "1-2 years?" I did not receive a response back. Not much to share, but wanted to share what I could.

 

[Nick47]

emailed him back and asked if there was any guess on timeframe for human clinical trials, and asked "1-2 years?" I did not receive a response back. Not much to share, but wanted to share what I could.

I see this thread as dead. In February he said he would have a lead candidate in 6 months. He has contributed to research but he is a million miles away from treatment.

 

[BB23]

I wonder how different Prof. Tzounopoulos' molecule is compared to BHV-7000.

It is pretty clear his stuff will either never come out or takes a LONG time to be out.

Why can't he get BHV-7000 and run trials for tinnitus, if that's a thing? At least we would know if it's effective or not, instead of guessing and wondering.

I believe his version of the drug won't be much different than BHV-7000. It seems like a waste of time and resources to me. Many more of us will be underground in the meantime...

 

[Luca73]

How many years does Prof. Tzounopoulos need to develop his drug?

 

[grate_biff]

How many years does Prof. Tzounopoulos need to develop his drug?

Probably as long as Susan Shore

 

[Luca73]

Probably as long as Susan Shore

10 years?

 

[Nick47]

10 years?

30 years.