Retigabine (Trobalt, Potiga) — General Discussion

[amandine]

That's the scary thing about this thread, how do you get an objective opinion here when people constantly throw around nonsense buzz terms like "believe" and "keep a positive mind".

I

It is the same with all the threads.....

 

[nills]

I

It is the same with all the threads.....

It`s not actually .. .here there is actually an experience to back it up ... the threads you refer to is just wishful thinking.

so it is not the same neither is it an opinion ... it is sharing an insight gained with experience.

 

[snow86]

this may be some important user experience for those with extreme T considering taking Trobalt

Some words about my Trobalt experience after 14 days of 3x400mg (highest dosage)

As some of you know, I have one of the worst T possible, along with some few users on this board. (I dont like to repeat this, almost sounds like some vanity attention talk, but there always will be people who haven´t read about my T situation and It is pretty important when it comes to taking trobalt ).

Reactive tinnitus: about 6-8 sounds. low frequency alternating sounds + high tonal + hyperacusis + occasional ear pain. 10/10 are my usual days and I often get 15/10 days....its just debilitating...ok enough. Rare good day : 7/10

So I think right now im the only person here with extreme 10/10 T whos taking trobalt or has taken it long enough with 3x400mg to see some T-changing effects (Im not countin @Geo because he ran out of trobalt afaik)

so take it from me when I say trobalt has HUGE RAW POTENTIAL, not only for some of the 3/10 T people here who take it ( I would not take it with 3/10...but thats just my opinion) but also for extreme T people...

why?

in the 14 days of taking 400mg at once(3 times) I had 8 events where trobalt lowered my T after taking it.
It usually works like this: I take 400mg and after 15-40 minutes I feel that im starting to get high.
Then at some point I start to feel that my T is going down within 10sec-5 minutes, I mean gradually going down.
And I mean the T is going down, not that im only GABAA drugged (or whatever) and I dont care about blasting 10/10 anymore

the most wonderful T experience of the last 1,5 years was this: after 400mg pill on empty stomach (ate pizza directly after popping pill) and screaming 10/10 T - Trobalt kicked in after 10minutes and i felt that within 20 seconds the T was lowering and lowering and my main sound "washing machine" almost disappeared and the other sounds were also very low. The T went from 10 to 2 within 20 seconds....

I muted my hearing aids (I was at a friends house) to isolate myself from running TV and air conditioning.
I listened within my head and my T like disappeared.
That was like a fu*** miracle....2 more friends came over and they were talking quietly and I could hear them very well because there were no loud sounds screaming in my head . (

downside? the 2/10 lasted 30minutes...then it gradually came back...5/10 lasted 2 hours...then it went up to 7/10 (which is even tolerable for me). Still it was the lowest T volume since about 16 months...

I had similar events but mostly with 10/10 going down to 6-7/10 and lasting only 10-30 minutes...then it often came back 10/10

But then again it often does nothing 15/10 T + 400mg in the evening sometimes...not even getting high.

(I keep a trobalt-diary, so I have records of every day)

So, before people start saying "im glad its working for you"....
My overall situation has not improved. I still wake up every day and my 7/10 T goes up to 10/10 and more sounds arise etc. Trobalt gives me a relief of 30minutes or maybe more every 2nd day by now (after 14 days)

whats the point of all this? Trobalt has potential...but its RAW...hitting at random, some time doing nothing while I have 15/10 T and 400mg have no effect.

As you know (and dannyboy often repeated). Trobalt was made by Dr Large and he´s busy with Autifony.
So maybe theres really hope for us extreme sufferers, that Autifony will make their drug more specific and sharpened to hit the right channels (or whatever) to reliably suppress even the hardest T.
In my case It is a huge difference between 10/10 and 5-6/10. So even if Autifony only gave some partial relief...it would be a great achievement.

For @linearb claim or thesis - Trobalt is more like a party drug and the suppression is only because you feel drugged - that is wrong. I really felt the T going down within seconds. (If that is his claim, maybe I got it wrong).

I was a bit disappointed at first but I would say Trobalt is definitely worth a try for extreme T...maybe it will work more consitently for you. (my overall situation has not improved though...but its just 14 days...dunno)

The overall drunkenness on 3x400 mg is not bad. But it really makes it hard to write, you feel like your IQ dropped and you forget words....(yeah it was great to write this long post). It lasts about 1-3 hours. depends on how much you eat and if you take it on full or empty stomach. it hits really fasts on empty stomach...so if you want to try out once if it has some effect, take it before eating.

in case youre interested what my "final results" with trobalt and extreme T will be...
click on my profile and click "follow"

grammatical mistakes sponsored by Trobalt

@Telis
@NiNyu
@dan
@invictus
@Geo
@Martin69
@Danny Boy
@preslys
@nills
@valeri
@Street Spirit
@Sailboardman
@Xorthian

 

[preslys]

I have done song analysis as usual free by my company.
all is well.

 

[preslys]

Benzo and trobalt? Living dangerously lol

it's just a test

 

[undecided]

I've also done the trobalt + benzo (lexotanil / tavor) combo.
I don't know which potentiates what but it's some strong shit.

 

[Greg Moreau]

SF0034: a less toxic, more targeted variant of retigabine?

I've only recently started researching this topic, but I found it interesting that Hearing Today wrote the following in June 2015 about findings from Retigabine reseearchers:

In 2013, Tzingounis began collaborating with Thanos Tzounopoulos, PhD, a tinnitus expert at the University of Pittsburgh, to create a new drug candidate. The new drug, SF0034, was chemically identical to retigabine, but included an extra fluorine atom. Originally developed by SciFluor, the company wanted to know whether the compound had promise for treating epilepsy and tinnitus.

In some types of epilepsy, the KCNQ potassium channels have trouble opening and shutting down runaway electrical potentials in the nerve synapse. Retigabine helps them open. According to the authors, there are five different kinds of KCNQ potassium channels in the body, but only two are important in epilepsy and tinnitus: KCNQ2 and KCNQ3. The problem with retigabine is that it acts on other KCNQ potassium channels as well. That's why it has so many unwanted side effects.

When testing SF0034 in neurons, the researchers found that it was more selective than retigabine. It appeared to open only KCNQ2 and KCNQ3 potassium channels, and to not affect the KCNQ 4 or 5 potassium channels. The research showed that SF0034 was more effective than retigabine at preventing seizures in animals, and it was also less toxic.

The results are promising, and SciFluor plans to start FDA trials with SF0034 to test its safety and efficacy in people. Treating epilepsy is the primary goal, but treating or preventing tinnitus is a secondary goal.

Additional citation: http://www.jneurosci.org/content/35/23/8829.short
​

 

[linearb]

For @linearb claim or thesis - Trobalt is more like a party drug and the suppression is only because you feel drugged - that is wrong. I really felt the T going down within seconds. (If that is his claim, maybe I got it wrong).

Hey @snow86,

two comments here: #1 I didn't say it's like a party drug and that the suppression is only because you feel drugged; all I said was that in addition to it's Kv channel action, it appears to be an allosteric modulator of GABAa, and because it's pushing both buttons at once (and probably more) it may be hard to say which of its effects are coming from which mechanism.

#2 I strongly feel that for some users, benzos have a suppressive effect on tinnitus which is not simply because they make you care about the noise less. I took Klonopin for a number of years, and I feel that it reduced the actual volume of my tinnitus by a good 75% while I was taking it. I know that some people do not experience this effect, and the reasons for that are not understood at present by anyone as far as I know.

With #1 I am not suggesting that Kv channels aren't a big part of the picture -- and I think we've seen some people on here respond to Trobalt who did not respond to benzos.

I will probably try a short Trobalt regimen starting two weeks from last Monday; I'll probably start at 50mg 3x/day and go from there. I am curious to see what it does, though I do not think I would take it for more than about 2 months consecutively no matter what happens, because the FDA "may cause blindness" warning is alarming to me even if it's not very likely.

 

[snow86]

Hey @snow86,

two comments here: #1 I didn't say it's like a party drug and that the suppression is only because you feel drugged; all I said was that in addition to it's Kv channel action, it appears to be an allosteric modulator of GABAa, and because it's pushing both buttons at once (and probably more) it may be hard to say which of its effects are coming from which mechanism.

#2 I strongly feel that for some users, benzos have a suppressive effect on tinnitus which is not simply because they make you care about the noise less. I took Klonopin for a number of years, and I feel that it reduced the actual volume of my tinnitus by a good 75% while I was taking it. I know that some people do not experience this effect, and the reasons for that are not understood at present by anyone as far as I know.

With #1 I am not suggesting that Kv channels aren't a big part of the picture -- and I think we've seen some people on here respond to Trobalt who did not respond to benzos.

I will probably try a short Trobalt regimen starting two weeks from last Monday; I'll probably start at 50mg 3x/day and go from there. I am curious to see what it does, though I do not think I would take it for more than about 2 months consecutively no matter what happens, because the FDA "may cause blindness" warning is alarming to me even if it's not very likely.

all right mate. Got you now. I agree, even when Trobalt doesnt give relief all the time...bein high makes you care less about the T.

Same for me on the last part...Im not planning on taking it more than 1,5-2 months on the highest dosage if the moments of relief remain short (hours). I need days of relief or at least more permanent lowered T so it is worth the risk taking trobalt long term. But I dont have much options, with my deadly T autifony and SF03xxx are far away.

Perampanel or tDCS, rTMS may be my next move after my trobalt trial is done...But dont know if its a good idea to flood your brain with another epilepsy drug after trobalt....

 

[linearb]

all right mate. Got you now. I agree, even when Trobalt doesnt give relief all the time...bein high makes you care less about the T.

Same for me on the last part...Im not planning on taking it more than 1,5-2 months on the highest dosage if the moments of relief remain short (hours). I need days of relief or at least more permanent lowered T so it is worth the risk taking trobalt long term. But I dont have much options, with my deadly T autifony and SF03xxx are far away.

Well, if Trobalt seems to work to some extent for you, that could be a reason to think that AUT00063 or the SF drug will also work, possibly better -- and in fact, that's one reason I want to experiment with Trobalt.

Perampanel or tDCS, rTMS may be my next move after my trobalt trial is done...But dont know if its a good idea to flood your brain with another epilepsy drug after trobalt....

I'd give yourself a washout period of a couple weeks before hopping from one drug to another, but then that would seem reasonable to me.

I'd like to try the rTMS protocol, but so far the only place I've contacted said it would be $400 a pop times ten sessions... that's pretty damn pricey for something that's basically a shot in the dark.

I did a tDCS research study which didn't seem to have much of a result, but, it was only a single session. tDCS you can do at home with DIY stuff pretty easily; rTMS is a lot harder.

 

[Geo]

this may be some important user experience for those with extreme T considering taking Trobalt

Some words about my Trobalt experience after 14 days of 3x400mg (highest dosage)

As some of you know, I have one of the worst T possible, along with some few users on this board. (I dont like to repeat this, almost sounds like some vanity attention talk, but there always will be people who haven´t read about my T situation and It is pretty important when it comes to taking trobalt ).

Reactive tinnitus: about 6-8 sounds. low frequency alternating sounds + high tonal + hyperacusis + occasional ear pain. 10/10 are my usual days and I often get 15/10 days....its just debilitating...ok enough. Rare good day : 7/10

So I think right now im the only person here with extreme 10/10 T whos taking trobalt or has taken it long enough with 3x400mg to see some T-changing effects (Im not countin @Geo because he ran out of trobalt afaik)

so take it from me when I say trobalt has HUGE RAW POTENTIAL, not only for some of the 3/10 T people here who take it ( I would not take it with 3/10...but thats just my opinion) but also for extreme T people...

why?

in the 14 days of taking 400mg at once(3 times) I had 8 events where trobalt lowered my T after taking it.
It usually works like this: I take 400mg and after 15-40 minutes I feel that im starting to get high.
Then at some point I start to feel that my T is going down within 10sec-5 minutes, I mean gradually going down.
And I mean the T is going down, not that im only GABAA drugged (or whatever) and I dont care about blasting 10/10 anymore

the most wonderful T experience of the last 1,5 years was this: after 400mg pill on empty stomach (ate pizza directly after popping pill) and screaming 10/10 T - Trobalt kicked in after 10minutes and i felt that within 20 seconds the T was lowering and lowering and my main sound "washing machine" almost disappeared and the other sounds were also very low. The T went from 10 to 2 within 20 seconds....

I muted my hearing aids (I was at a friends house) to isolate myself from running TV and air conditioning.
I listened within my head and my T like disappeared.
That was like a fu*** miracle....2 more friends came over and they were talking quietly and I could hear them very well because there were no loud sounds screaming in my head . (

downside? the 2/10 lasted 30minutes...then it gradually came back...5/10 lasted 2 hours...then it went up to 7/10 (which is even tolerable for me). Still it was the lowest T volume since about 16 months...

I had similar events but mostly with 10/10 going down to 6-7/10 and lasting only 10-30 minutes...then it often came back 10/10

But then again it often does nothing 15/10 T + 400mg in the evening sometimes...not even getting high.

(I keep a trobalt-diary, so I have records of every day)

So, before people start saying "im glad its working for you"....
My overall situation has not improved. I still wake up every day and my 7/10 T goes up to 10/10 and more sounds arise etc. Trobalt gives me a relief of 30minutes or maybe more every 2nd day by now (after 14 days)

whats the point of all this? Trobalt has potential...but its RAW...hitting at random, some time doing nothing while I have 15/10 T and 400mg have no effect.

As you know (and dannyboy often repeated). Trobalt was made by Dr Large and he´s busy with Autifony.
So maybe theres really hope for us extreme sufferers, that Autifony will make their drug more specific and sharpened to hit the right channels (or whatever) to reliably suppress even the hardest T.
In my case It is a huge difference between 10/10 and 5-6/10. So even if Autifony only gave some partial relief...it would be a great achievement.

For @linearb claim or thesis - Trobalt is more like a party drug and the suppression is only because you feel drugged - that is wrong. I really felt the T going down within seconds. (If that is his claim, maybe I got it wrong).

I was a bit disappointed at first but I would say Trobalt is definitely worth a try for extreme T...maybe it will work more consitently for you. (my overall situation has not improved though...but its just 14 days...dunno)

The overall drunkenness on 3x400 mg is not bad. But it really makes it hard to write, you feel like your IQ dropped and you forget words....(yeah it was great to write this long post). It lasts about 1-3 hours. depends on how much you eat and if you take it on full or empty stomach. it hits really fasts on empty stomach...so if you want to try out once if it has some effect, take it before eating.

in case youre interested what my "final results" with trobalt and extreme T will be...
click on my profile and click "follow"

grammatical mistakes sponsored by Trobalt

@Telis
@NiNyu
@dan
@invictus
@Geo
@Martin69
@Danny Boy
@preslys
@nills
@valeri
@Street Spirit
@Sailboardman
@Xorthian

very happy for you man.. i got my refill since 3 days ago but its so low it sucks(50mgx180)... i want to try 400x3) but ill run out in a week..and idk how to get the ones from spain in california...and recently my T has permanent shot up some more i think it was the bloody Keppra i know now since it spiked it months ago but i wasnt sure now i am now my T is even stronger my days are even harder and developed another head sound like a phone vibrating noise but its sound triggered ,its hard to live on but i do for my family if it wasnt for them i would be gone and the fact i dont have the balls to ever off myself its not me..and mY h is even worse too..i would pay just to hear silence or mild t for a day..so how low does it go can you hear silence...sorry if this message is written badly i am very drunk form the potiga..i even threw up my sweet bread i ate right before which might have been the problem lol..

 

[snow86]

@Geo

Hey bro,

Sober up and re-read my post, you will find the answers there how the 400mg work for me

I know ....same for me...every day different mix of diabolic low frequented sounds + some high pitched...Almost every day new sounds come, some go, some stay....Guess we are "special"

Dont know if 8x50mg will help you at once....I know what it is like to have suicidal T and fighting through every day until I finally get go to sleep and have a break from this shit for some hours

cant you have someone go to mexico and get you the real deal (200mg boxes) ? or will customs stop you with medical drugs which need prescription? try everything...

Dont be afraid that you can´t do stuff on 3x400...you can still "function" like you usually do (thats not much for us yeah..) and you will be pretty funny to your friends like nills said.

I have keppra here, but im not sure iif m gonna try it because it seems to be hard to taper it off, my main problem is this monster T...the H is like 5-6/10 but the T is reactive and maybe connected with the H

 

[Greg Moreau]

Hey @snow86,

#2 I strongly feel that for some users, benzos have a suppressive effect on tinnitus which is not simply because they make you care about the noise less. I took Klonopin for a number of years, and I feel that it reduced the actual volume of my tinnitus by a good 75% while I was taking it. I know that some people do not experience this effect, and the reasons for that are not understood at present by anyone as far as I know.

Do you mind if I ask: a) what was your dose for Klonopin and b) what was the impact on your T once you tapered off of Klonopin?

 

[linearb]

​

Do you mind if I ask: a) what was your dose for Klonopin and b) what was the impact on your T once you tapered off of Klonopin?

I was on Klonopin for anxiety and visual problems (static/afterimages/etc); I took 2mg/day for about 6 years. I never really thought about my tinnitus during that time, except that it would always get worse if I tried to reduce my dose. My journals from my taper off reflect that it would get worse with every reduction, then sort of fade back to normal over the next couple weeks.

I got off benzos in 2007, and don't remember having many issues with my T -- I'd be aware of it here and there, but not to a distressing degree. In 2010 I worsened my T with a noise trauma; the anxiety this caused led me to go back on benzos for a period of time. Taking them definitely still suppressed the noise at that point; again, trying to get off them led to spikes and anxiety about increases.

I do not know whether or not the current intensity of my tinnitus is related to my rather long-term use of benzos; it seems possible; it also seems possible that the same broken neurology that led to the obsessive anxiety states which led to benzo use, is related to the T, or at least to my predisposition to experience T after an acoustic trauma. I have always had a "sensitive" perceptual system, I was a premature baby and I took a fair share of serotonergic drugs in my teens / 20s.

 

[grate_biff]

I was on Klonopin for anxiety and visual problems (static/afterimages/etc); I took 2mg/day for about 6 years. I never really thought about my tinnitus during that time, except that it would always get worse if I tried to reduce my dose. My journals from my taper off reflect that it would get worse with every reduction, then sort of fade back to normal over the next couple weeks.

I got off benzos in 2007, and don't remember having many issues with my T -- I'd be aware of it here and there, but not to a distressing degree. In 2010 I worsened my T with a noise trauma; the anxiety this caused led me to go back on benzos for a period of time. Taking them definitely still suppressed the noise at that point; again, trying to get off them led to spikes and anxiety about increases.

I do not know whether or not the current intensity of my tinnitus is related to my rather long-term use of benzos; it seems possible; it also seems possible that the same broken neurology that led to the obsessive anxiety states which led to benzo use, is related to the T, or at least to my predisposition to experience T after an acoustic trauma. I have always had a "sensitive" perceptual system, I was a premature baby and I took a fair share of serotonergic drugs in my teens / 20s.

I`ve been taking benzo for over 20 years. Not every day, but as I always have had an anxiety problem I´ve had my fair share of the stuff. Went through withdrawls in 2012 and I am currently going through my second withdrawl fase, but this time with alcohol as the trigger. Guess my brain was not ready for it after my first benzo-spell.

Anyway. The only way I can see benzo being the culprit of T. is of excess glutumate in the blodstream as the brain conteracts for the GABA when on it. And glutumate is bad for the haircells. Atleast this is what I can gather after reading about benzo and T.

 

[papu]

More stable now at 700 mg per day (not all at once, divided in 200, 250 and 250) tinnitus down from troublesome 6 to 2 *most of the time* and sometimes even a 1 for an hour after the pill (no more roller coaster up and down). My question ( although i know that any answer is speculation, i do value any opinions) should i gradually increase up to 400 mg per take (1200 mg per day) or save as much of my precious and valuable trobalt (its hard and expensive to get in this side of the pond) and keep at this dosage so that the pills i have last longer.

 

[Greg Moreau]

I was on Klonopin for anxiety and visual problems (static/afterimages/etc); I took 2mg/day for about 6 years. I never really thought about my tinnitus during that time, except that it would always get worse if I tried to reduce my dose. My journals from my taper off reflect that it would get worse with every reduction, then sort of fade back to normal over the next couple weeks.

Interesting. I was on Klonopin for extreme anxiety (pretty much thought I was dying, but it was just somaticization disorder--something to this day no one has been able to say outright). I tapered myself off, without any issues, over a period of, well, a year, basically. Stopped fully two months ago. Now I'm back on it just to sleep--and stay asleep. The study about how it can reduce T seems "thin." I just posted a lengthy response on the anxiety/Tinnitus thread (https://www.tinnitustalk.com/threads/can-anxiety-cause-tinnitus.10651/#post-131800), including a possible connection w/ the auditory nerves and anxiety, and Dr. Bruce Hubbard's take on the subject.

If you don't mind me asking, what is your current "personal protocol" for dealing?

Cheers.

 

[Danny Boy]

Interesting. I was on Klonopin for extreme anxiety (pretty much thought I was dying, but it was just somaticization disorder--something to this day no one has been able to say outright). I tapered myself off, without any issues, over a period of, well, a year, basically. Stopped fully two months ago. Now I'm back on it just to sleep--and stay asleep. The study about how it can reduce T seems "thin." I just posted a lengthy response on the anxiety/Tinnitus thread (https://www.tinnitustalk.com/threads/can-anxiety-cause-tinnitus.10651/#post-131800), including a possible connection w/ the auditory nerves and anxiety, and Dr. Bruce Hubbard's take on the subject.

If you don't mind me asking, what is your current "personal protocol" for dealing?

Cheers.

I would try Nortriptyline as it blocks sodium channels and can calm down those pesky hyperactive neurons.

 

[Greg Moreau]

I would try Nortriptyline as it blocks sodium channels and can calm down those pesky hyperactive neurons.

Thanks, DB; appreciate that. I'll look into it. But I'd really like to avoid reliance on too many Rx tools, if at all possible. I'm only on Klonopin to enable sleep (my Fight or Flight reflex doesn't care if I know what's happening, it still loves to wake me up after a couple of hours, just to let me know that he's "got my back" ). My multi-pronged attack involves stabilization (in that now), CBT/RTR, general health, and a close eye on SF0034 trials. Any further info re: this modified version of Retigabine?

 

[Danny Boy]

Thanks, DB; appreciate that. I'll look into it. But I'd really like to avoid reliance on too many Rx tools, if at all possible. I'm only on Klonopin to enable sleep (my Fight or Flight reflex doesn't care if I know what's happening, it still loves to wake me up after a couple of hours, just to let me know that he's "got my back" ). My multi-pronged attack involves stabilization (in that now), CBT/RTR, general health, and a close eye on SF0034 trials. Any further info re: this modified version of Retigabine?

Personally, I don't care for the SF0034 as they have already stated they are prioritising it for epilepsy and for it to work on tinnitus would bonus. Autifony are targeting the correct channel KV7.3 (KV3) and are not aiming to treat epilepsy. The KV7.2 (KV2) channel are what causes fluid retention. It's best to just target the correct channel KV3 and not bothering adding more side-effects. Dr. Charles Large created trobalt and I believe he is the best person to treat tinnitus.

 

[Danny Boy]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569999/
http://www.jneurosci.org/content/26/30/7950.full

"Retigabine was developed in the 1980s as an analogue of flupirtine, a non-opioid analgesic that had demonstrated some anticonvulsant activity in the Antiepileptic Drug Development program supported by the U.S. National Institute of Health (Kupferberg, 1989). Initial studies revealed retigabine to be a potent anticonvulsant in a broad range of epilepsy and seizure models (Dailey et al., 1995; Rostock et al., 1996;Tober et al., 1996); however, the mechanism of action was unknown. Several studies tried to pinpoint retigabine's mechanism of action by studying its effects on established antiepileptic targets such as GABA receptors, sodium channels and calcium channels. Apart from some enhancement of GABAA receptor activity at high concentrations, retigabine did not conform to a known anticonvulsant mechanism of action. However, in 1997 retigabine was shown to augment a potassium current in NG108-15 neuronal cells, primary cultures of mouse cortical neurones and in differentiated hNT cells, a cell line derived from human neuronal cells (Rundfeldt, 1997). Subsequently, retigabine was found to specifically open KCNQ-encoded Kv, and more specifically the channels underling the 'M-current' (Wang et al., 1998) – KCNQ2 and KCNQ3 (Main et al., 2000; Rundfeldt and Netzer, 2000; Wickenden et al., 2000; Tatulian et al., 2001). Electrophysiological experiments performed on Xenopus oocytes (Main et al., 2000) and CHO cells (Rundfeldt and Netzer, 2000; Wickenden et al., 2000) overexpressing the KCNQ2/3 heteromultimer showed that retigabine shifted the voltage dependence of channel activation to a more hyperpolarized membrane potential, increased the rate of channel activation, and slowed channel deactivation. These results identified the mechanism by which retigabine reduced neuronal excitability in the animal seizure model studies (Dailey et al., 1995; Rostock et al., 1996; Tober et al., 1996). Retigabine's binding site has since been identified as a hydrophobic pocket containing a tryptophan residue (Trp-236 in Kv7.2; Trp-265 in Kv7.3) in the cytoplasmic part of S5 and S6 to stabilize the channel in the open state (Schenzer et al., 2005; Wuttke et al., 2005). Additionally, Leu-272 in S5, Leu-314 within the inner pore loop, and Leu-338 in S6 of the neighbouring subunit are of importance for the binding of retigabine (Lange et al., 2009). These four amino acids are not found in Kv7.1, thus explaining why this subtype is insensitive to retigabine-induced enhancement (Wuttke et al., 2005; Lange et al., 2009). Retigabine is now widely used to study Kv7 channel activity and as such we have a better understanding of neuronal KCNQ activity and the pathway by which retigabine exerts its novel anticonvulsant effects.

Retigabine's mechanism of action is different from all other currently approved antiepileptic treatments, making it a first in class anticonvulsant. In the last 3 years, two large-scale phase III clinical trials with retigabine have been completed in patients with partial epilepsy [RESTORE 1 (Study 301; French et al., 2011; retigabine titrated over 6 weeks to a dosage of 1200 mg day−1) and RESTORE 2 (Study 302; Brodieet al., 2010; retigabine titrated over 2–4 weeks to a dosage of 600 or 900 mg day−1)], in which the drug had a dose-dependent anticonvulsant efficacy. Both trials revealed retigabine produced significant reductions in seizure frequency versus the placebo control patients. Much excitement surrounds retigabine as a novel antiepileptic drug, highlighted by several reviews published in the last year alone (Fattore and Perucca, 2011; Gunthorpe et al., 2012; Harden, 2012; Large et al., 2012; Rejdak et al., 2012); however, in this article we will discuss KCNQ channels as a therapeutic target of treatment of non-neuronal, smooth muscle diseases."

 

[Greg Moreau]

Personally, I don't care for the SF0034 as they have already stated they are prioritising it for epilepsy and for it to work on tinnitus would bonus. Autifony are targeting the correct channel KV7.3 (KV3) and are not aiming to treat epilepsy. The KV7.2 (KV2) channel are what causes fluid retention. It's best to just target the correct channel KV3 and not bothering adding more side-effects. Dr. Charles Large created trobalt and I believe he is the best person to treat tinnitus.

Interesting; thanks. More stuff to look up! (Leave it to the Brits--the best music and, apparently, the lead on developing a sustainable solution.) That said, if SciFlour announces trials, I'll raise my hand; the two solutions seems to be related, potentially--at least according to this http://www.audres.pitt.edu/news-events/ which you've no doubt already read. If you don't mind me asking, what's your current regimen/personal set of protocols to deal with T?

 

[Danny Boy]

Interesting; thanks. More stuff to look up! (Leave it to the Brits--the best music and, apparently, the lead on developing a sustainable solution.) That said, if SciFlour announces trials, I'll raise my hand; the two solutions seems to be related, potentially--at least according to this http://www.audres.pitt.edu/news-events/ which you've no doubt already read. If you don't mind me asking, what's your current regimen/personal set of protocols to deal with T?

By the time the even get to a phase 2 trial, Autifony should be on the market. It matters not, as they are making it for epilepsy first and foremost.

 

[Greg Moreau]

By the time the even get to a phase 2 trial, Autifony should be on the market. It matters not, as they are making it for epilepsy first and foremost. I did find something interesting out about the KV2 channels though.

That's a great point. Here in the states, everything takes forever. So, you are chemistry lad then? I admit that I "glaze over" when thinking about molecular structures. Perhaps we can assign them all names and create a lively story around them? Seriously, though, the potassium channel seems to be the key (in all cases?) since it regulates neuronal excitability. Autifony, I assume, does this...?

 

[Danny Boy]

That's a great point. Here in the states, everything takes forever. So, you are chemistry lad then? I admit that I "glaze over" when thinking about molecular structures. Perhaps we can assign them all names and create a lively story around them? Seriously, though, the potassium channel seems to be the key (in all cases?) since it regulates neuronal excitability. Autifony, I assume, does this...?

Never done chemistry ever. I'm self-teaching myself really.

Also found this-

http://www.scbt.com/datasheet-362745.html

 

[Greg Moreau]

Interesting. The mother of invention. Never understood about fight or flight until I needed to learn. Now you can't get me to shut up about it. But to the issue: Autifony is expected to become available within the year-ish?

 

[Danny Boy]

That's a great point. Here in the states, everything takes forever. So, you are chemistry lad then? I admit that I "glaze over" when thinking about molecular structures. Perhaps we can assign them all names and create a lively story around them? Seriously, though, the potassium channel seems to be the key (in all cases?) since it regulates neuronal excitability. Autifony, I assume, does this...?

"AUT3, a Kv3.1 positive modulator, suppresses chronic noise-induced tinnitus in a rat model Jeremy G. Turner 1,2, Deb Larsen 1 , Charles Large 3 1 Southern Illinois University School of Medicine, Springfield IL, USA 2 Illinois College, Jacksonville IL USA 3 Autifony Therapeutics Limited, London, UK

Kv3.1 channels are voltage-gated potassium channels that enable fast repolarization of the neuronal action potential, and are essential for the high frequency, high fidelity firing of neurons in the auditory brainstem and midbrain. Altered activity of these neurons has been implicated in the generation of tinnitus induced by noise exposure. Furthermore, loss of Kv3 channel function has been observed shortly after noise exposure, which may contribute to the maladaptive plasticity leading to the emergence of tinnitus. In the current study, 20 Long Evans rats (and 10 sham controls) were exposed to a unilateral 116 dB, 16 kHz octave-band noise for one hour in order to induce temporary hearing loss and chronic tinnitus. Thirty days after the noise exposure, a subset of approximately half of the noiseexposed rats demonstrated deficits in auditory gap processing, consistent with the presence of tinnitus. All 30 rats were administered 30 and 60 mg/kg of AUT3 (a Kv3.1 positive modulator) and vehicle in a counterbalanced order, with 48-hours washout between treatments. Both the 30 and 60 mg/kg doses of AUT3 abolished evidence of tinnitus, while the drug had no effect on the behavior of control animals or noise-exposed animals without tinnitus. These results suggest that AUT3 has potential in the treatment of chronic tinnitus associated with noise-induced hearing loss."

 

[Greg Moreau]

"AUT3, a Kv3.1 positive modulator, suppresses chronic noise-induced tinnitus in a rat model ...AUT3 abolished evidence of tinnitus, while the drug had no effect on the behavior of control animals or noise-exposed animals without tinnitus. These results suggest that AUT3 has potential in the treatment of chronic tinnitus associated with noise-induced hearing loss."

And there it is. Thanks for this. Man, it would be wonderful if there were an app to translate the results. I get the gist, certainly, but would love to see how this works, graphically, or via flow diagram. Question: any luck, personally with RTR or notched therapy? The brain is plastic, after all, and while it would certainly take time, from what I understand, notched music and/or white noise can be helpful?

 

[Danny Boy]

And there it is. Thanks for this. Man, it would be wonderful if there were an app to translate the results. I get the gist, certainly, but would love to see how this works, graphically, or via flow diagram. Question: any luck, personally with RTR or notched therapy? The brain is plastic, after all, and while it would certainly take time, from what I understand, notched music and/or white noise can be helpful?

Here's a bio of both the Doctors.

Thanos Tzounopoulos, PhD

After earning my undergraduate degree in Biology from the University of Athens in Greece, I came to the US as a Fulbright Scholar. I was awarded my Ph.D. in Molecular and Medical Genetics at Oregon Health and Science University in 1997. I then completed my postdoctoral research at the University of California at San Francisco; Vollum Institute and at the Oregon Hearing Research Center. I was appointed as Assistant Professor at the Chicago Medical School in May 2006 and moved to University of Pittsburgh in November 2008. I was promoted to Associate Professor in 2012. In 2015, I was appointed to the Auditory Physiology Endowed Chair.

VS

Charles H. Large, PhD
(Chief Executive Officer)

Charles Large received his first degree and PhD from the University of Bristol and has more than 20 years of experience of drug discovery and development in the pharmaceutical industry. Before founding Autifony, he was Director of Molecular and Cellular Biology within the Neuroscience Centre of Excellence for Drug Discovery at GlaxoSmithKline, and has worked on programs focused on schizophrenia, Alzheimer's disease, epilepsy, bipolar disorder, and major depression. He is an expert on drugs that modulate voltage gated ion channels and their application to neurological and psychiatric disorders. He has built up a reputation in the field of sodium channel blocking drugs, and has collaborated widely with academic groups. He has authored over 50 papers, book chapters and patents relating to ion channel modulator

 

[Greg Moreau]

Well, in fairness, it's really not just about one man vs. another, is it? Both have teams of people working with them (although Large's resume/capabilities are quite substantial). To my mind, it's good to have various teams working simultaneously, even if the lead on Team USA is younger and less lettered. Sounds like Autifony is the way to go at this point, and frankly, don't much care who wins, as long as the treatment becomes available and is accessible to the widest possible audience. The question then, is, what are the best "personal protocols," in the interim, yes?