Retigabine (Trobalt, Potiga) — General Discussion

[jeannie]

Snow86,do you think it could your tinnitus was caused by meds or something other than hearing loss as to why it isn't working?just wondering???does trobalt just work on people that have a tinnitus due to noise I induced?

 

[Telis]

Snow86,do you think it could your tinnitus was caused by meds or something other than hearing loss as to why it isn't working?just wondering???does trobalt just work on people that have a tinnitus due to noise I induced?

For the majority of T suffers that try this drug it doesn't work. Not sure if you have read this entire thread along with all the user experiences, or maybe chatted personally with a lot of the users, if you have, you would not be surprised by snows experience with this medicine.

 

[nills]

For the majority of T suffers that try this drug it doesn't work. Not sure if you have read this entire thread along with all the user experiences, or maybe chatted personally with a lot of the users, if you have, you would not be surprised by snows experience with this medicine.

very few people have taken it at highest doses ... we all know it doens`t work when you don`t take enough of it.

 

[Danny Boy]

I don't think we have a tenth of the data necessary to make this statement. The way to get the data is to throw things at the wall and see what sticks. We already have two different KV3.1 drugs in the works, what's wrong with someone trying a KV7 one? If Autifony is right then they are only wasting their own time; on the other hand, if Autifony is partially wrong about how all this works, then we'll all benefit from other avenues of exploration.

Because the KV7 channels are dangerous. Why do you think people turn blue and your eyesight gets impaired? It's dangerous. As for Autifony, I think Dr. Large, love that name, knows what he is doing as he's been doing this for over 20 years. As for that SF drug it works on KV2 and KV3 channels and won't be out for ages and as they said epilepsy first, tinnitus second place...As it's always been. Autifony should be out first, if results are positive.

 

[Zechariah]

Because the KV7 channels are dangerous. Why do you think people turn blue and your eyesight gets impaired? It's dangerous. As for Autifony, I think Dr. Large, love that name, knows what he is doing as he's been doing this for over 20 years. As for that SF drug it works on KV2 and KV3 channels and won't be out for ages and as they said epilepsy first, tinnitus second place...As it's always been. Autifony should be out first, if results are positive.

Kv7.x channels aren't necessary dangerous. Only drugs which mess with them may be dangerous. This same fact goes for pretty much every drug there is. People don't turn blue because Kv7-channels are modulated. They turn blue because of drug side effects which has nothing to do with Kv7 channels.

I keep getting more scared that you the one bashing about drugs and suggesting dosages (like you encourage people to take bigger dosages of keppra, even when not required) when you seem to lack basic knowledge of pharmacology. And I feel worried because I seem to be only one trying to slow you down.

 

[passerby]

As for that SF drug it works on KV2 and KV3 channels and won't be out for ages and as they said epilepsy first, tinnitus second place...As it's always been. Autifony should be out first, if results are positive.

SF0034 works on Kv7.2/3 - and hence - is also a Kv7-channel modulator, like Retigabine (but does not carry the same side-effects as Retigabine).

a (concerned) passerby

 

[passerby]

I keep getting more scared that you the one bashing about drugs and suggesting dosages (like you encourage people to take bigger dosages of keppra, even when not required) when you seem to lack basic knowledge of pharmacology. And I feel worried because I seem to be only one trying to slow you down.

there is actually a section III in the netiquette of the forum which concerns the accuracy of information posted:

www.tinnitustalk.com/threads/netiquette-of-tinnitus-talk.1070

 

[Danny Boy]

Kv7.x channels aren't necessary dangerous. Only drugs which mess with them may be dangerous. This same fact goes for pretty much every drug there is. People don't turn blue because Kv7-channels are modulated. They turn blue because of drug side effects which has nothing to do with Kv7 channels.

I keep getting more scared that you the one bashing about drugs and suggesting dosages (like you encourage people to take bigger dosages of keppra, even when not required) when you seem to lack basic knowledge of pharmacology. And I feel worried because I seem to be only one trying to slow you down.

I say use the recommend dosage of 1,200mg or less if it has an effect on you. And really, it's nothing to do with it working on so many subset channels of the KV7 channels? What about the other KV7 drug? Flupirtine? It's toxic to the liver. And seriously, I got the recommend dose from this-


"Li et al. (2013) demonstrated the role of the KV7 channels in the induction of tinnitus in the mouse dorsal cochlear nucleus model, and showed that retigabine may prevent the development of tinnitus. We estimated the therapeutic potential of Kþ channel openers in suppressing tinnitus-like activity by quantifying the responses in the auditory cortical networks. Retigabine had the highest therapeutic potential, with a therapeutic concentration of 7.4 mM – a concentration at which counteraction against induced- hyperactivity were effective – followed by NS1619 (15.2 mM), flupir- tine (23.3 mM), and isopimaric acid (30.0 mM). These values were well within the range of their effective concentrations against epilepsy (3–100 mM; Kobayashi et al., 2008), thus, possible off-label treatment for tinnitus is plausible (and safe). Clinical studies had calculated the free brain concentration of retigabine taken at 1200 mg/day to be

around 2.0 mM (Large et al., 2012)"

 

[Danny Boy]

SF0034 works on Kv7.2/3 - and hence - is also a Kv7-channel modulator, like Retigabine (but does not carry the same side-effects as Retigabine).

a (concerned) passerby

"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.

Tzingounis and Tzounopoulos first tested SF0034 in neurons, and found that it was more selective than retigabine. It seemed to open only KCNQ2 and KCNQ3 potassium channels, not affecting KCNQ 4 or 5. It was more effective than retigabine at preventing seizures in animals, and it was also less toxic.The results are promising, both for research and medicine. SciFluor now plans to start FDA trials with SF0034 and see if it is safe and effective in people. Treating epilepsy is the primary goal, but tinnituscan be similarly debilitating, and sufferers would be thrilled to have a decent treatment."

And they even say the only channels which are important are the KV3-2 channels


Where does it say it activates the KV7 channels?

 

[Zechariah]

I say use the recommend dosage of 1,200mg or less if it has an effect on you. And really, it's nothing to do with it working on so many subset channels of the KV7 channels? What about the other KV7 drug? Flupirtine? It's toxic to the liver. And seriously, I got the recommend dose from this-


"Li et al. (2013) demonstrated the role of the KV7 channels in the induction of tinnitus in the mouse dorsal cochlear nucleus model, and showed that retigabine may prevent the development of tinnitus. We estimated the therapeutic potential of Kþ channel openers in suppressing tinnitus-like activity by quantifying the responses in the auditory cortical networks. Retigabine had the highest therapeutic potential, with a therapeutic concentration of 7.4 mM – a concentration at which counteraction against induced- hyperactivity were effective – followed by NS1619 (15.2 mM), flupir- tine (23.3 mM), and isopimaric acid (30.0 mM). These values were well within the range of their effective concentrations against epilepsy (3–100 mM; Kobayashi et al., 2008), thus, possible off-label treatment for tinnitus is plausible (and safe). Clinical studies had calculated the free brain concentration of retigabine taken at 1200 mg/day to be

around 2.0 mM (Large et al., 2012)"

You are missing my point again. My point is that stop suggesting dosages to people whose medical condition/size etc. you don't know. Stop suggesting to ramp up the dosage if their condition gets worse or they experience disturbing side effects. You simply don't have a background to do it. What you can do is to tell people your medical conditions, size and your dosage but stop playing a medical pro. Even the doctors on this forum hesitate to give any advice on drugs and dosages before seeing the patients.

I've seen someone on this forum to suggest stop taking heart medicines. Hopefully you don't go that far.

 

[snow86]

Snow86,do you think it could your tinnitus was caused by meds or something other than hearing loss as to why it isn't working?just wondering???does trobalt just work on people that have a tinnitus due to noise I induced?

yeah, thats a possibility. Theres surely a difference between ear-T and brain-T. I had (still have) a tonal tinnitus from 2006, back then it was ringing clearly in my ear. Now I have several sounds that are all around my brain.(not caused by ear trauma of any kind)

It doesnt seem like a wonderdrug, while someone shouted "cure" from the rooftops. I dont plan on staying long on 3x400mg. But it is worth a try.

But (other) scientists are interested in this drug. Tinnitus "guru" Dirk de Ridder refered me to some T doctors/scientists of the clinic / university of regensburg, he wrote highly of them. They know ATEOS very well.
Now I am in contact with them and they are interested in Trobalt and how im doing with and also in my special case of extreme T.

I have my eyes set on rTMS in Regensburg...I want to try it out.

@dan

 

[Zechariah]

"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.

Tzingounis and Tzounopoulos first tested SF0034 in neurons, and found that it was more selective than retigabine. It seemed to open only KCNQ2 and KCNQ3 potassium channels, not affecting KCNQ 4 or 5. It was more effective than retigabine at preventing seizures in animals, and it was also less toxic.The results are promising, both for research and medicine. SciFluor now plans to start FDA trials with SF0034 and see if it is safe and effective in people. Treating epilepsy is the primary goal, but tinnituscan be similarly debilitating, and sufferers would be thrilled to have a decent treatment."

And they even say the only channels which are important are the KV3-2 channels


Where does it say it actives the KV7 channels?

Interesting, there is plenty of sources which state that KCNQ4 is playing important role in cochleas sensory cells. Which in my opinion could have something to do with T. This is actually one point why Retigabine could actually treat "ear T" aswell. So maybe AM-101 can actually help?

Just some thoughts and a reminder that maybe you shouldn't stare at a single source which reflects your own views nicely.

And btw, we have more proof that AM-101 works rather than AUT00063

 

[Danny Boy]

Interesting, there is plenty of sources which state that KCNQ4 is playing important role in cochleas sensory cells. Which in my opinion could have something to do with T. This is actually one point why Retigabine could actually treat "ear T" aswell. So maybe AM-101 can actually help?

Just some thoughts and a reminder that maybe you shouldn't stare at a single source which reflects your own views nicely.

And btw, we have more proof that AM-101 works rather than AUT00063

Well, you better let Dr. Charles Large know about this. Email him. Good luck.

 

[passerby]

"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.

You have answered your own question - if by "KV3-2" you mean Kv7.2/3 (which I assume you do as KV3-2 is not a proper reference to a Kv-channel...):

And they even say the only channels which are important are the KV3-2 channels

And they even say the only channels which are important are the KV3-2 channels

Again... I don't really know whether you are referencing a Kv3.x- or a Kv7.x-channel. And who is "they"...?

Where does it say it actives the KV7 channels?

I don't know... where does it say it? You were the one who brought it up... If by "it" you mean SF034, then it says it right here, for instance... ("opener" = "activator"):

I think you might (also) find it helpful to read up on the documentation attached...

a (concerned) passerby

 

[Zechariah]

Well, you better let Dr. Charles Large know about this. Email him. Good luck.

You are getting it wrong. My text was for you. Not for Dr. Large.

 

[Danny Boy]

You have answered your own question - if by "KV3-2" you mean Kv7.2/3 (which I assume you do as KV3-2 is not a proper reference to a Kv-channel...):




Again... I don't really know whether you are referencing a Kv3.x- or a Kv7.x-channel. And who is "they"...?


I don't know... where does it say it? You were the one who brought it up... If by "it" you mean SF034, then it says it right here, for instance... ("opener" = "activator"):

View attachment 7493


I think you might (also) find it helpful to read up on the documentation attached...

a (concerned) passerby

Please use a quote where it states it functions on the KV7 channels. Trobalt is pretty clear it works on those channels. All it says on here is it works on the KV3 and KV2 channels. Anyway, I honestly don't care what drugs works on what anymore, as it doesn't matter. Autifony will be out first and this drug is designed with epilepsy in mind. Anyway, glad you're knowledgeable on this matter, you winner.

 

[Danny Boy]

You are getting it wrong. My text was for you. Not for Dr. Large.

Well, you don't need to entertain me. Go and tantalise Dr. Large.

 

[passerby]

Please use a quote where it states it functions on the KV7 channels. Trobalt is pretty clear it works on those channels. All it says on here is it works on the KV3 and KV2 channels.

KCNQ = Kv7... (which you yourself pointed out earlier on). So KCNQ2/3 = Kv7.2/3. Hence SF0034 is a drug with higher selectivity than Retigabine (and hardly surprising given that it - SF0034 - is a derivative of Retigabine...).

I don't think you actually have any idea what you are writing in your posts. There is no depth to your knowledge. You just write stuff, collate it, and hope for the best...

a (concerned) passerby

 

[Danny Boy]

KCNQ = Kv7... (which you yourself pointed out earlier on). So KCNQ2/3 = Kv7.2/3. Hence SF0034 is a drug with higher selectivity than Retigabine (and hardly surprising given that it - SF0034 - is a derivative of Retigabine...).

I don't think you actually have any idea what you are writing in your posts. There is no depth to your knowledge. You just write stuff, collate it, and hope for the best...

a (concerned) passerby

Ah, sorry I'm hook up to loads of meds. Hard to think straight. Anyway you're right. And I agree I do. I'll stop doing that from now on, as you've made me realise how foolish it is. I'm reading through this now, just to make sure I understand it all https://en.wikipedia.org/wiki/Voltage-gated_potassium_channel#Classification


And this-KCNQ genes encode a growing family of six transmembrane domains, single pore-loop, K(+) channel alpha-subunits that have a wide range of physiological correlates. KCNQ1 (KvLTQ1) is co-assembled with the product of the KCNE1 (minimal K(+)-channel protein) gene in the heart to form a cardiac-delayed rectifier-like K(+) current. Mutations in this channel can cause one form of inherited long QT syndrome (LQT1), as well as being associated with a form of deafness. KCNQ1 can also co-assemble with KCNE3, and may be the molecular correlate of the cyclic AMP-regulated K(+) current present in colonic crypt cells. KCNQ2 and KCNQ3 heteromultimers are thought to underlie the M-current; mutations in these genes may cause an inherited form of juvenile epilepsy. The KCNQ4 gene is thought to encode the molecular correlate of the I(K,n) in outer hair cells of the cochlea and I(K,L) in Type I hair cells of the vestibular apparatus, mutations in which lead to a form of inherited deafness. The recently identified KCNQ5 gene is expressed in brain and skeletal muscle, and can co-assemble with KCNQ3, suggesting it may also play a role in the M-current heterogeneity. This review will set this family of K(+) channels amongst the other known families. It will highlight the genes, physiology, pharmacology, and pathophysiology of this recently discovered, but important, family of K(+) channels.

 

[Zechariah]

Ah, sorry I'm hook up to loads of meds. Hard to think straight. Anyway you're right. And I agree I do. I'll stop doing that from now on, as you've made me realise how foolish it is. I'm reading through this now, just to make sure I understand it all https://en.wikipedia.org/wiki/Voltage-gated_potassium_channel#Classification

I don't mean to be mean but I hope you realize this in bigger picture aswell. Not only regarding the semantics related to potassium channel naming standards.

 

[Danny Boy]

I don't mean to be mean but I hope you realize this in bigger picture aswell. Not only regarding the semantics related to potassium channel naming standards.

No. I totally understand.

 

[Danny Boy]

I found this-

Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine.
Main MJ1, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA.
Author information

Abstract
Retigabine is a novel anticonvulsant with an unknown mechanism of action. It has recently been reported that retigabine modulates a potassium channel current in nerve growth factor-differentiated PC12 cells (), however, to date the molecular correlate of this current has not been identified. In the present study we have examined the effects of retigabine on recombinant human KCNQ2 and KCNQ3 potassium channels, expressed either alone or in combination in Xenopus oocytes. Application of 10 microM retigabine to oocytes expressing the KCNQ2/3 heteromeric channel shifted both the activation threshold and voltage for half-activation by approximately 20 mV in the hyperpolarizing direction, leading to an increase in current amplitude at test potentials between -80 mV and +20 mV. Retigabine also had a marked effect on KCNQ current kinetics, increasing the rate of channel activation but slowing deactivation at a given test potential. Similar effects of retigabine were observed in oocytes expressing KCNQ2 alone, suggesting that KCNQ2 may be the molecular target of retigabine. Membrane potential recordings in oocytes expressing the KCNQ2/3 heteromeric channel showed that application of retigabine leads to a concentration-dependent hyperpolarization of the oocyte, from a resting potential of -63 mV under control conditions to -85 mV in the presence of 100 microM retigabine (IC(50) = 5.2 microM). In control experiments retigabine had no effect on either resting membrane potential or endogenous oocyte membrane currents. In conclusion, we have shown that retigabine acts as a KCNQ potassium channel opener. Because the heteromeric KCNQ2/3 channel has recently been reported to underlie the M-current, it is likely that M-current modulation can explain the anticonvulsant actions of retigabine in animal models of epilepsy.

And this-

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1201633/

Lastly,

Amitriptyline is a potent blocker of human Kv1.1 and Kv7.2/7.3 channels.
Punke MA1, Friederich P.
Author information

Abstract
BACKGROUND:
Kv1.1 and Kv7.2/7.3 channels control excitability of neuronal cells. As hyperexcitability is a sign of neuropathic pain, epilepsy, and anxiety disorders, these channels may be important molecular targets of amitriptyline that cause pharmacological as well as toxicological effects by altering neuronal excitability. Since the molecular mechanisms underlying these effects of amitriptyline have not been fully elucidated, we aimed to characterize the interaction of amitriptyline with human Kv1.1 and Kv7.2/7.3 channels. We also intended to establish the interaction of amitriptyline with the Kv7.2/7.3 channel opener, retigabine.

METHODS:
Kv1.1 and Kv7.2/7.3 channels were expressed in human embryonic kidney cells and in Chinese hamster ovary cells. The effects of amitriptyline and retigabine were studied with the patch-clamp technique.

RESULTS:
Amitriptyline inhibited Kv1.1 and Kv7.2/7.3 channels in a concentration-dependent and reversible manner. The IC50-value was 22 +/- 3 microM (n = 33) and 10 +/- 1 microM (n = 40), respectively. Deactivating inward currents of Kv7.2/7.3 channels were inhibited with an IC50-value of 4.2 +/- 0.6 microM (n = 32). Inhibition of Kv7.2/7.3 channels by amitriptyline reversibly depolarized the resting membrane potential. Retigabine reversed both the inhibitory action of amitriptyline on Kv7.2/7.3 channels as well as the depolarization of the membrane potential.

CONCLUSIONS:
Since amitriptyline inhibited Kv1.1 and Kv7.2/7.3 channels only at toxicologically relevant plasma concentrations, our results suggest a role for these channels in the neuroexcitatory side effects of amitriptyline. As the inhibitory effects of amitriptyline were reversed by retigabine, a combination of amitriptyline and retigabine could be of additional benefit in the therapy of neuropathic pain.

 

[snow86]

I dont want to call all this copy&paste "spam". But theres no need you two throw this at each other. (of course the banana guy is right about medical advice from people on the internet)

Those who want to read about actual experiences of people who take it will find it faster without this "war" here

Fact is that if you have the worst kind of T and you tried everything else - Trobalt is worth a try. It may help or not. Theres no need to speculate if SF32049318 or Aut23445 will work for now.

( trobalt = Within "safe" dosages and doing some heart checkups at the GP etc. And as the banana-guy said, hesitate to take medical advice on dosages etc)

 

[jimH]

of course the banana guy is right about medical advice from people on the internet.

Thank god for the Banana guy!....that's all I can say....

 

[uae96]

banana-guy

Hehhahiehaheuhhaha banana guy "

 

[passerby]

But (other) scientists are interested in this drug. Tinnitus "guru" Dirk de Ridder refered me to some T doctors/scientists of the clinic / university of regensburg, he wrote highly of them. They know ATEOS very well.

That must be the Tinnitus Research Initiative...

www.tinnitusresearch.org/en/contact/contact_en.php

 

[snow86]

That must be the Tinnitus Research Initiative...

www.tinnitusresearch.org/en/contact/contact_en.php

thats right

 

[linearb]

Because the KV7 channels are dangerous. Why do you think people turn blue and your eyesight gets impaired? It's dangerous.

No one has any idea why the skin discoloration occurs; therefore, it's unreasonable to suggest that it's caused by one specific receptor site or another.

Trobalt is a complex molecule which does several things we know of, and maybe others -- it's entirely possible that the discoloration effect comes from something entirely unrelated to KV channels.

No one has any idea if AUT00063 might show similar effects, either -- this is exactly what phase III trials and post-release longitudinal studies are for.

I share your optimism that AUT00063 might provide some relief for a lot of people, but I think it's irresponsible to act like we have a ton of data on how all this works when we have almost none.

 

[Nucleo]

Because the KV7 channels are dangerous. Why do you think people turn blue and your eyesight gets impaired? It's dangerous. As for Autifony, I think Dr. Large, love that name, knows what he is doing as he's been doing this for over 20 years. As for that SF drug it works on KV2 and KV3 channels and won't be out for ages and as they said epilepsy first, tinnitus second place...As it's always been. Autifony should be out first, if results are positive.

Wtf. KV7 channels are not dangerous. They are necessary for proper neuron function. That's like saying livers are dangerous because you can get liver disease.

 

[Danny Boy]

Wtf. KV7 channels are not dangerous. They are necessary for proper neuron function. That's like saying livers are dangerous because you can get liver disease.

I meant trobalt is dangerous, not the KV7 channels. It was a mistake and ignorance on my part.