Flupirtine — Another Potassium Channel Opener

[JeffDamsko]

UPDATE

Thanks for this update. This sounds very promising, although I'm not letting myself get to excited.

 

[lapidus]

http://www.feinberg.northwestern.edu/news/2015/02/garcia-auditory-pathway.html
This discovery was made recently and there is a thread in research section for this too. I find these quotes interesting:

"The discovery offers an entirely new way of looking at the painful and intractable hearing conditions hyperacusis and tinnitus,"

"We do not know how to treat these debilitating conditions, and understanding what neuronal pathway might be involved is essential. If we find they are actually pain syndromes rather than hearing syndromes, perhaps they could be treated effectively with analgesic pain medication that acts on the brain."

Flupirtine is analgesic that acts on the brain.
How is it going now @attheedgeofscience ?

 

[Zimichael]

http://www.feinberg.northwestern.edu/news/2015/02/garcia-auditory-pathway.html

Good find @lapidus ...though looks like it will be a while before any of this may actually lead to a practical result and a "cure". So many "good ideas" out there in neuro-Tinnitus land, but still no platinum bullet.

Coming into 59 years of T, and still counting...

best, Zimichael

 

[nills]

Sorry I am going to be a bit technical here, but it may interest some of you.

Potassium channel modulators should not be compared, there is a ton of parameters and subtilities that can change drastically the impact of one drug.

Flupirtine acts mainly on the Kv7.3 , retigabine specifically acts on the neuronally expressed KCNQ2-KCNQ5 (Kv7.2-Kv7.5) channels, AUT00063 will act on the Kv3 channels.

Talking from a neuronal perspective, Kv7 and Kv3 mediate the channels and more precisely the action potential.
The action potential is an electrical signal generated near the cell body of a neuron that propagates along the axon to the axon terminals.

After an acoustic trauma, or after taking some drugs such as quinine there is an interference with the excitability of spiral ganglion neurons (The evil glutamate is guilty ). The membrane potential changes and the modification of the action-potential waveform induced by the problem put the individual in a T. state.

Going back to the potassium channels, Kv7 channels primarily control the interspike interval with a limited effect of the repolarization. Kv3 channels control the repolarization of the action potential and are expected to induce a new state.

The idea is to open the right channels to lead to a neuronal hyperpolarization, thereby stabilizing the membrane potential and decreasing excitability.(No or very little Tinnitus)

Conclusions:

• Despite a drug being potassium channel openers, it has to be very precise to work.
• Flupirtine doesn't act on any sub unit related to T. ( So no possible impact)
• Retigabine acts on interspike interval, meaning less T. spikes and it can possibly repolarize the action potential for some people. But the sub unit range is too wide with numerous side effects. (so it can work to stabilize T. and decrease it to some extent, but is not specific enough to be viable.)
• AUT00063 acts directly on the repolarization and is much more precise, so it's a viable solution providing it works as expected

Thanks for this great summary, I just have a technical question for you; Would previous use of one medicine influence the effect of the other. Would RTG have possible negative effects on the efficacy of AUT?

thanks

 

[DebInAustralia]

I ditto Nills above question. this also concerns me and is one of the reasons why I keep thinking ill hold off from trialling retigabine.

 

[undecided]

Thanks for this great summary, I just have a technical question for you; Would previous use of one medicine influence the effect of the other. Would RTG have possible negative effects on the efficacy of AUT?

thanks

Is there any evidence for the efficacy of AUT?

 

[Zimichael]

I ditto Nills above question. this also concerns me and is one of the reasons why I keep thinking ill hold off from trialling retigabine.

Well I can't answer for AUT00063, but if you believe the Pharma stuff then Retigabine plasma half-life is 8 - 10 hours, and plasma clearance = 98% after 10 days. By the time Autifony comes along for us it will be a LOT longer than that!

Plasma Clearance: Ezogabine and its N-acetyl metabolite have similar elimination half-lives (t½) of 7 to 11 hours. The clearance of ezogabine following intravenous dosing was approximately 0.4 to 0.6 L/hr/kg. Ezogabine is actively secreted into the urine.

Elimination: Results of a mass balance study suggest that renal excretion is the major route of elimination for ezogabine and NAMR. About 85% of the dose was recovered in the urine, with the unchanged parent drug and NAMR accounting for 36% and 18% of the administered dose, respectively, and the total N-glucuronides of ezogabine and NAMR accounting for 24% of the administered dose. Approximately 14% of the radioactivity was recovered in the feces, with unchanged ezogabine accounting for 3% of the total dose. Average total recovery in both urine and feces within 240 hours after dosing is approximately 98%.

Most of the sources I saw fell into these ranges above...But as we know, we are all "unique" in relation to detox pathways and whatever 'deficiencies'. If you have renal issues and such, I'm sure clearance may be slower.

Best, Zimichael

 

[linearb]

Is there any evidence for the efficacy of AUT?

the trials are still underway...

 

[Juan Carlos]

Well I can't answer for AUT00063, but if you believe the Pharma stuff then Retigabine plasma half-life is 8 - 10 hours, and plasma clearance = 98% after 10 days. By the time Autifony comes along for us it will be a LOT longer than that!

Plasma Clearance: Ezogabine and its N-acetyl metabolite have similar elimination half-lives (t½) of 7 to 11 hours. The clearance of ezogabine following intravenous dosing was approximately 0.4 to 0.6 L/hr/kg. Ezogabine is actively secreted into the urine.

Elimination: Results of a mass balance study suggest that renal excretion is the major route of elimination for ezogabine and NAMR. About 85% of the dose was recovered in the urine, with the unchanged parent drug and NAMR accounting for 36% and 18% of the administered dose, respectively, and the total N-glucuronides of ezogabine and NAMR accounting for 24% of the administered dose. Approximately 14% of the radioactivity was recovered in the feces, with unchanged ezogabine accounting for 3% of the total dose. Average total recovery in both urine and feces within 240 hours after dosing is approximately 98%.

Most of the sources I saw fell into these ranges above...But as we know, we are all "unique" in relation to detox pathways and whatever 'deficiencies'. If you have renal issues and such, I'm sure clearance may be slower.

Best, Zimichael

Interesting, so you mean that AUT half-live time is way longer than RTG? how long? how do u know this?

 

[Zimichael]

Well I can't answer for AUT00063, but if you believe the Pharma stuff then Retigabine plasma half-life is 8 - 10 hours, and plasma clearance = 98% after 10 days. By the time Autifony comes along for us it will be a LOT longer than that!

Sorry JC...sloppy English there.

What I meant was, that by the time AUT00063 comes along and is available to us it will be years. Thus much, much longer than "any half life" or "plasma clearing rate" of the drugs we are generally talking about, like Flupirtine, Retigabine, Keppra, etc.

I have no idea what the plasma clearance time is for AUT00063.

Hope that makes it clearer. Best, Zimichael

 

[linearb]

I have a friend who was too impatient to wait for suvorexant to come to market, and had his own batch custom synthesized by an unscrupulous overseas chemical lab.

On that note... does anyone know what the actual molecule is for AUT00063? That may be a closely held secret at the moment, but it will doubtless need to become public well before sales...

 

[Zimichael]

On that note... does anyone know what the actual molecule is for AUT00063? That may be a closely held secret at the moment, but it will doubtless need to become public well before sales...

Here you go...Good luck understanding it all!!! (And I guess this should be, or already is, in the Autifony thread):

http://www.faqs.org/patents/app/20130267510

 

[linearb]

Here you go...Good luck understanding it all!!! (And I guess this should be, or already is, in the Autifony thread):

http://www.faqs.org/patents/app/20130267510

well, that's everything one would need to know to cook this up, but wow is that a complex molecule. 200 step synthesis to get to (5R)-5-ethyl-5-methyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl- )-2,4-imidazolidinedione ..... this makes synthesizing LSD look simple!

 

[Zechariah]

UPDATE

Since my last update, I have been taking 400mg Flupirtine in the slow release tablet form. I take it just before bedtime as I might as well benefit from the sedation effect it has (Flupirtine is an analgesic/muscle relaxant) - however, I don't have problems to get to sleep otherwise (in general I take no medication for sleeping).

As I have previously experienced when taking Flupirtine, my right side tinnitus is pretty much eliminated; this would also happen from time-to-time even without being on Flupirtine as my right side tinnitus tends to have a cyclic pattern to it with a cycle of about 3 to 4 days. However, the last four days have been totally steady (right side) with an improvement of about 85% to 100%. So there is no doubt that Flupirtine does "something".

This morning, I woke up with a distinctly low left side tinnitus, as well. In fact, the first 10 minutes, I was essentially cured. It has started to pick-up just a tiny bit, but my left side tinnitus is no longer the usual tonal eeeeee-sound (more like a soft "electric hum", if that makes sense...).

It is by no means time to open the champagne bottles just yet; I am simply reporting what I experience, as I experience it...

Side-effects? Well, Flupirtine is very well tolerated by myself. I don't get anything close the side effects I have read about in the accounts in the main Trobalt-thread (and Flupirtine does act on the same channels as Trobalt). The only side-effects I experience is a mild sluggish feeling, slight cognitive impairment, and I notice I tend to write words that shouldn't be there or that make no sense. For example, in the sentence above, "This morning, I woke up with...", I initially wrote "This morning, I would up with..."; also my spelling is not as good as it would be when not taking Flupirtine.

Hi, ATEOS, anything worth updating? I assume you are closing up the end of your flupirtine course because of liver toxicity risk.

I'm asking because I'm really interested on trying flupirtine which seems to be, as you said earlier, a better alternative for Trobalt/Retigabine in means of side effects.

 

[Christian78]

Well is it ototoxic? how to behave with it, maybe some live regenerators....

Who will test it?

 

[1MW]

I can not find retigabine but i can find a lot of flupirtine is a good alternative ?

 

[cqman]

I did track down a 2006-paper on a treatment protocol trial for Flupirtine in relation to tinnitus - and carried out by none other than the well-known (tinnitus) neurosurgeon, Dirk De Ridder:

http://www.ncbi.nlm.nih.gov/pubmed/17114151

However, as can be seen, the study only used a maximum daily dosage of 200mg Flupirtine (in all cases). The study should - as a minimum - have put the various groups of patients on daily dosage of 200mg, 400mg, and 600mg, respectively. With just one group of volunteers using a daily dosage of 200mg, they might as well not have done the experiment in the first place; seems like one of those LLLT studies designed-to-fail, in my opinion. Problem is... this study was done - in part - by Dirk De Ridder, and that causes me a "headache"...

Still on 400mg per day?

just doubled the dosage, amazing result. Dosage really matters.

 

[Juan Carlos]

Still on 400mg per day?

just doubled the dosage, amazing result. Dosage really matters.

are you taking it? what are the results?

 

[cqman]

are you taking it? what are the results?

No, I meant ATEOS just doubled the dosage.

 

[Zechariah]

Does anyone know if @attheedgeofscience is waiting a bit to give a "proper" update on this thread? He seems to be logging to forum but not responding to this thread.

 

[1MW]

I got 400mg .
To me has some minor effect nothing special is like a low dose benzo.
Calms the edge of T & H a little.
Also gives me a general calm feeling.
Have anyone combined retigabine+flupirtine (in small doses)?

 

[attheedgeofscience]

I got 400mg .
To me has some minor effect nothing special is like a low dose benzo.

Potential suppression of tinnitus with potassium channel openers like Trobalt and Flupirtine is likely to depend on both the dosage and the length of treatment (most people on this forum have some understanding of this by now, needless to say).

The pioneering research paper on pharmacology and tinnitus (using currently available potassium channel modulators on the market) titled "Pharmacodynamics of potassium channel openers in cultured neuronal networks" by Prof. Moore and colleagues examines thoroughly the pharmacology of four different K+ channel openers. Here is a small excerpt from their paper:

The entire paper is now available for free @:

www.researchgate.net/publication/261220232_Pharmacodynamics_of_posstassium_channel_openers_in_cultured_neuronal_networks

As can be seen from the graphs, above, the normalization of the relative spike rate depends on both the dosage and the drug itself (i.e. Trobalt [RTG] would be "superior" to Flupirtine [FPT], in this case). This is what is defined as the therapeutic concentration (TC). How that translates into dosages in the "human laboratory" is another matter, of course. But the graphs illustrate clearly how dosage plays a potentially significant factor in the suppression of tinnitus.

Maximum daily allowed dosage with Flupirtine is 600 mg. Apparently the maximum recommended treatment duration is restricted to two weeks. The (potential) treatment of tinnitus using Flupirtine is off-label. Ultra short-term (e.g. for one day) dosage increase beyond 600 mg / day is "probably safe", but not really recommended (based on discussions I have had with a professor of neurosurgery).

I have reliable information that the professors behind the research paper, above, have both the capability and the competence to quantify the neurotoxicity of the drugs investigated in the paper as well as undertake research into more advanced compounds with higher selectivity of the specific potassium channels (and less toxicity). Being researchers at public universities, I have no doubt that they would appreciate further funding. I also have no doubt that they would be able to "make a difference" in tinnitus research.

attheedgeofscience
27/MAR/2015.

 

[Martin69]

@attheedgeofscience
ATEOS. Thanks for sharing. As always, highly valuable for us.
So if I understand correctly, this paper confirms the efficiency in calming neuronal acticity and therefore suppressing Tinnitus. But we have no long-term studies, right? Do you know if anything is planned in this direction (for example by a pharma company)?
Or is it up to the board members here to continue doing their own studies with Trobalt?
Thanks again.

 

[NiNyu]

http://www.feinberg.northwestern.edu/news/2015/02/garcia-auditory-pathway.html
This discovery was made recently and there is a thread in research section for this too. I find these quotes interesting:

"We do not know how to treat T, and understanding what neuronal pathway might be involved is essential. If we find they are actually pain syndromes rather than hearing syndromes, perhaps they could be treated effectively with analgesic pain medication that acts on the brain."

That's profoundly interesting! I've been asking myself the very same question lately. Did anybody for example try opioids like morphine?

 

[attheedgeofscience]

So if I understand correctly, this paper confirms the efficiency in calming neuronal acticity and therefore suppressing Tinnitus.

The study was done in vitro (i.e. not done on animals or humans, but in a lab). In this setting, the study simulated tinnitus like activity and observed the effects of four different drugs (along with various concentrations of the drugs). Under these simulated conditions, the study showed that the four drugs tested would have the potential to suppress tinnitus.

But we have no long-term studies, right?

Right now, we have no proper studies at all (i.e. no short or long term studies). The only "kind of" study we have is the study that the members of TinnitusTalk are behind (i.e. the informal Trobalt Trial) - which means that TinnitusTalk is actually ahead of the game, so to speak. The problem is that the data Team Trobalt collected does not live up to scientific standards. With a bit of luck, the publication of the research paper that TRI is behind will pave the way for a proper study (by creating awareness).

Do you know if anything is planned in this direction (for example by a pharma company)?

See above. Also see:

www.tinnitustalk.com/threads/retigabine-trobalt-potiga-%E2%80%94-general-discussion.5074/page-141#post-101671

And...

Based on the bits in the forum on this we're trying to get a meeting to discuss with GSK. However such a reaction to a drug (e.g. drug prescribed for X is helping Y) is always going to come from people with the condition, whatever it is. Agree the charities representing these groups then have a role in advocating research to verify - we might have been a bit slow to pick up on it, but we're trying to get through the door now. We've done similar lobbying/advocacy in the past when people have told us in meetings or we've found out about a potential drug/treatment already in market (most obvious/biggest example - Ginkgo Biloba)

Source: www.tinnitustalk.com/threads/british-tinnitus-association-q-a.7746/#post-89720

Personally, I believe the best route to follow is to get involved in advocacy and contact relevant government organizations and/or pharmas. Share the knowledge - as appropriate - and persevere. Spending hours on a forum brings little value.

What top-class researchers such as professor Moore can do, is to undertake research into the pharmacology of the current compounds and/or look for safer and/or more effective alternatives. This is a slightly different topic.

Or is it up to the board members here to continue doing their own studies with Trobalt?

Trobalt is currently available (even off-label). Anyone who wishes to try it can do so (provided they can find a doctor willing to prescribe it...). What members on TinnitusTalk can do, is help understand just how effective Trobalt is (by reporting their progress reliably and in a timely fashion). With enough reliable results, that could pave the way for a proper study of Trobalt under controlled conditions. Such a study may then indicate that Trobalt is or - is not - effective against tinnitus in general or it may show just efficacy with a specific sub-type of tinnitus.

 

[1MW]

The good with flupirtine is that a pill 400mg last many hours.
With RTG the result lasts max 1.5-2 hours.
For liver toxicity maybe we can use some antidote for use more than 15 days...

 

[1MW]

Update i got 2nd pill today and seems better than RTG.
Is like RTG plus benzo.
Nice effect on T & H.
I remember when my T stopped on it's own without any med for a couple of hours i had the same feeling/calmness that gives the flupirtine

 

[attheedgeofscience]

Still on 400mg per day?

just doubled the dosage, amazing result. Dosage really matters.

Yes it does, doesn't it? And so does the health of my liver...

 

[1MW]

I will do exams for liver enzymes after 7 days of use.
We must find antidote for liver toxicity because this drug is very good.

 

[undecided]

@1MW out of curiosity, how did you get your hands on Flupirtine?
It's not available on greek pharmacies? Did you order from abroad?