Flupirtine — Another Potassium Channel Opener

[Mikel]

During my research about potassium channel openers I stumbled across this study:

http://www.ncbi.nlm.nih.gov/pubmed/24681057

We then compared the pharmacodynamics of the four channel activators, retigabine and flupirtine (voltage-gated K(+) channel KV7 activators), NS1619 and isopimaric acid ("big potassium" BK channel activators). The EC50 of retigabine, flupirtine, NS1619, and isopimaric acid were 8.0, 4.0, 5.8, and 7.8µM, respectively. The reduction of hyperactivity compared to the reference activity was significant. The present results highlight the notion of re-purposing the K(+) channel activators for reducing hyperactivity of spontaneously active auditory networks, serving as a platform for these drugs to show efficacy toward target identification, prevention, as well as treatment of tinnitus.

One drug which stood out for me was Flupirtine, which is a pain medicine and quite common in Germany.

And it turned out that they registered a patent in 2001!

English (Google Translate):
https://www.google.com/patents/WO2002015907A1?cl=en

Original Text in German:
https://www.google.com/patents/WO2002015907A1?cl=de

In acoustic stimuli-processing neurons can this be traumatized by extreme sound events or prolonged noise disturbance from low intensity. Causes may be due to deficiency of oxygen deficiency and nutritional deficiency, such as ischemia by stress, inflammation, stroke or other. The deficiencies also lead to glutamate matausschüttung with the consequences mentioned above. The previous studies of more than 90 patients with acute, subacute or chronic tinnitus resulted in 70% to a complete disappearance of the tinnitus. The necessary treatment time was 14 days up to six months.
For other patients, a marked improvement occurred. The improvement remained even after stopping the drug.
According to the results it can be assumed that the duration of therapy is up to success with the duration of the disease correlated, ie a longer disease requires prolonged therapy. Similar to the experience with chronifizier th pain it can be assumed that some patients need long term therapy.
The active substance flupirtine may be administered orally, rectally, intravenously or intramuscularly (systemic) are administered. The doses used are as they are also used to treat chronic pain in the area. The doses are between 200 mg and 600 mg per 24 hours. They are presented in three to four servings per day at a distance of about 6 to 8 hours.
Another possible application form is the local administration of nerve cells in the auditory pathway via micro pump systems.
The treatment with flupirtine can and should begin simultaneously with the treatment of the causes of the tinnitus. The simultaneous initiation of treatment avoids "learning," which enhance or maintain the tinnitus, ie • Have become chronic. With already chronic tinnitus the active substance and / or the therapeutic principle resulting neuroplastic changes can be undone.

I am unable to receive a prescription for the medicine myself since I don't live in Germany or India but I hope that this will be able to help some others.

In the package insert they mention that the medicine shouldn't be given to patients with acute or recent tinnitus due to increased liver enzymes. In Germany they also put a general warning since this medicine led to liver damage and even death. They instruct to test the liver on a weekly basis.

It might also be worthwhile to take Acetyl-cysteine together with it to protect the liver?

[Edit]
I found another study, with negative results. It is worth to mention that they used a smaller dose (200mg instead of 300mg-600mg per day) and that they stopped the treatment after 3 weeks. In the German study they say that the treatment took up to 6 months.

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

 

[attheedgeofscience]

I can certainly look into it. My (new) GP is more than willing to help (in order to keep me from going through with brain surgery - which I "threatened" would be my next step; she began to become a little anxious when I showed her the invitation papers from the clinic in Switzerland when I went to see her last Friday).

As it happens, I briefly looked into Katadolon/Flupirtine last year - it is indeed a relatively common medication here in Germany for back pain (it is a muscle relaxant). My chiropractor - who is also a doctor - was overseeing my initial treatment for tinnitus last year.

I did not experience any beneficial effects from Katadolon (in terms of lowering my tinnitus volume) but it did help me sleep as intended. But from reading the above documentation, the dosage I was on was probably far too low to have a therapeutic effect for tinnitus. Katadolon was well tolerated by myself - I essentially had no adverse effects. I would much rather go on a muscle relaxant for a couple of weeks - than go on the epileptic drugs with similar tinnitus reducing effects eg. Trobalt.

 

[jazz]

@Mikel I know about Flupirtine and also read that negative pubmed article with it being used for tinnitus. That study made me dismiss the drug for tinnitus, but I will do more research on it now.

Thanks for the links!!!

 

[lapidus]

Hmm, there's quite a huge difference between 3 weeks and 6 months. The German study had some promising results and also that the improvements remained after the study is very uplifting.

 

[Mikel]

I just had a quick look on German boards and there are only few people which report big changes. But most seem to have taken the medicine for a short timeframe.

Some had to cancel the treatment because blood tests were showing liver problems but I don't think that anyone took Acetyl Cysteine at the same time.

 

[benryu]

I can certainly look into it. My (new) GP is more than willing to help (in order to keep me from going through with brain surgery - which I "threatened" would be my next step; she began to become a little anxious when I showed her the invitation papers from the clinic in Switzerland when I went to see her last Friday).

As it happens, I briefly looked into Katadolon/Flupirtine last year - it is indeed a relatively common medication here in Germany for back pain (it is a muscle relaxant). My chiropractor - who is also a doctor - was overseeing my initial treatment for tinnitus last year.

I did not experience any beneficial effects from Katadolon (in terms of lowering my tinnitus volume) but it did help me sleep as intended. But from reading the above documentation, the dosage I was on was probably far too low to have a therapeutic effect for tinnitus. Katadolon was well tolerated by myself - I essentially had no adverse effects. I would much rather go on a muscle relaxant for a couple of weeks - than go on the epileptic drugs with similar tinnitus reducing effects eg. Trobalt.

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

 

[Mikel]

thanks for the explanation. finally something understandable (compared to the random results on Google )

 

[Mpt]

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

hi benyru--
where did you find information regarding the specific kv7 channels that flupirtine works on. The wikipedia page I found just lists it as working on kv7 channels like retigabine which it is chemically very similar to undoubtedly-- I was just wondering as flupirtine doesn't seem to have the potential retina pigment-change impact that retigabine does, and if they act similarly it could be a replacement for retigabine
http://en.wikipedia.org/wiki/Flupirtine

 

[attheedgeofscience]

A little bit of information (some of it specifically relevant to the thread, some of it, less so).

I went to see my (new) GP today; I have delayed seeing the professor of neurology as I am not particularly interested in his insight at this moment. The reason is quite simple: theoretical insight belongs to the world of mathematics and physics. Medicine - on the other hand - cannot be practiced on a "blackboard". It must be practiced in the "real" world and using (a)live specimens. So I saw my GP today, and we basically pushed all theoretical discussions about cell membranes aside, and went straight ahead with a treatment plan using Flupirtine. Why did we push theories aside? Because neither my GP, nor me, know anything about potassium modulators; so why bother to have a "discussion" in the first place?

Before seeing my GP, I did have a brief e-mail exchange with Autifony Therapeutics (today). For those who are interested, the very latest info is that the clinical trial in the UK will go ahead in September/October, and there should be information made available on the Autifony homepage in September (but it is unlikely that there will be content about enrollment available much earlier than that). I did have a few additional questions about off-label drug usage and potassium modulators such as Flupirtine and Trobalt. But Mr. Large (CEO) skillfully dodged those questions. In a sense, his response had a somewhat "rehearsed" feel to it, I must say. However, I do appreciate that he took the time to personally respond to my e-mail and that he did so within two hours. As I have noted in some of my financial analyses on this site, otology companies often have limited manpower due to their very small size (headcount is typically around 10-20 in total). And on top of that, I can only imagine Autifony is quite busy at this particular time. I will not release the e-mail itself in public (as it is personal - and I owe Mr. Large that much respect in return; but I have supplied @Markku with a copy).

So I am going into this Flupirtine treatment blindly. My doctor suggested taking the slow-release form of Flupirtine called Katadolon S Long. This will ensure a daily dosage of 400 mg. Therapeutic dosage for tinnitus seems to lie between 200 and 600 mg (using Flupirtine). I will start off with a two week treatment course. I will meet her (my GP) again in roughly two weeks for a follow-up and possibly extend the treatment. However, I do not plan to stay on this drug for very long (regardless of whether it works or not).

 

[lapidus]

Well you truly are a pioneer @attheedgeofscience
But remember that the german studies that had positive results for T with Flupiritne used it for 6 months. Don't know how long you are planning to stay on it but 6 months is rather long imo.

 

[Johno]

Very interesting thing is written in documentation of Flupirtine Glenmark 100 mg.

In list of contraindications is written:
Neužívajte liek, ak ste pacient s nedávno prekonaným hučaním v ušiach (tinnitus), alebo ním stále trpíte, pretože štúdia preukázala, že u pacientov s hučaním v ušiach, ktorý sa liečia flupirtíniummaleinátom je zvýšené riziko rozvoja zvýšených hodnôt pečeňových enzýmov.

My english is not very good, but it means - Dont use this drug, if you had or still have Tinnitus, because trials proves, than T sufferers who takes maleate of flupirtine has increased risk to develop high liver enzymes.

WTF??? This is one of the most weird attention text i ever read. Liver and T? How can be my liver connected with my acoustic trauma? W?T?F?

 

[Christian_B]

@attheedgeofscience - i'm very curious if this drug can be found in denmark? i'm asking since you are from denmark and maybe have some knowledge of that.. maybe another name of it? i can't find it myself tho...

But.. i would much rather take this drug, than ratigabine.. the side effects scare me a bit. thanks in advance

 

[attheedgeofscience]

@attheedgeofscience - i'm very curious if this drug can be found in denmark? i'm asking since you are from denmark and maybe have some knowledge of that.. maybe another name of it? i can't find it myself tho...

But.. i would much rather take this drug, than ratigabine.. the side effects scare me a bit. thanks in advance

I don't believe it is available in Denmark. But a quick visit to the local pharmacy could eradicate any doubt.

 

[attheedgeofscience]

First 24 hours on the drug. Took 100 mg before sleeping yesterday. Then a 400 mg slow release tablet this morning. I mentioned earlier on that I have been on this drug sporadically in the past. So I know what to expect. No major side effects, but after the 400 mg pill this morning, I have felt sluggish during the day, today. My GP said I am legally allowed to drive while being on this drug, but she wouldn't recommend driving for the first week (side effects tend to wear off and get better she said). I agree, I would not really want to drive in the state I am in right now - although the sluggish feeling is not bad (best comparison is probably 100 mg of tramadol, or 60 mg of Codeine).

The advantage - possibly - with this drug is that side effects are far(?) less than with Trobalt, but that it has a similar potassium modulator action. Obviously I would not have expected any benefit (in terms of tinnitus) from the Flupirtine at this point. Tinnitus has felt lower during the day, today, but that is purely subjective, and not objectively (because of the sluggish feeling).

I don't really see much point in adding many more posts to this thread - unless something "dramatic" happens. So basically this is a let-you-know-I-started post, and then I will do a final or update post in two weeks time (ie. I will either extend my treatment at that point or discontinue it altogether). I do not plan on staying on Flupirtine for any lengthy period of time.

 

[RaZaH]

Good luck mate !

 

[lapidus]

I do not plan on staying on Flurpirtine for any lengthy period of time.

Out of curiosity, how long would you estimate that you will be on this drug? The german study mentioned 6 months. If you're not planning on taking this for several months I can't really see the point of taking it at all.

However, I wish you the best of luck

 

[Telis]

Out of curiosity, how long would you estimate that you will be on this drug? The german study mentioned 6 months. If you're not planning on taking this for several months I can't really see the point of taking it at all.

However, I wish you the best of luck

Do you mind posting the link to the study? Thanks

 

[attheedgeofscience]

Out of curiosity, how long would you estimate that you will be on this drug? The german study mentioned 6 months. If you're not planning on taking this for several months I can't really see the point of taking it at all.

However, I wish you the best of luck

I start with 14 days. Then I will make a decision as to whether it is worth continuing ie. if I see at least some small improvements, then I will continue for a while longer.

Experimental medicine is always a balance between risks and benefits. Why do six months of Flupirtine "therapy" if I end up with a "broken" liver and no improvement in my tinnitus loudness...? And if I was guaranteed a tinnitus improvment, if - and only if - I continued for six months, would I then do it? These are the questions that anyone should always ask themselves before embarking on a journey into the unknown. Decision making with limited information is one of the hardest disciplines we humans can be confronted with. And it is also a discipline that many people are not very good at. At least that is my perception after living 36 years on a planet called Earth...

Remember...

"If you do what you always did, you will get what you always got."
--Albert Einstein, physicist

So in my opinion, always choose action over inaction.

 

[lapidus]

@Telis
Just scroll up to the first post in this thread

@attheedgeofscience
Okay, I totally understand. Thanks for the answer.

 

[undecided]

I am actually quite interested to see ATEOS's results from trying the Flup.
He should be finishing his 2 week attempt by now.

 

[Hengist]

I start with 14 days. Then I will make a decision as to whether it is worth continuing ie. if I see at least some small improvements, then I will continue for a while longer.

14 days is really short duration unless you have some heavy sideeffects that outweight the benefit, I would reccomend at least a month because those channels are hard to modify.

 

[Zimichael]

@attheedgeofscience ...Ref. to your potential update on your Flupirtine trial after seeing your doc on Tuesday.

Any news, views, results, non results???

Start date was August 6th. from above, so we are a week over your initial "2 week" time frame.

Sorry if I missed an update on another thread, but as you know the Kv threads are pretty "heavy traffic zones"!

Best, Zimichael

 

[Zimichael]

@attheedgeofscience ... J. are you around???????? OK???????????

Zimichael

 

[undecided]

Lol, the flup probably worked and he is partying at a loud concert as we speak

 

[Christian_B]

Lol, the flup probably worked and he is partying at a loud concert as we speak

i doubt it tho

 

[Zimichael]

@attheedgeofscience ..."Earth to ATEOS. Earth to ATEOS. Are you receiving me?"

You have to have been a "Tintin" fan to understand that one, but point made.

Best, Zimichael

 

[cdog]

@attheedgeofscience : Any results to update about your experience with flupirtine?

 

[attheedgeofscience]

Update...

I did 14 days of 400 mg Flupirtine "therapy" per day. The medication was well tolerated. Sluggish feeling after intake of pills which lasts 2-3 hours. Sluggish feeling all day long for the first 4-5 days ie. side-effects improve over time. No other side-effects except a slight/some disability to concentrate and a tendency to mix up words when typing on a computer. No insomnia. No urinary problems (coloration or retention).

Towards the end of the therapy I would experience auditory "u-boat sonar pings" for brief periods of time. Very mild, but noticeable. It felt as if a change in my tinnitus loudness level was about to happen. I have had experiences of extreme 5-seconds fleeting tinnitus incidents following my stem cell treatments and, to a certain degree, following my cold laser therapy. But these u-boat pings were different. Something seemed to be happening. I did go see my GP for renewal of prescription. However, I decided not to continue the therapy for other reasons.

 

[locoyeti]

Something seemed to be happening. I did go see my GP for renewal of prescription. However, I decided not to continue the therapy for other reasons.

Could you please elaborate on why you have decided not to continue with Flupertine? Just wondering if it was a personal/scheduling reason, or some other (medical? scientific?) reason.

 

[locoyeti]

I have contacted @attheedgeofscience and he has informed me that he has resumed his experiment with Flupertine.

" I can - and will - try to go up to a daily dose of 600mg in a few days (I already started on the 400mg daily dose). "

Let's hope for good results. If I get any updates from him in the future I will update this thread.