AM-101

[Hudson]

http://www.biospace.com/News/key-results-from-auris-medical-ags-phase-iib-study/265134

It appears that Dykey guy never reposted about his eventual experience with this anyway. Be careful to form your opinion around a couple of people out of a sample of a total of 248 patients. Keep in mind Tinnitus is subjective in nature. If someone receives this treatment and still experiences tinnitus somewhat, they may not know that the drug did indeed have its intended effect. It may have prevented them from having it much worse.

I'm not going to get into an argument over statistics here or he said who said what. At the end of the day, this company is going to move forward with their phase 3 experiments with this drug. I hope it does well and helps as many people as possible. I notice there's a lot of people quick to trash this thing in here. I for one am very excited that there are even pharmaceutical companies trying tinnitus research and drugs on people. Without it, there would be no cure.

That's what research is. You search, and then you RE-search. 10 years ago, there wasn't squat besides tinnitus retraining therapy and/or "just living with it".

**Edit - keep in mind that as a safety precaution, only one ear was treated in each patient. Theoretically benefits could have been higher but due to ethical standards a drug won't be tested on both organs in question.

I really doubt that a pharmaceutical company would risk their bread and butter on something that's snake oil, especially considering the massive amount of capital and time invested in clearing regulatory hurtles if it didn't really have any effect. So keep your heads up everyone. This kind of stuff is how cures happen.

 

[Fish]

Positive results??? Do you have a reference for your conclusion?
It didn't work for Dykey and Fish!

I think you shouldn't take me into account. As I admitted before, I've bent some rules to help myself so I am not a good example (I took betahistine and underwent upper cervical kinesistherapy at the same time). Also, I wouldn't say it didn't work for me. I had a very sudden and intense reaction to this drug but in the long run, my tinnitus has improved Maybe if I took a 3rd dose I would be completely free of tinnitus... I will never know.

I would like to remind you that 3 months rule is so far completely arbitrary and while AM-101 did indeed work better for early-onset patients, nobody can be 100% certain it won't help them at least to some extent. Truth is they probably used this rule to make the drug get the best results possible.

I am very glad personally that this drug is being developed. At least we know they look for a cure

 

[Fish]

Dan I think you shouldn't take my case into account - I am not a good example since I've bent some rules to help myself (I used betahistine, vitamins and underwent kinesistherapy at the time). Also, I wouldn't say it didn't work for me - I had a very sudden and intense reaction to this drug, but in the end my tinnitus did improve Maybe if I had taken the final dose I would be tinnitus free today, I will never know. I don't even know for sure if I got the real drug or placebo

While I had no chance to meet other participants, my doctor told me the results are really nice so far.

Finally, please remember that the 3 months rule is arbitrary - while the drug did indeed work better for early-onset patients, there is no research so far at what point it stops working. Who knows, perhaps it might still help others to some extent?

I am very glad this drug exists and is being researched - at least we know they try to find a cure and there's a chance it will be a gateway to even more effective drugs and therapies in the future.

EDIT: Hudson - as far as I know it was possible to have both ears treated at the same time, at least it said so in the document I had to sign. I had only one ear treated because I had tinnitus mostly in my right ear at the time. I think the safety precaution you have mentioned was from earlier phase I trials? But I could be wrong...

 

[dan]

oh yeah, I'm sure many people will get better within the first 3 months of getting tinnitus, but any research is very good and better than none.

 

[Louise]

The very fact that they're actually making tinnitus drugs and there are drugs entering human trials is a huge step forward. When I got Tinnitus in 2003, nobody was doing research besides seeing how effective TRT was. This is huge.

I believe the real tipping point has been that this condition is no longer a "go home and live with it" - literally hundreds of thousands of veterans have tinnitus and it's costing the VA a massive amount of money. You can bet that's going to get this going much faster.

I totally agree. At least they are doing something now and it looks like AM101 is going to come though.

 

[mick]

Found this on on Auri Medical's web site in reference to AM-101:

From http://www.aurismedical.com/p/disorders/tinnitus.php?lg=
-----
Recent scientific findings focus on the glutamatergic synapse between inner hair cells and auditory nerve to explain the genesis of tinnitus within the cochlea. Tinnitus is considered as sort of "epileptic" firing in the auditory nerve, induced by excitotoxicity, a form of neuronal degeneration, which can occur when glutamate is released in large amounts (e.g. after exposure to very loud noise) or when incompletely recycled.

Since glutamate is heavily involved in anxiety, and because people who suffer from anxiety are thought to have an imbalance of glutamate and GABA, it seems like this relationship might explain the high correlation between tinnitus and anxiety. I guess what I found most intriguing is that a compound made by our bodies in an exicited state can be toxic.

Some other related info:
From http://www.pnas.org/content/102/24/8740.full
------ (this is from a journal article about a method to measure glutamate release from neurons, but this background info in interesting particularly the last sentence)

In addition to being an intermediate of primary metabolism in all biological cells, glutamate serves as the major excitatory amino acid neurotransmitter in the vertebrate central nervous system (1). As such, glutamate influences essentially all forms of behavior, including consciousness, sensory perception, motor control, and mood. Changes in the strength of connectivity at glutamatergic synapses in the form of long-term potentiation and long-term depression are considered to be the cellular mechanisms underlying learning and memory (2). In addition to its role in normal nervous system physiology, glutamate is also thought to be directly involved in neurologic damage occurring in stroke and neurodegenerative disorders, including AIDS-dementia complex, motor neuron disease, and Alzheimer's and Parkinson's diseases, through receptor-mediated toxicity (3).

Since Xanax is a potentiator of GABA, it would have to be considered a possible cause of GABA and glutamate imbalance, and therefore a possible cause of tinnitus. That might explain why there is considerable anecdotal evidence that it is ototoxic. Similarly, anything that could effect the GABA/glutamate axis could to ototoxic - just about any antidepressants or antianxiety medication.

Bottom line - more things linking anxiety and tinnitus. Also, understanding this makes something like AM-101 more appealing to me. I previously did not think it sounded like a very promising treatment for tinnitus because it effects the cochlea, and I had been pretty much convinced that tinntius was completely in the brain.

 

[Louise]

I dont understand this bit.............

"Since Xanax is a potentiator of GABA, it would have to be considered a possible cause of GABA and glutamate imbalance, and therefore a possible cause of tinnitus. That might explain why there is considerable anecdotal evidence that it is ototoxic. Similarly, anything that could effect the GABA/glutamate axis could to ototoxic - just about any antidepressants or antianxiety medication."

Xanax leads to the increase of GABA which leads to less Glutamate or rather negates the effects of Glutamate to an extent and the article said high glutamate is bad for T and anxiety so why would something that negates its effect be ototoxic necessarily?

I take something that slows the release of Glutamate. Hope thats ok!!

 

[jazz]

Great information!

I do wonder why AM-101 was only tested for acute tinnitus?

The company has another drug, AM-111, for acute sensorineural hearing loss.

 

[Louise]

Good point Jazz.

I always thought that this drug was for stopping the inflammation. And thats why it needs to be done early on whilst the inflammation is still there. Guess I read something wrong somewhere.

 

[jazz]

Louise,

Anti-oxidants and other drugs will protect your brain from glutamate excitotocity. Any damage from tinnitus is small compared with other neurological disorders like Parkinson's. (Of course, we want to prevent all damage, and that's why research into a cure is so important.)

I would not worry about your medications being ototoxic. Xanax and klonapin are the most frequently prescribed drugs for tinnitus. Many people do note, however, that their tinnitus is worsened when they come off these medications. This is because your brain will become used to them. To prevent this, your doctor will help you taper off the drugs. But that's only when he feels they are no longer working for you.

There is a correlation between antidepressants and tinnitus. But many--probably most--people with tinnitus do not find the drugs increase their noise. If you think your antidepressant is worsening your tinnitus, ask your doctor to prescribe another one. In general, most people with tinnitus report relief with their medications--both antidepressants and anti-anxiety drugs.

 

[Louise]

Yes, I know a common side-effect of Benzo withdrawl is T and I intend to taper the small amount I take slowly. Its 're-bound disinhibition' and its because the body has compensated for the drug by reducing the amount of GABA receptors. So when the drug has gone you still have less GABA receptors until the body builds them back up again.

I wouldnt expect my doctors to know anything about how to taper or that Benzo withdrawl can cause T. They're just not interested in T. All along I've just told them what I want and treat myself.

Still, I thought the point of AM101 is to stop the inflammatory reaction. Well, maybe it is as maybe its the inflammation that causes too much glutamate to be released?

 

[Aisling]

When I emailed the guy about AM101 he did say that the 3 months criteria was arbitrary and they don't know if it will work in older tinnitus. I truly believe the theory that tinnitus is like epilepsy but in the ear. It is exactly what mine sounds like a constant erratic signal being sent to my ear. Lets be optimistic sure a baby born with aids was cured recently

 

[mick]

I'm not an expert and I'm just theorizing, but my educated guess of Xanax's action is that mimics the effect of GABA at a GABA receptor, and does not actually cause an increase of GABA. When it does this, the body makes less GABA because it does not need it. You are probably right about there being an inverse relationship between GABA and glutamate; i.e. GABA kind of neutalizes glutamate. If Xanax substitutes for GABA rather than increases GABA then its presences disturbs the the GABA-glutamate balance towards excess glutamate. Furthermore, when Xanax wears-off it wears-off quickly and the brain can not produce GABA quickly enough to satisfy the starved GABA receptors. This is what produces the well know withdrawal symptoms which are very much like anxiety. So even if Xanax counts as GABA in the GABA-glutamate balance, when it wears off, the balance is tipped towards excess glutamate relative to GABA. In either case, excitotoxicity could occur assuming that excess glutamate relative to GABA is sufficient to cause excitotoxicity.

In support of my educated guess as to how Xanax works, the below info came from the prescribing information for Xanax provided by Pfizer.

Pharmacodynamics
CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.

I could not find any mention of GABA in the prescribing information, but lots of other resources state that it effects gamma-amino-butyric acid (GABA) receptors.

 

[jazz]

When I emailed the guy about AM101 he did say that the 3 months criteria was arbitrary and they don't know if it will work in older tinnitus. I truly believe the theory that tinnitus is like epilepsy but in the ear. It is exactly what mine sounds like a constant erratic signal being sent to my ear. Lets be optimistic sure a baby born with aids was cured recently

That's great news! Now, we need to quicken the approval process!

 

[Louise]

I'm not an expert and I'm just theorizing, but my educated guess of Xanax's action is that mimics the effect of GABA at a GABA receptor, and does not actually cause an increase of GABA. When it does this, the body makes less GABA because it does not need it. You are probably right about there being an inverse relationship between GABA and glutamate; i.e. GABA kind of neutalizes glutamate. If Xanax substitutes for GABA rather than increases GABA then its presences disturbs the the GABA-glutamate balance towards excess glutamate. Furthermore, when Xanax wears-off it wears-off quickly and the brain can not produce GABA quickly enough to satisfy the starved GABA receptors. This is what produces the well know withdrawal symptoms which are very much like anxiety. So even if Xanax counts as GABA in the GABA-glutamate balance, when it wears off, the balance is tipped towards excess glutamate relative to GABA. In either case, excitotoxicity could occur assuming that excess glutamate relative to GABA is sufficient to cause excitotoxicity.

In support of my educated guess as to how Xanax works, the below info came from the prescribing information for Xanax provided by Pfizer.

Pharmacodynamics
CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.

I could not find any mention of GABA in the prescribing information, but lots of other resources state that it effects gamma-amino-butyric acid (GABA) receptors.

Hi Mick, thanks for the info. Hypnosis! Cool

Dont you just hate it when you read, (and this is true of so many drugs I've looked at lately), "exact mechanism of action is unknown". Dont they know anything these scientists? It was news to me that they dont understand the inner ear/auditory brain when I read that in the first months. Now I just expect they dont know much at all about anything. This is 2013 right? I mean, its been a long time since we were hacking off people's legs with a rusty saw whilst getting them to bite on a lump of wood for the pain. Sorry, it just really disappoints me.

Anyhow, back to Benzos..... it never occurred to me that once the drug has gone that the balance of glutamate to GABA could cause excitotoxicity. Would it though? Wouldnt we only have the same amount of Glutamate as before taking the drug and hence no extra hyperactivity would occur?

The action you describe of the GABA dropping down as the drug wears off due to the brain not being able to make the missing GABA quickly enough isnt the full story. There's something worse.... after long term use (I dont know how long) the body compensates for this excess GABA by losing some of the GABA receptors. Thats why it takes some people years to recover from Benzo use - these receptors take a long time to come back. I reckon when coming off them the taper should be so slow as to allow these receptors to come back before dropping the dose again. That might actually take years.

 

[mick]

Hi Mick, thanks for the info. Hypnosis! Cool
Anyhow, back to Benzos..... it never occurred to me that once the drug has gone that the balance of glutamate to GABA could cause excitotoxicity. Would it though? Wouldnt we only have the same amount of Glutamate as before taking the drug and hence no extra hyperactivity would occur?
.

I wish I knew the answer for sure, and as you noted so well, the scientists probably don't know either. The lack of first principles in the science behind many drugs is very disconcerting,

To give my thoughts on your question (and mind you this is just me thinking/wondering out loud more than anything), whether glutamate excitotoxicity occurs would depend on whether it is the result of the absolute amount of glutamate, or the relative amount with respect to GABA (or maybe even some other compound the can forestall excitotoxicity). I think you're right that the absolute amount of glutamate wouldn't change as the drug mimicing GABA is metabolized, and if it is the absolute amount of glutamate that triggers the excitotoxicity (that is, it becomes excitotoxic only if it exceeds X concentration) then it probably would not be a problem. But if excitotoxicity is triggered when glutamate concentration exceeds GABA concentration by some amount (perhaps GABA protects against exitotoxicity), then the shortage of GABA could trigger it.

Hope that makes sense. Again - just my hypothesis.

 

[Louise]

It makes total sense and you put the conundrum very well. And I want to know the answer! How can we find out?
In times like this I normally google some random stuff like 'neuro scientist' and just track them down and send an email!! Sometimes I hit paydirt, (has anyone noticed how my Americanisms have increased since I joined this site? ), most times not.

 

[just1morething]

I wish I knew the answer for sure, and as you noted so well, the scientists probably don't know either. The lack of first principles in the science behind many drugs is very disconcerting,

To give my thoughts on your question (and mind you this is just me thinking/wondering out loud more than anything), whether glutamate excitotoxicity occurs would depend on whether it is the result of the absolute amount of glutamate, or the relative amount with respect to GABA (or maybe even some other compound the can forestall excitotoxicity). I think you're right that the absolute amount of glutamate wouldn't change as the drug mimicing GABA is metabolized, and if it is the absolute amount of glutamate that triggers the excitotoxicity (that is, it becomes excitotoxic only if it exceeds X concentration) then it probably would not be a problem. But if excitotoxicity is triggered when glutamate concentration exceeds GABA concentration by some amount (perhaps GABA protects against exitotoxicity), then the shortage of GABA could trigger it.

Hope that makes sense. Again - just my hypothesis.

The glutamate excitotoxicity with respect to Gaba. WTH are they talking about Spock? Why don't they just ask Dykey if it STOPPED THE DAMN NOISE!! Unclear Captain, maybe Columbo was right. I theorize Captain, that eating squirrel turds would have a beneficial effect on tinnitus as well.

 

[Hudson]

Dykey never responded anymore... Fish said she thinks it may have helped hers. If Dykey's T went away it's perfectly reasonable to assume he would have just bothered not to post here anymore too bad for us though. That seems to happen a lot though. People's T either diminishes or they become habituated to it and don't frequent a board like this. There's some argument that habitually looking up T information and posting on forums can contribute to T stress because you keep reminding yourself about it. When I originally habituated to mine, I found that as I slowly stopped reading about it over time, I stopped paying attention to it.

Habituation is great and all, but I believe people habituating and "learning to live with" tinnitus is part of what has contributed to the fact that it's taken so long for it to be taken seriously as a medical condition and to have serious money and research dedicated to it. Tinnitus isn't visible like cancer, so it isn't really sexy to go on a fund raising walk for Tinnitus awareness.

Fish may have some answers for you, she participated in the AM-101 trial.

 

[just1morething]

Dykey never responded anymore... Fish said she thinks it may have helped hers. If Dykey's T went away it's perfectly reasonable to assume he would have just bothered not to post here anymore too bad for us though. That seems to happen a lot though. People's T either diminishes or they become habituated to it and don't frequent a board like this. There's some argument that habitually looking up T information and posting on forums can contribute to T stress because you keep reminding yourself about it. When I originally habituated to mine, I found that as I slowly stopped reading about it over time, I stopped paying attention to it.

Habituation is great and all, but I believe people habituating and "learning to live with" tinnitus is part of what has contributed to the fact that it's taken so long for it to be taken seriously as a medical condition and to have serious money and research dedicated to it. Tinnitus isn't visible like cancer, so it isn't really sexy to go on a fund raising walk for Tinnitus awareness.

Fish may have some answers for you, she participated in the AM-101 trial.

Fish is a HE, and I was just trying to humor is all. Takes your mind off of T.

 

[Hudson]

My apologies to Fish, I always pictured Fish as a woman for some reason. Maybe the avatar lol.

Humor is good, I'm not immune to it.

 

[Fish]

I guess my avatar is at fault... But since people liked this cat so much I thought to keep it

I wish I could help but I don't have anything more than you already know plus my vocabulary is a bit limited.

I remember the doctor who explained me the mechanism of action compared tinnitus to arrhytmia and AM-101 to a defibrillator. It's supposed to bring back the balance of overly excited hair cells in the ear after noise trauma.

As I've said before, AM-101 is based on esketamine hydrochloride, which is an anaesthetic.

Also, I've been in contact with Dykey for a while, unfortunately AM-101 did not work for him. But he seems better anyway!

 

[mick]

the mechanism of action compared tinnitus to arrhytmia and AM-101 to a defibrillator

I really like this analogy. It goes so well with the idea of T being the manifestation of misfiring neurons. To me there has always been an electrical feeling that goes along with T that goes beyond just the alien noises. The idea of knocking that feeling out with a defibrillator like action just sounds so right - almost comforting.

 

[mick]

eating squirrel turds would have beneficial effect on tinnitus as well

You know, if someone came up with a semi-reasonable explaination for squirrel turds being able to stop my T, I would not hesitate to eat some.

 

[erik]

The researchers at OHSU Tinnitus Clinic were not very positive on AM-101 last July. They were originally contacted by Auris to be one of the research/clinical trial sites for AM-101 but they refused on the basis that they were not confident in AM-101 after reviewing the data. Either way, I am glad there are companies out there that are doing research and work in this area. I am confident there will be a break thru at some point.

 

[Louise]

I really like this analogy. It goes so well with the idea of T being the manifestation of misfiring neurons. To me there has always been an electrical feeling that goes along with T that goes beyond just the alien noises. The idea of knocking that feeling out with a defibrillator like action just sounds so right - almost comforting.

I have electrical noise. The ANM hopes to bust up synchronous neurons like a defibrillator I guess. But much more gently and over time! Its such a complex problem with all the different areas of the brain being involved. The more I read and hear about it the more depressed I become about there being a solution.

 

[erik]

Louise I too have electrical noise and always had. I am just about to hit the 1 year mark. I must say though I have had the most improvement just in the last month. It is not as much electrical. Like the misfirings are tapering off or my brain is adjusting them is what I like to think. Seems to have calmed down much. Not sure why but even noisy events like 2 nights in a row of going to a loud Hockey game did not even set it off. It has been the best this past 4 weeks then it ever has in the last year so keep hope alive!

 

[just1morething]

Mine is very bad today as well—almost like an electrical sound, similar to overhead power lines. It was so much better yesterday. I really hope medical science finds a solution soon, as my trial-and-error methods haven't been very effective lately. My last resort is receiving facial nerve block injections below the external auditory canal for tinnitus relief.

 

[Louise]

Louise I too have electrical noise and always had. I am just about to hit the 1 year mark. I must say though I have had the most improvement just in the last month. It is not as much electrical. Like the misfirings are tapering off or my brain is adjusting them is what I like to think. Seems to have calmed down much. Not sure why but even noisy events like 2 nights in a row of going to a loud Hockey game did not even set it off. It has been the best this past 4 weeks then it ever has in the last year so keep hope alive!

That's good news Erik and yes it does give hope Did yours ever get louder along the way? Mine has and still is.

 

[Markku]

Thomas Meyer of Auris Medical contacted me with the following message and asked to share it.


Statement about AM-101 trial in forum

Hello,
I have been reading some of the most recent posts about our company and the AM-101 project. I appreciate your member's interest and comments. There is however one piece of information that is not correct: in all of our clinical trials so far we had a 3 month time window corresponding to the definition of acute tinnitus - it was never 6 months, and hence never narrowed down to 3 months. Since we did not see a decrease in therapeutic effect towards the end of the 3 month time window (which is based on a somewhat arbitrary cut-off... but the line has to be drawn somewhere), we are planning to test AM-101 in one of our forthcoming phase III trials in the post-acute stage up to 12 months.
I would appreciate if you could share this information with your members.

Kind regards,

Thomas Meyer
Founder and Managing Director
Auris Medical