Sound Pharmaceuticals (SPI-5557 & SPI-1005)

[xyz]

@weab00 do you think Ebselen will be good for hyperacusis? If yes, why?

I think @FGG already linked this paper somewhere in this thread.

A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus

So at least it could treat hyperacusis in mice.

 

[Sam99]

Is it required that stock Ebselen powder is dissolved in pure DMSO and then injected, instead of just taking the powder orally?

 

[FGG]

Is it required that stock Ebselen powder is dissolved in pure DMSO and then injected, instead of just taking the powder orally?

Absolutely not. It has unusually good penetrance across the blood/cochlear barrier.

 

[Aaron91]

I think @FGG already linked this paper somewhere in this thread.

A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus

So at least it could treat hyperacusis in mice.

Amazing find. Is anyone with hyperacusis thinking of ordering this from a lab?

 

[FGG]

Amazing find. Is anyone with hyperacusis thinking of ordering this from a lab?

Just to clarify, this paper concerns acute loudness hyperacusis, not noxacusis.

Though some here have speculated that it may help some of the inflammatory portion contributing to the ATP leakage. Keep in mind, if it does help with that, it likely won't be quickly imo as the fibers are still sensitized.

 

[Aaron91]

Just to clarify, this paper concerns acute loudness hyperacusis, not noxacusis.

@FGG I hope you don't mind if I press you on how we know this for sure, as the study doesn't seem to distinguish between the two different types.

Is it not possible the mice in the study had both loudness hyperacusis and noxacusis? If I've understood the paper correctly, the method of testing for hyperacusis (presumably loudness) in the mice was examining whether the threshold for invoking a startle response had lowered. Is it not possible then that the mice had both: a reduced startle response (loudness hyperacusis) and pain (noxacusis?). Speaking personally and of course anecdotally, I have both - as do many others on here.

Obviously, in this study, Ebselen showed a resolution in this lower threshold startle response, so my takeaway is that they had no way of measuring whether pain hyperacusis had also resolved. That doesn't mean of course Ebselen didn't help resolve the pain (if present) through whatever mechanism that may be?

 

[FGG]

@FGG I hope you don't mind if I press you on how we know this for sure, as the study doesn't seem to distinguish between the two different types.

Is it not possible the mice in the study had both loudness hyperacusis and noxacusis? If I've understood the paper correctly, the method of testing for hyperacusis (presumably loudness) in the mice was examining whether the threshold for invoking a startle response had lowered. Is it not possible then that the mice had both: a reduced startle response (loudness hyperacusis) and pain (noxacusis?). Speaking personally and of course anecdotally, I have both - as do many others on here.

Obviously, in this study, Ebselen showed a resolution in this lower threshold startle response, so my takeaway is that they had no way of measuring whether pain hyperacusis had also resolved. That doesn't mean of course Ebselen didn't help resolve the pain (if present) through whatever mechanism that may be?

Sure, I don't mind.

They are talking about loudness hyperacusis because they refer to central sensitization, not sensitization of the type 2 fibers (as in noxacusis).

 

[Aaron91]

Sure, I don't mind.

They are talking about loudness hyperacusis because they refer to central sensitization, not sensitization of the type 2 fibers (as in noxacusis).

@FGG Ok, so my understanding is that they found an increased ABR wave III/1 ratio, which to your point suggests they are indeed seeing central sensitisation, or increased centralised activity. But they also follow that statement up with the following:

"This evidence suggests that the amikacin treatment model could be a good candidate for studying temporary central gain increases due to peripheral inflammation".

So unless I'm reading this wrong, my understanding is that we have a peripheral issue potentially causing a central gain issue (loudness hyperacusis). It is also my understanding that the central gain issue (loudness) is treated through treating the peripheral issue (the cochlea). I understand that the type II sensitisation theory suggests a different mechanism entirely for pain (ATP leakage), but then I see this quote from this same study:

"However, it is uncertain if the behavioral manifestations of hyperacusis/tinnitus seen in this study are caused by peripheral or central inflammation (Fuentes-Santamaría et al., 2017; Wang et al., 2019). We hypothesize that AGs lead to inflammation of the auditory nerve fibers resulting in hyperactivity, which may ascend through the central auditory pathway"

So there's two things here. Firstly, my interpretation of "behavioural manifestions" relating to hyperacusis is the reduced startle reflex they saw in these mice. So although they have the ABR wave measurement as an indicator of centralised gain, they do seem to be unsure as to whether the difference in the startle response is due to this centralised gain (central inflammation) at all. Is it not then possible that peripheral inflammation, in the context of this sentence, alludes to some kind of pain hyperacusis, especially given that it then refers to inflammation of the auditory nerve fibres in the next sentence? So I come back to my original question: how do we know the mice did not have both loudness and pain hyperacusis, and how do we know the change in the mice's behaviour wasn't down to a change in peripheral inflammation and as you suggested, a change in the inflammatory processes contributing to the ATP leakage?

It has occured to me that they may be referring to the type I auditory nerve fibres only, which I guess would make sense given that these are the fibres that carry sound information. But even if this is the case, I would be surprised if there was inflammation present in only one type of fibre and not the other. Assuming that this quote is referring to the type I AND/OR type II fibres, is it not possible that Ebselen could help with both loudness and pain hyperacusis, given that they both start (and in the latter case, remain) as peripheral issues?

 

[FGG]

@FGG Ok, so my understanding is that they found an increased ABR wave III/1 ratio, which to your point suggests they are indeed seeing central sensitisation, or increased centralised activity. But they also follow that statement up with the following:

"This evidence suggests that the amikacin treatment model could be a good candidate for studying temporary central gain increases due to peripheral inflammation".

So unless I'm reading this wrong, my understanding is that we have a peripheral issue potentially causing a central gain issue (loudness hyperacusis). It is also my understanding that the central gain issue (loudness) is treated through treating the peripheral issue (the cochlea). I understand that the type II sensitisation theory suggests a different mechanism entirely for pain (ATP leakage), but then I see this quote from this same study:

"However, it is uncertain if the behavioral manifestations of hyperacusis/tinnitus seen in this study are caused by peripheral or central inflammation (Fuentes-Santamaría et al., 2017; Wang et al., 2019). We hypothesize that AGs lead to inflammation of the auditory nerve fibers resulting in hyperactivity, which may ascend through the central auditory pathway"

So there's two things here. Firstly, my interpretation of "behavioural manifestions" relating to hyperacusis is the reduced startle reflex they saw in these mice. So although they have the ABR wave measurement as an indicator of centralised gain, they do seem to be unsure as to whether the difference in the startle response is due to this centralised gain (central inflammation) at all. Is it not then possible that peripheral inflammation, in the context of this sentence, alludes to some kind of pain hyperacusis, especially given that it then refers to inflammation of the auditory nerve fibres in the next sentence? So I come back to my original question: how do we know the mice did not have both loudness and pain hyperacusis, and how do we know the change in the mice's behaviour wasn't down to a change in peripheral inflammation and as you suggested, a change in the inflammatory processes contributing to the ATP leakage?

It has occured to me that they may be referring to the type I auditory nerve fibres only, which I guess would make sense given that these are the fibres that carry sound information. But even if this is the case, I would be surprised if there was inflammation present in only one type of fibre and not the other. Assuming that this quote is referring to the type I AND/OR type II fibres, is it not possible that Ebselen could help with both loudness and pain hyperacusis, given that they both start (and in the latter case, remain) as peripheral issues?

I agree and made that point before that inflammatory processes are involved in noxacusis generation, too. My question is and has always been: what happens to nerve fiber sensitization once the inflammation is reduced or removed?

I am hopeful that eventually (this will very likely not be instantaneous imo) the fibers can be desensitized again.

In any case, that has nothing to do with the posted study and I just wanted to make that clear.

 

[serendipity1996]

@FGG Ok, so my understanding is that they found an increased ABR wave III/1 ratio, which to your point suggests they are indeed seeing central sensitisation, or increased centralised activity. But they also follow that statement up with the following:

"This evidence suggests that the amikacin treatment model could be a good candidate for studying temporary central gain increases due to peripheral inflammation".

So unless I'm reading this wrong, my understanding is that we have a peripheral issue potentially causing a central gain issue (loudness hyperacusis). It is also my understanding that the central gain issue (loudness) is treated through treating the peripheral issue (the cochlea). I understand that the type II sensitisation theory suggests a different mechanism entirely for pain (ATP leakage), but then I see this quote from this same study:

"However, it is uncertain if the behavioral manifestations of hyperacusis/tinnitus seen in this study are caused by peripheral or central inflammation (Fuentes-Santamaría et al., 2017; Wang et al., 2019). We hypothesize that AGs lead to inflammation of the auditory nerve fibers resulting in hyperactivity, which may ascend through the central auditory pathway"

So there's two things here. Firstly, my interpretation of "behavioural manifestions" relating to hyperacusis is the reduced startle reflex they saw in these mice. So although they have the ABR wave measurement as an indicator of centralised gain, they do seem to be unsure as to whether the difference in the startle response is due to this centralised gain (central inflammation) at all. Is it not then possible that peripheral inflammation, in the context of this sentence, alludes to some kind of pain hyperacusis, especially given that it then refers to inflammation of the auditory nerve fibres in the next sentence? So I come back to my original question: how do we know the mice did not have both loudness and pain hyperacusis, and how do we know the change in the mice's behaviour wasn't down to a change in peripheral inflammation and as you suggested, a change in the inflammatory processes contributing to the ATP leakage?

It has occured to me that they may be referring to the type I auditory nerve fibres only, which I guess would make sense given that these are the fibres that carry sound information. But even if this is the case, I would be surprised if there was inflammation present in only one type of fibre and not the other. Assuming that this quote is referring to the type I AND/OR type II fibres, is it not possible that Ebselen could help with both loudness and pain hyperacusis, given that they both start (and in the latter case, remain) as peripheral issues?

This reminds me of something that Liberman remarked upon from an interview in 2019.

"A challenge in pursuing these ideas is to develop an animal model of pain hyperacusis. I believe that pain hyperacusis, which can be very long-lasting, is fundamentally different from annoyance hyperacusis, where the discomfort ends when the stimulus ends, and it will be difficult to distinguish these two types of hyperacusis in an animal model."

In conversation with Professor Charles Liberman

Would be keen to hear about whether they are developing animal models - I wonder if the Fuchs lab is working on this and how researchers to plan to ascertain this.

 

[Aaron91]

I agree and made that point before that inflammatory processes are involved in noxacusis generation, too. My question is and has always been: what happens to nerve fiber sensitization once the inflammation is reduced or removed?

Do we have any examples from injuries to other parts of the body that could give us any clues here? I recall @serendipity1996 making the point that patients with chronic hip pain, regardless of how long they had it and how bad it was, seeing their pain resolve/improve after a hip replacement. So this would seem to be a case of centralised pain resolving from treatment to the peripheral area, but it's unclear to me whether this example is transferable to what's happening in the cochlea with the type II fibres, assuming that noxacusis is peripheral in nature only. Perhaps this specific example is more applicable to loudness hyperacusis, but in any case I'd still like to know if there's an example we can glean from with regards to noxacusis.

This reminds me of something that Liberman remarked upon from an interview in 2019.

"A challenge in pursuing these ideas is to develop an animal model of pain hyperacusis. I believe that pain hyperacusis, which can be very long-lasting, is fundamentally different from annoyance hyperacusis, where the discomfort ends when the stimulus ends, and it will be difficult to distinguish these two types of hyperacusis in an animal model."

In conversation with Professor Charles Liberman

Would be keen to hear about whether they are developing animal models - I wonder if the Fuchs lab is working on this and how researchers to plan to ascertain this.

Thanks for sharing, and this is what I was trying to get at although I think I wasn't getting the message across very well, which is: just because we are looking at one type of hyperacusis in an animal study (such as the one above), how do we know the other type of hyperacusis isn't also present (and potentially being treated) as well? As far as I understand it, the latest models we have to explain hyperacusis, as convincing as I find them, are still just that: models. So I completely agree: if we are to roll with these models for what they are, we need to be able to distinguish between them in a lab setting.

 

[FGG]

Do we have any examples from injuries to other parts of the body that could give us any clues here? I recall @serendipity1996 making the point that patients with chronic hip pain, regardless of how long they had it and how bad it was, seeing their pain resolve/improve after a hip replacement. So this would seem to be a case of centralised pain resolving from treatment to the peripheral area, but it's unclear to me whether this example is transferable to what's happening in the cochlea with the type II fibres, assuming that noxacusis is peripheral in nature only. Perhaps this specific example is more applicable to loudness hyperacusis, but in any case I'd still like to know if there's an example we can glean from with regards to noxacusis.

Thanks for sharing, and this is what I was trying to get at although I think I wasn't getting the message across very well, which is: just because we are looking at one type of hyperacusis in an animal study (such as the one above), how do we know the other type of hyperacusis isn't also present (and potentially being treated) as well? As far as I understand it, the latest models we have to explain hyperacusis, as convincing as I find them, are still just that: models. So I completely agree: if we are to roll with these models for what they are, we need to be able to distinguish between them in a lab setting.

The only one I could come up with last time was fibromyalgia. In those cases, the pain remains even after the stimulus is removed.

However, I wonder if there are undiagnosed ongoing conditions in many if not all of those cases (eg. viral) that perpetuate the inflammation rather than it just being a central issue.

 

[Marin]

Amazing find. Is anyone with hyperacusis thinking of ordering this from a lab?

I definitely have thought about it. I assume that it is similar to steroids; the sooner you reduce the inflammation, the better, and waiting for this to come out in a year or two seems like FOREVER.

Want to split a batch? I'm only kind of joking around...

 

[Aaron91]

I definitely have thought about it. I assume that it is similar to steroids; the sooner you reduce the inflammation, the better, and waiting for this to come out in a year or two seems like FOREVER.

Want to split a batch? I'm only kind of joking around...

Even if I had the funds to do it I'm not sure if I could bring myself to take it without knowing the full extent of the side effects and/or some kind of medical supervision. I rarely take a supplement without doing research first.

Having said all this, I've had a really bad setback with my hyperacusis this week and I'm in a lot of pain. It's taken me 8 months to come to terms with everything I've lost already, but to have this chronic pain on top of it all, even when in silence, is becoming unbearable. So if this continues and a Chinese lab was a viable source I'd certainly consider it...

 

[weab00]

The clinical trial page says 200 mg Ebselen twice daily. Does that mean 2 doses of 100 mg or 2 doses of 200 mg?

In any case it will set you back either $3,430 or double that for a one week course at low dosage--assuming the Alibaba lab is legit. If only I had that kind of money to burn.

 

[FGG]

Even if I had the funds to do it I'm not sure if I could bring myself to take it without knowing the full extent of the side effects and/or some kind of medical supervision. I rarely take a supplement without doing research first.

Having said all this, I've had a really bad setback with my hyperacusis this week and I'm in a lot of pain. It's taken me 8 months to come to terms with everything I've lost already, but to have this chronic pain on top of it all, even when in silence, is becoming unbearable. So if this continues and a Chinese lab was a viable source I'd certainly consider it...

You can have this made in US labs. I found like 5 with a quick Google search (though I can't vouch for any specifically, they seemed like authentic labs).

 

[Marin]

Even if I had the funds to do it I'm not sure if I could bring myself to take it without knowing the full extent of the side effects and/or some kind of medical supervision. I rarely take a supplement without doing research first.

Having said all this, I've had a really bad setback with my hyperacusis this week and I'm in a lot of pain. It's taken me 8 months to come to terms with everything I've lost already, but to have this chronic pain on top of it all, even when in silence, is becoming unbearable. So if this continues and a Chinese lab was a viable source I'd certainly consider it...

I am very sorry to hear about your setback, and completely understand where you are coming from. Prior to hyperacusis I never took medication and I was very careful about what supplements I took. I still carefully research supplements before I take them for hyperacusis. Having chronic pain in silence for months now that can reach unbearable levels has made me consider things I never thought I'd do... I hope your setback improves soon.

 

[vttbx]

The clinical trial page says 200 mg Ebselen twice daily. Does that mean 2 doses of 100 mg or 2 doses of 200 mg?

In any case it will set you back either $3,430 or double that for a one week course at low dosage--assuming the Alibaba lab is legit. If only I had that kind of money to burn.

I found it here for $59.99, but it's out of stock.

https://science.bio/product/ebselen-powder/

 

[Aaron91]

My question is and has always been: what happens to nerve fiber sensitization once the inflammation is reduced or removed?

It's a million dollar question. For what it's worth, I came across this today on hyperacusis research. I'm sure I've read it before but I didn't make a mental note of it at the time. It's from the section about the ATP leakage theory:

"This may tie in with our emerging understanding of neuropathic pain and the maintenance of chronic pain generally: When nociceptors are damaged or situated in a chronically inflamed local environment, they participate in positive-feedback loops that maintain nociceptive sensitivity (as described below)."

You can have this made in US labs. I found like 5 with a quick Google search (though I can't vouch for any specifically, they seemed like authentic labs).

I'm EU based so I'm not too sure what kind of import duties I'd be looking at, or whether the drug could be compromised during transit due to bad temperatures etc if I got it from the US.

I found it here for $59.99, but it's out of stock.

https://science.bio/product/ebselen-powder/

Damn, that's enough for 2.5 days. There are other labs charging the same amount for 25mg, so that's pretty affordable compared to many of the other labs out there. How come the price varies so much?

 

[Joly]

So there are no solutions for someone who suffers from noxacusis?

 

[weab00]

I found it here for $59.99, but it's out of stock.

https://science.bio/product/ebselen-powder/

This I could swing. I wonder if it's just as good as the more expensive stuff. I will put myself on the email least in any case.

They're both above 98% purity.

However, "Terms: This material is sold for laboratory research use only. Terms of sale apply. Not for human consumption, nor medical, veterinary, or household uses. Please familiarize yourself with our Terms & Conditions prior to ordering."

So maybe they are so cheap because they sell to researchers only.

 

[AfroSnowman]

This I could swing. I wonder if it's just as good as the more expensive stuff. I will put myself on the email least in any case.

They're both above 98% purity.

However, "Terms: This material is sold for laboratory research use only. Terms of sale apply. Not for human consumption, nor medical, veterinary, or household uses. Please familiarize yourself with our Terms & Conditions prior to ordering."

So maybe they are so cheap because they sell to researchers only.

There might also be quality control differences between this and medical grade.

 

[weab00]

There might also be quality control differences between this and medical grade.

Less quality control for the science.bio one? They seem reputable.

 

[AfroSnowman]

Less quality control for the science.bio one? They seem reputable.

Maybe. I assume that the liability/damages for an impure drug harming someone's health or killing someone would be much higher than messing up an experiment but perhaps it makes no difference.

 

[vttbx]

This I could swing. I wonder if it's just as good as the more expensive stuff. I will put myself on the email least in any case.

They're both above 98% purity.

However, "Terms: This material is sold for laboratory research use only. Terms of sale apply. Not for human consumption, nor medical, veterinary, or household uses. Please familiarize yourself with our Terms & Conditions prior to ordering."

So maybe they are so cheap because they sell to researchers only.

I emailed their customer service. Here is their response:

I'm afraid we have no plans of restocking Ebselen at the moment. For anything else, please let me know!

 

[weab00]

I emailed their customer service. Here is their response:

I'm afraid we have no plans of restocking Ebselen at the moment. For anything else, please let me know!

Welp, fuck.

 

[HootOwl]

Sorry guys, this is late inbound but I wanted to post these ever since @FGG sent me Fuad Lechin's neuro circuitry book.

Here are his before and after pics for various conditions that had a large inflammation component, which he treated over various lengths of time.

This is to show how damaging inflammation can be in an uncoping stress immune profile, and with proper anti-inflammatory treatment you can see near resolution or complete resolution of symptoms. Lechin's is just a hyper specialized form of this.

It's hard to believe the inner ear would be an exception.

 

[__nico__]

Can someone provide me with a link to purchase a week's course of Ebselen that isn't out of stock? I have money to burn and I literally do not care about side effects.

There are other labs charging the same amount for 25mg, so that's pretty affordable compared to many of the other labs out there.

Could you provide a link for those "other labs"? I'm desperate enough to try Ebselen. I've got nothing to lose and I'm sure it would benefit the forum if I took this chance.

 

[iGL0CK]

Can someone provide me with a link to purchase a week's course of Ebselen that isn't out of stock? I have money to burn and I literally do not care about side effects.

Could you provide a link for those "other labs"? I'm desperate enough to try Ebselen. I've got nothing to lose and I'm sure it would benefit the forum if I took this chance.

Where are you from? It's possible to buy Ebselen in Poland but delivery is only available around the Europe. I know nothing about chemistry, so you have to check if it's exactly the same thing you're looking for.

It's about $240 for 25 mg.

Here's the link:
https://pol-aura.pl/ebselen-980-60940-34-3-p-6813.html

 

[FGG]

Can someone provide me with a link to purchase a week's course of Ebselen that isn't out of stock? I have money to burn and I literally do not care about side effects.

Could you provide a link for those "other labs"? I'm desperate enough to try Ebselen. I've got nothing to lose and I'm sure it would benefit the forum if I took this chance.

Has anyone tried applying for Compassionate Use? That would eliminate the question of purity from the labs.