Sound Pharmaceuticals (SPI-5557 & SPI-1005)

[GBB]

I've asked a similar question before but now I have reason to revisit. I took 60 mg Prednisone a few hours ago and after fleeting tinnitus, all my most piercing strong tones are temporarily gone.

Is it conceivable that I could achieve the same effect with Sound Pharmaceuticals' cochlear inflammation drug? I'm in HEAVEN - the remaining sounds are still loud but they have no force to them. I fully expect this will stop when I taper off the Prednisone, but my god, it's wonderful...

 

[GBB]

I don't think so at all. They have very different mechanisms of action. If you have inflammation from immune cell recruitment and volume/pressure expansion Prednisone is more likely to help. SPI-1005 is better for glutamate hyperexcitabilty, oxidative stress etc.

Also, oral steroids don't have great cochlear penetrance (SPI-1005 is unique for an oral med in that it does) and intratympanic steroids apparently have a polarity problem which makes their cochlear penetrance highly variable.

In addition, inflammation is incredibly complex even when the cause is more clear. I can give you a veterinary example of what I mean:

IMHA is a condition in dogs (and cats) where the immune system destroys their red blood cells causing a severe anemia that may result in blood transfusions and death if not treated.

Some dogs respond to Prednisone others have no response and need Cyclosporine or Mycophenolate. This is despite the fact that the disease involves similar auto immunity and inflammation in each set of dogs.

So just to clarify, for those of us who do get tinnitus relief from Prednisone, this would likely have no crossover utility? Thanks!

 

[FGG]

So just to clarify, for those of us who do get tinnitus relief from Prednisone, this would likely have no crossover utility? Thanks!

IMO Prednisone response has little to no bearing on whether or not this would help but it may be a good additional treatment.

 

[weab00]

IMO Prednisone response has little to no bearing on whether or not this would help but it may be a good additional treatment.

Where are your expectations at with regards to hyperacusis for this drug?

 

[FGG]

Where are your expectations at with regards to hyperacusis for this drug?

You mean Noxacusis right? Using them interchangeably adds to a lot of confusion on this thread.

Truthfully, I don't know. There are so many factors. But I think the more drugs in the arsenal, the better. I think it's a beatable problem, the question is what drug or drugs will be the key.

 

[weab00]

You mean Noxacusis right? Using them interchangeably adds to a lot of confusion on this thread.

Truthfully, I don't know. There are so many factors. But I think the more drugs in the arsenal, the better. I think it's a beatable problem, the question is what drug or drugs will be the key.

Yes, noxacusis. I hope it can help with pain if pain hyperacusis is associated with inflammation.

 

[100Hz]

So, if I am understanding the description here correctly, it could mean that it might take only 1 OHC being reconnected to the "pool" of Type-2 nerves to begin resolving hyperacusis/noxacusis?

Since the nerve seems to only become over-sensitized from the entire "pool" of OHC dying, then doesn't it stand to reason that restoring connection to at least one through regeneration, and thereby providing a "signal" would provide notable treatment?

This is one of the big questions (is the type II sensitization permanent regardless of what now gets fixed) and why I always end up going full circle through the possible treatments and ending up back at RL-81 and XEN as a catch-all in case it is.

Whether or not sensitization is recoverable or takes the effect of a permanent on switch will no doubt be discovered once we can start taking the drugs, but in the meantime the questions I really hope Paul Fuchs / John Hopkins can uncover answers to are, do these remain permanently sensitized or not? And where exactly does excess ATP come from, is it just support cells, or from Gap junction / connexions, anywhere else etc. upon exposure to noise (in other words the locations responsible for the setback flood when it reaches that critical level).

 

[serendipity1996]

This is one of the big questions (is the type II sensitization permanent regardless of what now gets fixed) and why I always end up going full circle through the possible treatments and ending up back at RL-81 and XEN as a catch-all in case it is.

Whether or not sensitization is recoverable or takes the effect of a permanent on switch will no doubt be discovered once we can start taking the drugs, but in the meantime the questions I really hope Paul Fuchs / John Hopkins can uncover answers to are, do these remain permanently sensitized or not? And where exactly does excess ATP come from, is it just support cells, or from Gap junction / connexions, anywhere else etc. upon exposure to noise (in other words the locations responsible for the setback flood when it reaches that critical level).

I wonder if there are any other conditions we could look to that could possibly shed light on this - conditions where some type of peripheral sensitisation occurs following trauma/injury and what the prognosis is - I'm no scientist by any means though so not sure where to begin lol.

 

[FGG]

I wonder if there are any other conditions we could look to that could possibly shed light on this - conditions where some type of peripheral sensitisation occurs following trauma/injury and what the prognosis is - I'm no scientist by any means though so not sure where to begin lol.

Warning this is a lot of speculation and it may or not be comparable:

Fibromyalgia is similar in that it involves nerve sensitization. And one of the reasons that I'm hopeful for Sound Pharmaceuticals' drug is hyperexcitability through Glutamate is one of the co-factors of this sensitization:

Sensitization, glutamate, and the link between migraine and fibromyalgia

However, fibromyalgia seems to involve a lot more central sensitization.

But what's interesting to me is that the purine receptors seem involved in fibromyalgia peripheral pain too.

Physiological Process of Peripheral Sensitization

Back to Glutamate, though. Glutamate is involved in chronic peripheral pain and sensitization too not just centrally:

Emerging Trends in Pain Modulation by Metabotropic Glutamate Receptors

Unfortunately, Glutamate blocking drugs can have negative motor and cognitive affects so there are some concerns with using systemic Glutamate blockers for pain.

Sound Pharmaceuticals' drug is different in that it doesn't block Glutamate receptors but can dampen hyperexcitabilty which makes it really promising (and so far has passed safety in two studies).

Is it the answer? I don't know but I think it shows promise.

 

[Croaker]

Warning this is a lot of speculation and it may or not be comparable:

Fibromyalgia is similar in that it involves nerve sensitization. And one of the reasons that I'm hopeful for Sound Pharmaceuticals' drug is hyperexcitability through Glutamate is one of the co-factors of this sensitization:

Sensitization, glutamate, and the link between migraine and fibromyalgia

However, fibromyalgia seems to involve a lot more central sensitization.

But what's interesting to me is that the purine receptors seem involved in fibromyalgia peripheral pain too.

Physiological Process of Peripheral Sensitization

Back to Glutamate, though. Glutamate is involved in chronic peripheral pain and sensitization too not just centrally:

Emerging Trends in Pain Modulation by Metabotropic Glutamate Receptors

Unfortunately, Glutamate blocking drugs can have negative motor and cognitive affects so there are some concerns with using systemic Glutamate blockers for pain.

Sound Pharmaceuticals' drug is different in that it doesn't block Glutamate receptors but can dampen hyperexcitabilty which makes it really promising (and so far has passed safety in two studies).

Is it the answer? I don't know but I think it shows promise.

Thanks for doing research on something that isn't your problem. Do you (or anyone) have an opinion on whether ebselen's ability to treat toxin-induced hyperacusis in mice has any relevance to hyperacusis caused by acoustic trauma? My impression is that the damage is often similar, seeing as most companies are testing their drugs on many forms of hearing loss regardless of the cause, rather than specifically saying Drug X is only for presbycusis or damage from chemotherapy. Perhaps, while it won't restore your hearing, this might aid in some of your symptoms?

Here is the paper I'm referring to:

A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus

 

[100Hz]

I wonder if there are any other conditions we could look to that could possibly shed light on this - conditions where some type of peripheral sensitisation occurs following trauma/injury and what the prognosis is - I'm no scientist by any means though so not sure where to begin lol.

@100HzWhat I mean by a progressive is a condition whereby the hyperacusis starts off mildly but gradually and steadily gets noticeably worse over time until the point of complete despair. I think for almost most people, including myself (despite my observation above), we go from complete normality to absolute devastation in an instant.

I wonder if also, an acoustic shock symptoms cluster and the damage it leaves behind could be relative to both these points above. As interrelated as the mid ear and cochlea pathology seem to be in noxacusis, they still appear to be fundamentally separate pathologies. Is a sensitized trigeminal nerve another example of sensitization that does not recover? As sure as it is that certain frequencies and levels of noise will trigger a setback long after apparent recovery (cochlea type II's presumably), just as certain is that this will have a secondary effect of re-igniting the trigeminal nerve related areas of pain for those with a sensitized trigeminal nerve (middle ear). Unless it takes a ridiculously long period of time to recover (I think you'd need to be talking multiple years) I would say the trigeminal nerve does not recover either once sensitized.

'In summary the nocioceptor terminals become more sensitive to the same quantity of the chemical mediators.' - this was quoted in one of your links above @FGG. I wonder when it comes to reading about sensitivity in its various forms, could it be talking about 3 potentially different states of sensitivity. Firstly a state where sensitivity is variable and can reduce as well as increase, secondly a state where sensitivity notches up but then does not go back down again, and finally a full on maxed out permanently 'sensitized' state?

And for your point @Aaron91, from my own experience, I followed a similar pattern of slowly worsening in terms of tinnitus spikes, and particularly ear fatigue in the beginning. My switch to 'absolute devastation in an instant' as you put it came the moment of the acoustic shock. Whether the shock was the catalyst that sparked the full on noxacusis, or a separate albeit linked (by the noise assault) thing to what was already going on in my inner ear it seemed to be the significant turning point in the life changing-ly severe worsening of symptoms. I know this is where it gets murky because lots of people don't necessarily get an acoustic shock or maybe even know they've suffered one, but, what if they'd already sensitized their trigeminal nerve previously (I consider this sensitization to be the lasting legacy of an acoustic shock), even years before hand due to some other cause like an ear infection etc.? It could be sitting there dormant but primed for re-stimulation due to a setback thanks to the newly damaged cochlea.

 

[Aaron91]

Warning this is a lot of speculation and it may or not be comparable:

Fibromyalgia is similar in that it involves nerve sensitization. And one of the reasons that I'm hopeful for Sound Pharmaceuticals' drug is hyperexcitability through Glutamate is one of the co-factors of this sensitization:

Sensitization, glutamate, and the link between migraine and fibromyalgia

However, fibromyalgia seems to involve a lot more central sensitization.

But what's interesting to me is that the purine receptors seem involved in fibromyalgia peripheral pain too.

Physiological Process of Peripheral Sensitization

Back to Glutamate, though. Glutamate is involved in chronic peripheral pain and sensitization too not just centrally:

Emerging Trends in Pain Modulation by Metabotropic Glutamate Receptors

Unfortunately, Glutamate blocking drugs can have negative motor and cognitive affects so there are some concerns with using systemic Glutamate blockers for pain.

Sound Pharmaceuticals' drug is different in that it doesn't block Glutamate receptors but can dampen hyperexcitabilty which makes it really promising (and so far has passed safety in two studies).

Is it the answer? I don't know but I think it shows promise.

Really interesting @FGG. What I'd be curious to know then is, assuming a drug like this could work for us hyperacusis sufferers by dampening hyperexcitability, is this something we would only have to take once or a short course of, or would we probably have to be on it for life? Or would it be like other peripheral injuries? Perhaps this is a bad analogy, but for example, we might take some Ibuprofen/Paracetomol after spraining our ankle to help deal with the pain until it heals - the only difference being that the capacity of the cochlea to heal is limited/unknown. Not just that, but not all ankle injuries recover...

 

[FGG]

Thanks for doing research on something that isn't your problem. Do you (or anyone) have an opinion on whether ebselen's ability to treat toxin-induced hyperacusis in mice has any relevance to hyperacusis caused by acoustic trauma? My impression is that the damage is often similar, seeing as most companies are testing their drugs on many forms of hearing loss regardless of the cause, rather than specifically saying Drug X is only for presbycusis or damage from chemotherapy. Perhaps, while it won't restore your hearing, this might aid in some of your symptoms?

Here is the paper I'm referring to:

A Novel Mouse Model of Aminoglycoside-Induced Hyperacusis and Tinnitus

I believe this paper is referring to loudness hyperacusis and not noxacusis.

But I have talked to someone who had noxacusis after oral Neomycin so I'm sure it happens occasionally and I suspect would require similar treatments (though Aminoglycosides destroy way more hair cells and even synapses than noise, so I'm sure regenerative medicine would be even more helpful here).

 

[Aaron91]

Warning this is a lot of speculation and it may or not be comparable:

Fibromyalgia is similar in that it involves nerve sensitization. And one of the reasons that I'm hopeful for Sound Pharmaceuticals' drug is hyperexcitability through Glutamate is one of the co-factors of this sensitization:

Sensitization, glutamate, and the link between migraine and fibromyalgia

However, fibromyalgia seems to involve a lot more central sensitization.

But what's interesting to me is that the purine receptors seem involved in fibromyalgia peripheral pain too.

Physiological Process of Peripheral Sensitization

Back to Glutamate, though. Glutamate is involved in chronic peripheral pain and sensitization too not just centrally:

Emerging Trends in Pain Modulation by Metabotropic Glutamate Receptors

Unfortunately, Glutamate blocking drugs can have negative motor and cognitive affects so there are some concerns with using systemic Glutamate blockers for pain.

Sound Pharmaceuticals' drug is different in that it doesn't block Glutamate receptors but can dampen hyperexcitabilty which makes it really promising (and so far has passed safety in two studies).

Is it the answer? I don't know but I think it shows promise.

Just to follow up on this, I started taking Lion's Mane a couple of days ago as part of my own protocol because I read that it can help with neurogenesis and neuroinflammation. I already feel a bit sharper and my mood has been lifted, but as always it could just be placebo.

But more importantly: I'm now reading that Lion's Mane can also attenuate glutamic acid! Apparently it can take a few months to really see the full effects of Lion's Mane, so I'll be really interested to see whether this has any effect on my hyperacusis or not in the coming months.

 

[FGG]

Just to follow up on this, I started taking Lion's Mane a couple of days ago as part of my own protocol because I read that it can help with neurogenesis and neuroinflammation. I already feel a bit sharper and my mood has been lifted, but as always it could just be placebo.

But more importantly: I'm now reading that Lion's Mane can also attenuate glutamic acid! Apparently it can take a few months to really see the full effects of Lion's Mane, so I'll be really interested to see whether this has any effect on my hyperacusis or not in the coming months.

Does it cross the blood cochlea layer?

 

[Aaron91]

Does it cross the blood cochlea layer?

As in the blood-labyrinth barrier? I have no idea, but apparently the active ingredients in Lion's Mane - hericenones and erinacines - have a low molecular weight, so they can easily cross the blood-brain barrier and stimulate NGF synthesis directly in the brain.

Whether this means they can also cross the blood-cochlea layer I have no idea. Any way we can find out?

Edit: I do remember reading some time ago that if something can't pass through the blood-labyrinth barrier, at least not in big quantities, you could in theory get something through the barrier provided you took it for a long enough time systemically. Again though, I have no idea how accurate or true this is.

 

[FGG]

As in the blood-labyrinth barrier? I have no idea, but apparently the active ingredients in Lion's Mane - hericenones and erinacines - have a low molecular weight, so they can easily cross the blood-brain barrier and stimulate NGF synthesis directly in the brain.

Whether this means they can also cross the blood-cochlea layer I have no idea. Any way we can find out?

Edit: I do remember reading some time ago that if something can't pass through the blood-labyrinth barrier, at least not in big quantities, you could in theory get something through the barrier provided you took it for a long enough time systemically. Again though, I have no idea how accurate or true this is.

Well, report back if it helps (there is a Lion's Mane thread as I recall). I don't think there was overwhelming response but it might be a good adjunctive supplement to try for some people.

 

[wwtsai]

Sound Pharmaceuticals modified the estimated start and completion dates for their two Phase 2 COVID-19 clinical trials from August and December 2020 to December 2020 and April 2021, respectively. That's a bit unfortunate, but hopefully they can still use these trials to expedite getting SPI-1005 to the market.

See: https://clinicaltrials.gov/ct2/show/NCT04484025

 

[Croaker]

Sound Pharmaceuticals modified the estimated start and completion dates for their two Phase 2 COVID-19 clinical trials from August and December 2020 to December 2020 and April 2021, respectively. That's a bit unfortunate, but hopefully they can still use these trials to expedite getting SPI-1005 to the market.

See: https://clinicaltrials.gov/ct2/show/NCT04484025

 

[weab00]

Sound Pharmaceuticals modified the estimated start and completion dates for their two Phase 2 COVID-19 clinical trials from August and December 2020 to December 2020 and April 2021, respectively. That's a bit unfortunate, but hopefully they can still use these trials to expedite getting SPI-1005 to the market.

See: https://clinicaltrials.gov/ct2/show/NCT04484025

Why

 

[TrevorSanders]

Sound Pharmaceuticals modified the estimated start and completion dates for their two Phase 2 COVID-19 clinical trials from August and December 2020 to December 2020 and April 2021, respectively. That's a bit unfortunate, but hopefully they can still use these trials to expedite getting SPI-1005 to the market.

See: https://clinicaltrials.gov/ct2/show/NCT04484025

There is always a delay, jesus fucking christ.

 

[wwtsai]

Why

There is always a delay, jesus fucking christ.

It's frustrating. I wish we could get something now to at least tide us over until we have more comprehensive treatments.

 

[FGG]

It's frustrating. I wish we could get something now to at least tide us over until we have more comprehensive treatments.

You can buy it now if you are willing to be a guinea pig and also have a few thousand dollars to spare. Like the Hough pill, labs can synthesize this and sell it for "research purposes." A quick 2 minute search turned up two such labs.

Of course, I think it's better to have phase 3 data, but if anyone feels that they truly can't wait a few more months, that is an option.

Of course, you would want to buy extra and have it tested at an outside lab for purity first *and* I would caution people against this route unless they are being sincere and it is this or suicide.

 

[Mentos]

You can buy it now if you are willing to be a guinea pig and also have a few thousand dollars to spare. Like the Hough pill, labs can synthesize this and sell it for "research purposes." A quick 2 minute search turned up two such labs.

Of course, I think it's better to have phase 3 data, but if anyone feels that they truly can't wait a few more months, that is an option.

Of course, you would want to buy extra and have it tested at an outside lab for purity first *and* I would caution people against this route unless they are being sincere and it is this or suicide.

Are you sure the Hough Ear Institute Pill could be synthetized? I haven't seen that info before.

 

[GBB]

Are you sure the Hough Ear Institute Pill could be synthetized? I haven't seen that info before.

The substance can be synthesized but as to how much to dose and for how long, no one has any idea. The patent provides a milligram dosage range that is comically obtuse.

 

[FGG]

The substance can be synthesized but as to how much to dose and for how long, no one has any idea. The patent provides a milligram dosage range that is comically obtuse.

Yes. It's easier with Ebselen though. The ClinicalTrials page has dosing and it's common (or rather not uncommon or hard to find) to find labs that will make it.

 

[weab00]

Let's pray there are no more delays after this and it can come out before 2022.

 

[Marin]

Please excuse my ignorance, but if SPI-1005 contains some form of Glutathione, would Glutathione IVs be potentially beneficial for hearing loss and hyperacusis? Those IVs are offered in wellness clinics all over.

Seeing that those trials have been pushed back is soul crushing.

Also, I've heard of people with high levels of mercury reacting badly to Glutathione. Could that also be a problem with SPI-1005?

 

[tommyd87]

Please excuse my ignorance, but if SPI-1005 contains some form of Glutathione, would Glutathione IVs be potentially beneficial for hearing loss and hyperacusis? Those IVs are offered in wellness clinics all over.

Seeing that those trials have been pushed back is soul crushing.

Also, I've heard of people with high levels of mercury reacting badly to Glutathione. Could that also be a problem with SPI-1005?

The question I have is when are they going to run their Phase 3 trial for Meniere's? Getting this (successfully) completed means that the medicine is available for an ear indication and will then be available for patient use.

 

[FGG]

Please excuse my ignorance, but if SPI-1005 contains some form of Glutathione, would Glutathione IVs be potentially beneficial for hearing loss and hyperacusis? Those IVs are offered in wellness clinics all over.

Seeing that those trials have been pushed back is soul crushing.

Also, I've heard of people with high levels of mercury reacting badly to Glutathione. Could that also be a problem with SPI-1005?

It doesn't contain any Glutathione. The names are similar but ebselen has Glutathione Peroxidase inducing activity. Glutathione Peroxidase is an intracellular family of enzymes that helps break down mediators of oxidative damage.

Glutathione is a free anti-oxidant.

Also, ebselen has a boat load of other effects (some known, some unknown). And importantly, it has excellent penetrance into the cochlea.

It's possible IV Glutathione might help though. FWIW, I had 3 sessions of IV Glutathione and it didn't do anything for me but maybe it would have helped more in the first few months.