The NO/ONOO- Cycle as the Etiological Mechanism of Tinnitus

[click]

This made an interesting read - I was trying to find out whether nitrous oxide was ototoxic (dentists use it) & came across this.

Twelve stressors, eleven of which are short-term and the twelfth (genetic) chronic, are reported to initiate tinnitus in humans or animal models (or both), and all twelve are able to increase nitric oxide levels or other cycle elements.

→ The NO/ONOO- Cycle as the Etiological Mechanism of Tinnitus

Apologies if it's already in a thread somewhere - I did a search and found no references to it.

 

[Lane]

Just ran across this information:

Peripheral tinnitus is a good candidate for inclusion under the NO/ONOO cycle etiological mechanism, fitting each of the five principles of this mechanism.​

Cases of tinnitus are initiated by at least 11 short-term stressors increasing nitric oxide or other cycle mechanisms. Such cycle elements as N-methyl-D-aspartate activity; oxidative stress; nitric oxide; peroxynitrite; vanilloid activity; NF-kappaB activity; and intracellular calcium levels are all reported to be elevated in tinnitus.​

Tinnitus is comorbid with some putative NO/ONOO- cycle diseases. Most important, multiple agents that down-regulate NO/ONOO- cycle biochemistry are reported to be helpful in the treatment of tinnitus and related diseases. Previous studies suggested that NO/ONOO cycle diseases may be best treated with complex combinations of agents predicted to lower NO/ONOO- cycle biochemistry, and such combinations may be helpful in tinnitus treatment.​

Other inner-ear-related defects, such as acute or progressive hearing loss, vertigo, and dizziness, may also be NO/ONOO cycle diseases​

He has articles that list many remedies for peroxynitrite, too, which is one thing I really appreciate about him.​

I suppose there could be a variety of causes, though.​

The NO/ONOO- cycle as the etiological mechanism of tinnitus​

The NO/ONOO- cycle as the etiological mechanism of tinnitus​

 

[StoneInFocus]

Interesting article. This paper was published in 2007. It seems like it gained barely any traction in the scientific community. I wonder why. Could be a valuable piece of the puzzle.

 

[gameover]

Importantly it calls it disease, and not just a "symptom".

 

[Utdmad89]

Importantly it calls it disease, and not just a "symptom".

But tinnitus isn't a disease though. It is a symptom of brain/ear damage.

 

[gameover]

But tinnitus isn't a disease though. It is a symptom of brain/ear damage.

I suppose, yes. But somehow that seems to diminish its importance. Maybe not. I still do not understand the lack of awareness / education around it. So infuriating.

In the end, yes, it is a brain damage/malfunction condition. ALWAYS. Because many, or rather most, people with hearing damage do not have tinnitus (or hyperacusis).

 

[StoneInFocus]

In the treatment of the multisystem illnesses, agents lowering NO/ONOO– cycle biochemistry individually generally produce modest improvements, but complex treatment protocols, including 14 or more such agents, are reported to be substantially more effective. Most agents used in these complex treatment protocols are classified as nutritional supplements and are, thus, widely available. Possibly tinnitus and other good candidates for inclusion under the NO/ONOO– cycle disease paradigm will also respond well to such complex treatment protocols.

I've tried to gather information on which protocols Dr. Pall proposes for NO/ONOO diseases.

In this document, Dr. Pall describes an antioxidant regimen consisting of 5 different supplement formulas he co-sells (red flag, I know), "that together may assist in down-regulating this NO/ONOO- cycle mechanism."

The supplement formulas together contain more than 50 different ingredients.

I have calculated that the treatment protocol would cost 8,98 EUR per day to follow, which is quite expensive, imo.

From the attached article, this is the list of agents included in Dr. Pall's other protocol, which he seems to expound in his book:

Agents from Pall/Ziem Protocol Predicted to Down-Regulate NO/ONOO- Cycle Biochemistry

• Nebulized, inhaled reduced glutathione
• Nebulized, inhaled hydroxocobalamin (some use sublingual)
• Mixed, natural tocopherols including g-tocopherol
• Buffered vitamin C
• Magnesium as malate
• Four different flavonoid sources: Ginkgo biloba extract, cranberry extract, silymarin, and bilberry extract
• Selenium as selenium-grown yeast
• Coenzyme Q10 Folic acid ]
• Carotenoids including lycopene, lutein and b-carotene a-Lipoic acid
• Zinc (modest dose), manganese (low dose) and copper (low dose)
• Vitamin B6 in the form of pyridoxal phosphate
• Riboflavin 5′-phosphate (FMN)
• Betaine (trimethylglycine)

Dr. Ziem has recently added two additional agents: green tea extract (flanonoids) and acetyl L-carnitine.

I found a supposed elaboration of Dr. Pall on another website:

Let me add three additional important points: It is important, with all of these treatments, to avoid up-regulating NO/ONOO- cycle biochemistry. A number of things will tend to produce such up-regulation. These include chemical exposure in MCS patients, excessive exercise in CFS patients, excitotoxin exposure (including MSG and aspartame) in all of these diseases/illnesses, exposure to food allergens in those who have food intolerances and psychological stress in those sensitive to such stress.

These treatments are only effective when the agents down-regulating NO/ONOO- cycle biochemistry are taken along with avoidance of stressors predicted to up-regulate such biochemistry.

The second point is that I think that all of these protocols can be improved and I suspect that the physicians who developed them [@StoneInFocus note: this refers to the other protocols mentioned in the article] would agree with this. Nevertheless, I would argue that we now know how to effectively treat these diseases/illnesses and that such treatment consistently involves down-regulating the fundamental etiologic cycle that causes them.

The third is that we now have sufficient evidence supporting the NO/ONOO cycle etiology of these diseases/illnesses. This is the only detailed explanation for the many overlaps among these illnesses, their substantial comorbidity with each other and the extraordinary variation in symptoms and signs from one case to another.

I have not been able to find the precise protocol including dosages, times to take, when to stop etc. If anyone could find it, I would greatly appreciate it.

As said before, the article I attached mentions other protocols by other physicians, do check it out!

If you haven't already, read the article of the OP!

 

[ZFire]

It seems like it gained barely any traction in the scientific community. I wonder why.

I think you found your answer as to why, chief:

In this document, Dr. Pall describes an antioxidant regimen consisting of 5 different supplement formulas he co-sells (red flag, I know), "that together may assist in down-regulating this NO/ONOO- cycle mechanism."

 

[cjbhab]

I have not been able to find the precise protocol including dosages, times to take, when to stop etc. If anyone could find it, I would greatly appreciate it.

Hello,

I did some searching around and this is what I found.

1. #75930 CoQ-Gamma E with Tocotrienols & Carotenoids: one capsule per day in the morning. Those with body weights over 100 lbs should add a second capsule at mid-day.

2. #75780 FlaviNox: one capsule, four times per day, three preferably with or after meals. Those with body weights over 120 lbs, should add a second capsule with each of three meals.

3. #75940 MVM-A Antioxidant Protocol, multivitamin mineral supplement with added N-acetyl carnitine: one capsule, four times per day, three preferably with or after meals. Those with body weights over 120 lbs, should add a second capsule, with breakfast and with dinner.

4. #75960 NAC Enhanced Antioxidant Formula: one each twice per day, with or after breakfast and supper.

5. #71250 & #73870 Super EPA (fish oil): one per day in the morning after breakfast. Those with body weights over 100 lbs, should add a second capsule at mid-day, taken with or after lunch.

6. #75910 FibroBoost (Ecklonia cava extract): one each twice per day, with or after breakfast and supper.

7. #70010 Buffered Vitamin C: one capsule, four times per day, preferably three with or after meals.

Three products that are to be taken four times per day, be taken at the same times, with three being taken with or after the three meals of the day and the fourth taken at bedtime.

For those intending to try all seven, that you start with the first, trying it alone for three days to see if it is well tolerated, adding second for three days, and so forth. By doing this you should find if there are any products that are not well tolerated, such that they can be eliminated for the time being and perhaps be tested later with either the same or possibly lower dosage. It will take 21 days, in this way, to get to the end of the initial period, into a period where all tolerated products are being taken.

These products contain:

Zinc, copper, manganese, Vitamin C, Vitamin E, Magnesium, NAC, Fish Oil, Flavonoids, Carotenoids, Selenium, Acetyl-L Carnitine, Ecklonia Cava extract, Vitamin B6 including pyridoxal phosphate, Hydroxocobala-min form of vitamin B-12, Folic Acid, Niacin, Riboflavin, Thiamine, R-Alpha-Lipoic acid, Other B vitamins, Tri-methyl glycine, coenzyme Q10, RNA, Taurine.

The source for this information is here. It links to thetenthparadigm.org/arg.htm which outlines the information I posted above. Today this site no longer exists, but I was able to use an internet archive to see a snapshot of the information.

 

[StoneInFocus]

I think you found your answer as to why, chief:

Oh God, you're one of those paranoid freaks that think everything is a scam and the whole world is out to get you, aren't you?

Here's another conspiracy; Dr. Pall was actually PAID by the Washington State University to write this paper on tinnitus! I wonder what corrupt forces could be at play here?

The article was published in 2007, who says Dr. Pall didn't start selling his supplements well after that date?

Dr. Pall was a professor of biochemistry and basic medical sciences at Washington State University. He has published multiple papers about the NO/ONOO cycle. I think it's safe to assume there could be some merit to his theories.

But again, read the papers for yourself and critique his arguments there. Not these unsubstantiated attacks on his reputation.

Hello,

I did some searching around and this is what I found.

1. #75930 CoQ-Gamma E with Tocotrienols & Carotenoids: one capsule per day in the morning. Those with body weights over 100 lbs should add a second capsule at mid-day.

2. #75780 FlaviNox: one capsule, four times per day, three preferably with or after meals. Those with body weights over 120 lbs, should add a second capsule with each of three meals.

3. #75940 MVM-A Antioxidant Protocol, multivitamin mineral supplement with added N-acetyl carnitine: one capsule, four times per day, three preferably with or after meals. Those with body weights over 120 lbs, should add a second capsule, with breakfast and with dinner.

4. #75960 NAC Enhanced Antioxidant Formula: one each twice per day, with or after breakfast and supper.

5. #71250 & #73870 Super EPA (fish oil): one per day in the morning after breakfast. Those with body weights over 100 lbs, should add a second capsule at mid-day, taken with or after lunch.

6. #75910 FibroBoost (Ecklonia cava extract): one each twice per day, with or after breakfast and supper.

7. #70010 Buffered Vitamin C: one capsule, four times per day, preferably three with or after meals.

Three products that are to be taken four times per day, be taken at the same times, with three being taken with or after the three meals of the day and the fourth taken at bedtime.

For those intending to try all seven, that you start with the first, trying it alone for three days to see if it is well tolerated, adding second for three days, and so forth. By doing this you should find if there are any products that are not well tolerated, such that they can be eliminated for the time being and perhaps be tested later with either the same or possibly lower dosage. It will take 21 days, in this way, to get to the end of the initial period, into a period where all tolerated products are being taken.

These products contain:

Zinc, copper, manganese, Vitamin C, Vitamin E, Magnesium, NAC, Fish Oil, Flavonoids, Carotenoids, Selenium, Acetyl-L Carnitine, Ecklonia Cava extract, Vitamin B6 including pyridoxal phosphate, Hydroxocobala-min form of vitamin B-12, Folic Acid, Niacin, Riboflavin, Thiamine, R-Alpha-Lipoic acid, Other B vitamins, Tri-methyl glycine, coenzyme Q10, RNA, Taurine.

The source for this information is here. It links to thetenthparadigm.org/arg.htm which outlines the information I posted above. Today this site no longer exists, but I was able to use an internet archive to see a snapshot of the information.

Hey, this is the antioxidant protocol described in the document I linked to above, excluding the buffered vitamin C. However, I believe this is something different than the Pall/Ziem protocol I was looking for.

After doing some investigation I found out that there are at least 3, maybe 4 overlapping yet distinct protocols inspired by Dr. Pall's research:

1. Dr. Ziem's Chemical Injury Treatment Protocol, also called the 'Neural Protocol'.
2. Dr. Pall's ARG [Allergy Research Group] protocol (the antioxidant protocol described above).
3. Pall/Ziem's Treatment protocol. This protocol is alluded to in the 'Agents from Pall/Ziem Protocol Predicted to Down-Regulate NO/ONOO- Cycle Biochemistry' table. However, I have not yet found the actual protocol itself. Possibly described in his book 'Explaining Unexplained Illnesses'.
4. Possibly another Pall protocol developed independently from Dr. Ziem.

 

[cjbhab]

There seems to be a lot of overlap in ingredients between the neural protocol, the antioxidant protocol and Dr. Pall/Dr. Ziem's protocol. Is it possible they are one and the same or different updated versions?

 

[StoneInFocus]

Grace E. Ziem, M.D. Surrenders Her Maryland Medical License

On December 11, 2015, the Maryland State Board of Physicians ordered Grace Ziem, M.D. to cease medical practice. The summary suspension order (shown below) was based on the board's conclusion that Ziem was habitually intoxicated as evidenced by:

• Alcohol abuse that results in poor judgment, lack of emotional control, verbal abuse of office staff members, and slurred speech on many occasions since at least 2013
• Being intoxicated during office hours
• Failing to see patients as scheduled due to being asleep and very difficult to arouse, being overwhelmed by personal problems, and/or being distracted from patient care by being on the Internet
• Ordering controlled dangerous substances for her personal use and dispensing to family, friends, or patients without a permit to dispense prescription drugs
• Explanations for her actions which are not logical
• The conclusions of neuropsychological testing performed during the board's investigation

I suppose Dr. Ziem has fallen from grace.

There seems to be a lot of overlap in ingredients between the neural protocol, the antioxidant protocol and Dr. Pall/Dr. Ziem's protocol. Is it possible they are one and the same or different updated versions?

I'm not entirely sure about the supposed Dr. Pall/Ziem protocol but the ARG and the Neural one are definitely distinct protocols.

For instance, the daily intake of B12 would be 180 mcg orally in the ARG protocol, and up to 5 mg nebulized in the Neural protocol.

 

[cjbhab]

@StoneInFocus, but really... who isn't occasionally intoxicated during office hours? Lol.

 

[ZFire]

Grace E. Ziem, M.D. Surrenders Her Maryland Medical License
On December 11, 2015, the Maryland State Board of Physicians ordered Grace Ziem, M.D. to cease medical practice. The summary suspension order (shown below) was based on the board's conclusion that Ziem was habitually intoxicated as evidenced by:

• Alcohol abuse that results in poor judgment, lack of emotional control, verbal abuse of office staff members, and slurred speech on many occasions since at least 2013
• Being intoxicated during office hours
• Failing to see patients as scheduled due to being asleep and very difficult to arouse, being overwhelmed by personal problems, and/or being distracted from patient care by being on the Internet
• Ordering controlled dangerous substances for her personal use and dispensing to family, friends, or patients without a permit to dispense prescription drugs
• Explanations for her actions which are not logical
• The conclusions of neuropsychological testing performed during the board's investigation

I suppose Dr. Ziem has fallen from grace.

I'm not entirely sure about the supposed Dr. Pall/Ziem protocol but the ARG and the Neural one are definitely distinct protocols.

For instance, the daily intake of B12 would be 180 mcg orally in the ARG protocol, and up to 5 mg nebulized in the Neural protocol.

 

[StoneInFocus]

@StoneInFocus, but really... who isn't occasionally intoxicated during office hours? Lol.

Yeah I wanted to share it because I thought it was somewhat funny, although I do feel a bit bad for her. This is her side of the story where she denies the allegations.

Despite all of this I believe in the potency of the NO/ONOO theory. I also think Dr. Ziem's neural injury protocol is legit, but maybe a bit outdated (this page was last revisited on 2008).

It's a shame really. I suppose there has been lots of research published about tinnitus, hyperacusis, and (components of or elements pertaining to) the NO/ONOO cycle since 2015, let alone 2008. Maybe new supplements or even drugs have become available in that time?

I suspect the knowledge and materials (drugs, supplements etc) are already out there to support a treatment protocol powerful enough to realize a complete tinnitus remission, maybe even a cure. Could be an intricate protocol or maybe even a simple one. Could be an expensive protocol or a cheap one. It just needs to be unearthed and synthesized.

 

[MrChips13]

OK, so I read the entire study. But I am not a scientist. I am confused by one thing. It has been shown in several studies that there are strong links between the use of Proton Pump Inhibitors (Omeprazole, Prevacid) and tinnitus, but the one thing PPIs do is suppress the creation of Nitric Oxide in both the digestive and endothelial pathways. The brain gets deprived of NO. But, this study seems to say that NO is a bad thing?

 

[Utdmad89]

OK, so I read the entire study. But I am not a scientist. I am confused by one thing. It has been shown in several studies that there are strong links between the use of Proton Pump Inhibitors (Omeprazole, Prevacid) and tinnitus, but the one thing PPIs do is suppress the creation of Nitric Oxide in both the digestive and endothelial pathways. The brain gets deprived of NO. But, this study seems to say that NO is a bad thing?

There isn't a strong link between Omeprazole and tinnitus. These studies are mainly bollocks.

 

[MrChips13]

There isn't a strong link between Omeprazole and tinnitus. These studies are mainly bollocks.

Hardly. They are serious studies. It says "take for 14 days" on the box for a reason.

Are you saying NO has no purpose?

 

[Utdmad89]

Hardly. They are serious studies. It says "take for 14 days" on the box for a reason.

Are you saying NO has no purpose?

No, they aren't serious studies. It's a load of bull. I've taken Omeprazole every day for 17 years.

 

[MrChips13]

No, they aren't serious studies. It's a load of bull. I've taken Omeprazole every day for 17 years.

Lucky you. But they are very serious studies. You ought to know that not every drug affects every person in the same way. The fact that Omeprazole is highly ototoxic simply puts you at risk. It also greatly increases the chance of heart attack, stroke, and blood clots. That doesn't mean you were going to get those either. It's simply a risk factor.

But you also don't answer my original question. It was simply about nitric oxide in regard to the study at the beginning of this thread.

 

[Utdmad89]

Lucky you. But they are very serious studies. You ought to know that not every drug affects every person in the same way. The fact that Omeprazole is highly ototoxic simply puts you at risk. It also greatly increases the chance of heart attack, stroke, and blood clots. That doesn't mean you were going to get those either. It's simply a risk factor.

But you also don't answer my original question. It was simply about nitric oxide in regard to the study at the beginning of this thread.

There are no conclusive evidence that Omeprazole is ototoxic or has any of those side effects. These serious studies don't exist. Not everything you read on the Internet is true, I'm afraid. I don't have the foggiest idea about NO.

 

[MrChips13]

There are no conclusive evidence that Omeprazole is ototoxic or has any of those side effects. These serious studies don't exist. Not everything you read on the Internet is true, I'm afraid. I don't have the foggiest idea about NO.

The studies exist. Look harder. But, what is the point of your arguing, unless you're worried about it. If so, switch to an H2 blocker like Pepcid. If not, that is your choice. Not mine.

But Merry Christmas.