Patent filing for the use of nitric oxide with or without B-cell depletion in CFS

[Hip]

Chronic Infections And Nitric Oxide (NO) Levels

I have often wondered whether the chronic infections of ME/CFS might lead to low NO levels, high NO levels, or a combination of both (some bodily areas low in NO, others high in NO).

Nitric oxide is used for three distinct purposes in the body:
• For vasodilation (NO dilates blood vessels)
• For neurotransmission (NO is an important neurotransmitter)
• By the immune system for antimicrobial purposes (NO is a potent antiviral, antibacterial, antifungal and antiprotozoal).

Corresponding to these three functions, there are three enzymes in the body that produce nitric oxide: eNOS (in the endothelium for vasodilation), nNOS (in the brain for neurotransmission), and iNOS (created anywhere in the body for immune purposes).

The immune system makes NO for its potent antimicrobial effects. Interestingly, the amount of NO produced by the immune system via the iNOS enzyme is hundreds or thousands of times higher than the levels of NO produced by eNOS and nNOS for vasodilation and neurotransmission purposes. When the immune system makes NO, it makes it in bucketloads; whereas the NO used for vasodilation and neurotransmission is only made in relatively tiny amounts.

So I wonder whether these bucketloads of NO from the immune system might actually be disturbing the dynamics of the tiny amounts of NO used for vasodilation and neurotransmission. If there were disturbances in the NO levels employed for vasodilation and neurotransmission, this might help explain the reduced cerebral blood flow sometimes found in ME/CFS, and might help explain the mental and cognitive symptoms of ME/CFS (as a neurotransmitter, NO is associated with learning and memory, so might be behind brain fog).


The disturbance to NO in vasodilation and neurotransmission could simply result from the very high amounts of NO produced by the immune system as it combats a chronic local infection (of the brain for example). With the immune system producing NO at levels hundreds or thousand of times higher than the NO manufactured for vasodilation and neurotransmission, this immune-derived NO might entirely swamp the vasodilation-derived and neurotransmission-derived NO.

Furthermore, there may be paradoxical effects of the high levels of immune-derived NO, that actually lead to lowered NO levels in other parts of the body.

For example, if we consider asymmetric dimethylarginine (ADMA), which is an inhibitor of the nitric oxide synthase (NOS) enzymes and is intimately involved with NO metabolism, we find in chronic infections, ADMA can be raised.

This paper mentions that in HIV-infected patients there are elevated plasma levels of ADMA. And in Helicobacter pylori infection you also find increases in ADMA levels; see here.

So some chronic infections seem to increase blood levels of ADMA. And since ADMA inhibits all three of the NOS enzymes, high levels of ADMA due to infection might alter the dynamics of eNOS and nNOS vasodilation and neurotransmission.

Or if, as @aimossy mentioned above, we consider Mady Hornig's results of significantly reduced ADMA in the first 3 years of ME/CFS, this might also alter the dynamics of eNOS and nNOS vasodilation and neurotransmission.

 

[Hip]

We might be touching again on the difference that many of us have between the levels of vasodilation in large and small blood vessels. It isn't clear what the effect of NO is in these cases--is it?

I was just Googling to find an answer to this question, but did not find much. NO definitely dilates veins, arteries, and the microvasculature though. But NO is not the only mechanism of vasodilation.

 

[Jonathan Edwards]

Perhaps that happens at higher NO concentrations? In this paper they talk about inhaling NO at concentrations of 20 ppm for medical purposes.


Apparently dietary nitrates raise NO levels. High levels of nitrates can be found in beetroot juice. A few years ago I tried taking potassium nitrate 2 grams daily, but did not notice much in the way of symptom improvements.

Interesting, but I suspect NO is not much use in a practical medical situation since it only stays as NO if mixed with pure nitrogen and inhaling pure nitrogen for more than a few seconds would seem to be a bad idea! Maybe a quick whiff of NO in N2 gets the lung perfusion up for a while. I am not sure how they know that the effect is not due to NO2 reacting with water to form nitrate and nitrite (which will probably re-create NO at some further stage) but it is a long time since I did this sort of chemistry.

 

[Hip]

Tip: Folic Acid Prevents Nitroglycerin-Induced Nitric Oxide Synthase Dysfunction

(I posted the following elsewhere, but since it may be useful info, I will repost here).

Note that this study says:

In healthy humans, continuous treatment with nitroglycerin (GTN) causes nitric oxide synthase dysfunction, probably through the reduced bioavailability of tetrahydrobiopterin.

Recent studies proposed that folic acid is involved in the regeneration of tetrahydrobiopterin in different disease states. Therefore, we investigated whether folic acid administration would prevent this phenomenon. We also sought to determine if folic acid supplementation could prevent the development of tolerance to GTN.

And the study concludes:

Our data demonstrate that supplemental folic acid prevents both nitric oxide synthase dysfunction induced by continuous GTN and nitrate tolerance in the arterial circulation of healthy volunteers. We hypothesize that the reduced bioavailability of tetrahydrobiopterin is involved in the pathogenesis of both phenomena. Our results confirm the view that oxidative stress contributes to nitrate tolerance.

And this study demonstrates that folic acid reverses the endothelial dysfunction induced by BH4 depletion.

More info on BH4 as an essential cofactor for the activation of nitric oxide synthase is found in this article. The article mentions that methylfolate (L-5-MTHF) may help substitute for BH4 when BH4 is deficient.

So folic acid and BH4 supplementation may help nitroglycerin regain its vasodilating effect. You can buy BH4 in 2.5 mg capsules at these places: 1, 2, 3, 4. But 2.5 mg is quite low compared to the 100 mg found in the prescription BH4 medication called Kuvan. I understand that BH4 is sensitive to degradation by free radicals, so you would be advised to take antioxidants when you take BH4.


By the way, the reason tetrahydrobiopterin (BH4) is so expensive, and without a prescription is only available in small dose tablets, is because BH4 was given orphan drug status in 2002, and this gives specific companies the exclusive right to sell BH4. Biomarin and Merck Serono have this right, and they sell their BH4 (trade name Kuvan) in 100 mg tablets.

However, this BH4 orphan drug status is due to expire in June 2015, ending the exclusivity, so thereafter we can expect the price of BH4 to drop, and the general availability and dosage amounts of BH4 to increase.

 

[Sidereal]

I have some 2.5 mg capsules of BH4. Might be worth trying to see what happens. You'd probably need to swallow the whole bottle to get an adequate dose though.

 

[Hip]

I have some 2.5 mg capsules of BH4. Might be worth trying to see what happens. You'd probably need to swallow the whole bottle to get an adequate dose though.

You could just take folic acid, which the study above says helps recycle BH4.


It's interesting that the two main components of Rich Van Konynenburg's methylation protocol, namely hydroxocobalamin and folate, both interact with the nitric oxide system: hydroxocobalamin is a scavenger of nitric oxide, and folate recycles BH4, with BH4 being essential for the activation of the nitric oxide synthase enzymes that make NO.

Makes me wonder whether the benefits of Rich's protocol might come from something else other than (or in addition to) methylation, such as a modulation of the NO system. This is the difficulty with biochemistry: with each drug or supplement sometimes having hundreds of different effects in the body, when you do notice benefits from a given medication, it's hard to pinpoint the mechanism by which it might be helping.

 

[Sidereal]

You could just take folic acid, which the study above says helps recycle BH4.

Folate makes me extremely sick.

 

[melihtas]

You could just take folic acid, which the study above says helps recycle BH4.

I wouldn't touch folic acid. I beleive that over use of folic acid involves in developing cfs/me. ME is common in developed countries. Folic acid fortification in wheat flour is mandatory in the developed countries and also multivitamin use is common in developed countries due to high income levels.

I live in Turkey where folic acid fortification is not mandatory. ME is very rare here. I took a lot of folic acid for many years before I got ME because some doctors told me that I needed folic acid supplementation and they said it is water soluble therefore very safe.

By the way, I started taking Isosorbide Mononitrate (Imdur generic) yesterday and I have already seen some improvements in my ME symptoms. If the improvements persist, I will share my experience.

 

[Hip]

I wouldn't touch folic acid. I beleive that over use of folic acid involves in developing cfs/me. ME is common in developed countries. Folic acid fortification in wheat flour is mandatory in the developed countries and also multivitamin use is common in developed countries due to high income levels.

From what I can see, the data is just not available for comparing ME/CFS prevalence rates in developed countries to those of developing countries. Are there any published studies on the prevalence rate of ME/CFS in Turkey, for example?

In any case, food vitamin fortification is not the only difference between developed and developing countries. For example, people in developing countries often naturally have intestinal worm (helminth) infections as part of their gut microbiota, and helminths modulate the immune system in a way that may protect against autoimmunity. Such worm infections are rare in developed countries. (One person on this forum who paid money to infect his intestine with helminths found his ME/CFS worsened).


Many on this forum find that active folates, when taken as part of the methylation protocol, significantly improve ME/CFS symptoms. I did not benefit from the methylation protocol myself, but if you look at this poll, you see that around 25% get major improvements from methylation.

 

[alex3619]

hydroxocobalamin is a scavenger of nitric oxide

Also peroxynitrite if I recall correctly.

 

[alex3619]

I wouldn't touch folic acid. I beleive that over use of folic acid involves in developing cfs/me. ME is common in developed countries. Folic acid fortification in wheat flour is mandatory in the developed countries and also multivitamin use is common in developed countries due to high income levels.

Folic acid is not the vitamin, and there is concern that even low doses may be toxic, especially for subsets of the young populatoin, and up to 80% or so of older people. It blocks proper metabolism of the actual vitamin, which is usually called methyl folate. Folic acid and methyl folate are equivalent in some circumstance, but folic acid may be toxic to far too many people. I have wondered if folic acid might not increase the risk factor for getting ME.

 

[melihtas]

From what I can see, the data is just not available for comparing ME/CFS prevalence rates in developed countries to those of developing countries. Are there any published studies on the prevalence rate of ME/CFS in Turkey, for example?

Many on this forum find that active folates, when taken as part of the methylation protocol, significantly improve ME/CFS symptoms. I did not benefit from the methylation protocol myself, but if you look at this poll, you see that around 25% get major improvements from methylation.

Folic acid is not the vitamin, and there is concern that even low doses may be toxic, especially for subsets of the young populatoin, and up to 80% or so of older people. It blocks proper metabolism of the actual vitamin, which is usually called methyl folate. Folic acid and methyl folate are equivalent in some circumstance, but folic acid may be toxic to far too many people. I have wondered if folic acid might not increase the risk factor for getting ME.

No, there is no data about prevalence rates, that is why I said "I beleive" because it is speculation based on observation rather than established facts. However, online presence of ME patients are very clear indication to me. For example on this PR forums almost all the people are from the U.S, the U.K., Australia, Canada, Northern and Western Europe. I don't see many people from Eastern or Southern Europe, Africa, Middle East and Asia.

There is nothing published about ME in Turkey let alone prevalence rates. I have been searching for five years and I haven't come across any ME patients in person or online.

I know the difference between folic acid and methylfolate and I believe that folic acid might be one of the culprits for ME, not all folates. I tried late Rich Von Konynenburg's Simplified Methylation Protocol and Fredd's methylation protocol with higher doses in the past without success, the latter made me worse.

 

[gregh286]

I wouldn't touch folic acid. I beleive that over use of folic acid involves in developing cfs/me. ME is common in developed countries. Folic acid fortification in wheat flour is mandatory in the developed countries and also multivitamin use is common in developed countries due to high income levels.

I live in Turkey where folic acid fortification is not mandatory. ME is very rare here. I took a lot of folic acid for many years before I got ME because some doctors told me that I needed folic acid supplementation and they said it is water soluble therefore very safe.

By the way, I started taking Isosorbide Mononitrate (Imdur generic) yesterday and I have already seen some improvements in my ME symptoms. If the improvements persist, I will share my experience.

Did you doc give you the isosorbide?
I get temporary relief in 2 ways, i have noticed in last 2.5 years, both unsustainable:
1. hard/liquor alcohol...fast infusion..I guess rapid dilation of blood vessels, obviously unrealistic long term.
2. extreme exercise which is albeit near impossible with CFS...but a forced sprint for as long as you physically can...energy improvement for 12-24hours until PEM kicks in and your muscles ache for days. However it does drop blood pressure (and most likely improve dilation, possibly NO production?) in the very short term.

Moderate hypertensive (135-145/80-95S).
No POTS. Tingling in arms and hands is usual. Awake with numb hands on majority of days. Cold feet persistent symptom.
Anyway, will see what KDM makes of all this next monday, as a trained cardiologist it will be interesting to hear his take on it.

 

[MeSci]

No, there is no data about prevalence rates, that is why I said "I beleive" because it is speculation based on observation rather than established facts. However, online presence of ME patients are very clear indication to me. For example on this PR forums almost all the people are from the U.S, the U.K., Australia, Canada, Northern and Western Europe. I don't see many people from Eastern or Southern Europe, Africa, Middle East and Asia.

There is nothing published about ME in Turkey let alone prevalence rates. I have been searching for five years and I haven't come across any ME patients in person or online.

The ME Research UK database of research has several abstracts from Turkey relating to CFS and fibromyalgia - might be worth emailing the researchers to see if they know about prevalence. You can download the database from here.

 

[melihtas]

Did you doc give you the isosorbide?

No, I bought it directly from a chemist. It is slow release form. The lowest dose was 40 mg and I took one. It was too much to start, it lowered my BP to 80/40 mm Hg from 110/65 in two hours. This caused me strong headache and pounding heart when I get up. I drank salty water to raise my BP. Today, I opened a capsule and emptied half of the granules in it, so I took roughly around 20 mg. I also took Florinef to raise my blood volume and I feel much better.

The day before I started taking Isosorbid mononitrat, I had to go out and walk a few kilometers because I don't have a car. This walk triggered PEM as usual and it was supposed to make my life miserable for a week but only one day after taking Isosorbid 50% of muscle pain and 80% of brain fog is gone. I think better blood flow clears lactic acid.

 

[melihtas]

The ME Research UK database of research has several abstracts from Turkey relating to CFS and fibromyalgia - might be worth emailing the researchers to see if they know about prevalence. You can download the database from here.

Thank you very much for the link. It is a big database, it will take time to read all of it but according the my first searches, almost all of the papers from Turkey are about Fibromyalgia. There are four papers about CFS, only one from the city where I live (Istanbul) and it is from a military hospital, so I don't have access to those doctors. They tried hyperbaric oxygen (HBO2) therapy on 15 CFS patients according to Fukuda criteria.

OBJECTIVE: Chronic fatigue syndrome (CFS) is a chronic disease with social components that ensue secondary to the incapacity of the person to fulfill work, social and family responsibilities. Currently, there is no consensus regarding its treatment. The aim of this study was to determine the efficacy of hyperbaric oxygen (HBO2) therapy in CFS.

DESIGN: Sixteen patients included in the study were diagnosed with CFS according to the Fukuda criteria. Patients received 15 treatment sessions of HBO2 therapy over a period of three consecutive weeks (five days per week). The outcome measures (visual analog fatigue scale (VAFS). Fatigue Severity Scale (FSS) and Fatigue Quality of Life Score (FQLS) were assessed before the treatment and after completion of the 15 sessions.

RESULTS: HBO2 therapy was well tolerated, with no complications. After treatment, patients' scores were found to have improved with respect to VAFS, FSS and FQLS (all p<0.005).

CONCLUSIONS: We may infer that HBO2 therapy decreases the severity of symptoms and increases the life quality of CFS patients. It may be a new treatment modality for the management of CFS. However, further studies with larger sample sizes and control groups are definitely awaited.

 

[Hip]

No, there is no data about prevalence rates, that is why I said "I beleive" because it is speculation based on observation rather than established facts.

Well with the prevalence of ME/CFS being around 1 in 500, you would have to have around 500 acquaintances to stand a chance observing just 1 ME/CFS patient out of the people you know.

However, online presence of ME patients are very clear indication to me. For example on this PR forums almost all the people are from the U.S, the U.K., Australia, Canada, Northern and Western Europe. I don't see many people from Eastern or Southern Europe, Africa, Middle East and Asia.

Er, don't you think that might just be something to do with the ability to understand and write English?

English is not widely spoken in Eastern or Southern Europe, Africa, Middle East and Asia (except for India). Whereas it is widely spoken as a second language in many Northern European countries, and of course is spoken in the US, UK, Ireland, Canada, Australia and New Zealand.

I believe that folic acid might be one of the culprits for ME

Mandatory folic acid fortification began in the late 1990s in the USA and Canada (not sure when voluntary fortification began). If this was increasing the risk of ME/CFS, presumably we would have seen increases in the incidence of ME/CFS at this time.

 

[Gingergrrl]

I can't understand the sciencey parts of this thread but since there are many here who do (Alex, zzz, Sidereal, Hip and anyone I am forgetting!) I have a question-

Would there by anything dangerous if my cardio recommends the Nitro patch on Fri for me to try it and/or for me to try the beet root extract supplements? (No chance I can tolerate real beets or the juice version !)

I would of course try only one at a time and afraid of lowering my BP too much.

Thanks for any feedback in advance!

 

[Sushi]

or for me to try the beet root extract supplements? (No chance I can tolerate real beets or the juice version !)

Just curious about why you wouldn't tolerate beet juice--is it something that is high histamine?

 

[Hip]

Would there by anything dangerous if my cardio recommends the Nitro patch on Fri for me to try it and/or for me to try the beet root extract supplements?

There are some contraindications for nitroglycerin / nitrates listed here.