Fluge/Mella Take out Patent on Nitric Oxide Treatment for ME/CFS

[Cort]

"She reported a clear improvement on most ME/CFS symptoms during the next days, which she described to be remarkably alike the response she had previously experienced from 6-7 weeks after Rituximab"
Thus, the administration of a NO donor surprisingly allow a treatment of CFS patients for immediate relief of symptoms without any delay as described for e.g. a B-cell depleting agent, like Rituximab, before.​

Thanks to Tate for passing this on. This lady was one of the Fluge/Mella's original lymphoma patients with ME/CFS. She found that Ritxumab cleared up her cancer and her ME/CFS but she relapsed after she went off the Rituximab.

Now lightning has struck again. She checked into the hospital for transient ischemic heart pain and upon receiving isosorbide mononitrate (Imdur®) she experienced significant symptom relief from her ME/CFS as well.

Imdur reduces blood pressure and is used in the treatment of angina. Essentially it dilates the blood vessels - letting the blood flow more freely.

Fluge and Mella appear to be using this combination: An alternative strategy was applied, using supplement with relatively high doses of L-Arginine 5 g twice daily combined with L-Citrulline 200 mg twice daily. They note that other combinations may work:

"Examples thereof include compounds inhibiting arginase, e.g. arginase II, a competitor of the NO synthase (NOS). Other examples comprise compounds stimulating the activity of NO synthase, in particular, of the eNOS, either by increasing the amount or level of NOS or the turn over rate of the enzyme." Plus they discuss using it in combination with Rituximab.

They treated six patients and found a moderate response in all of them. The idea of dilating the blood vessels seems to make sense in FM and ME/CFS. (Lowering blood pressure does not - I don't think). Fluge and Mella believe ME/CFS may be an autoimmune disorder that attacks the blood vessels. I certainly hope they are right and this woman's experience suggests they may be - at least for her. An autoimmune treatment (rituximab) and blood vessel dilator achieved the same results. That's very interesting!

https://data.epo.org/publication-server/pdf-document/EP13168487NWA1.pdf?PN=EP2805730 EP 2805730&iDocId=7868378&iepatch=.pdf

EUROPEAN PATENT APPLICATION Nitric oxide donor for the treatment of chronic fatigue syndrome - Inventors: Fluge, Oystein; Mella, Olla

In particular, the present inventors recognized that an immediate relief after administration of an NO donor can be observed. In contrast to medication administered so far for treatment of CFS, which are characterized by a remarkable lag time of treatment success, as described for example for the treatment with Rituximab or Methotrexate, see e.g. WO 2009/083602.

Thus, the administration of a NO donor surprisingly allow a treatment of CFS patients for immediate relief of symptoms without any delay as described for e.g. a B-cell depleting agent, like Rituximab, before. An alternative strategy was applied, using supplement with relatively high doses of L-Arginine 5 g twice daily combined with L-Citrulline 200 mg twice daily. L-Arginine is the sole substrate of Nitric Oxide Synthases (NOS), thus this approach aims to overcome the dysregulated nitric oxide system in CFS/ME patients by providing relatively high doses of the substrate.

Index observation

The patient was a 48 years old woman with previous thyroiditis. She had ME/CFS following mononucleosis in 1997 (33 years of age). She had a Hodgkin lymphoma stage II-A in 2003, and experienced in 2004 a transient response of her ME/CFS symptoms after chemotherapy for lymphoma relapse which has been described [Fluge O, Mella O (2009) BMC Neurol 9:28], and which later led to a pilot case series using Rituximab, also with a major but transient responses of ME/CFS symptoms for this patient.

After high-dose chemotherapy with autologous stem cell support, she has been relapse-free from lymphoma since 2006. In autumn 2012, she was admitted to a local hospital with a transient ischemic attach with paresis in left side of 30 minutes duration. She had previously received radiotherapy to the mediastinum and neck as treatment for limited-stage Hodgkin lymphoma, and due to a reduced left ventricular function, her cardiologist started oral isosorbide mononitrate (Imdur®) 30 mg which she received for five days before cessation of the therapy.

She had headache and some dizziness the first days, but also noticed an initial response of her ME/CFS symptoms starting within the first 24 hours. She reported a clear improvement on most ME/CFS symptoms during the next days, which she described to be remarkably alike the response she had previously experienced from 6-7 weeks after Rituximab infusion (as a pilot patient in 2007). After Imdur® treatment was stopped on day five, the symptom improvement vanished during the following two days, consistent with a direct symptomatic effect on her ME/CFS disease.

 

[JennyJenny]

Very, very interesting. There is a blood vessel theory floating around for Fibromyalgia also.

 

[Merry]

On one visit to the doctor who diagnosed my CFS (1990), I mentioned the pain in my blood vessels. He said, oh yes, CFS patients have vasculitis. A few years later when I saw a gastroenterologist, I mentioned the vasculitis, and he burst out laughing: "You don't have vasculitis!" What did I know?

I have often wondered about that pain in my blood vessels, which I have felt most often in my throat and face on the right side. I have also wondered if the all-over achiness is blood vessel pain.

I don't recall hearing other patients complain of pain in the blood vessels, nor have I often seen blood vessels mentioned by ME/CFS experts. I would like to know more. Perhaps someone can direct me to a summary of the hypothesis that ME/CFS may be an autoimmune disorder that attacks the blood vessels? Thank you.

 

[Cort]

On one visit to the doctor who diagnosed my CFS (1990), I mentioned the pain in my blood vessels. He said, oh yes, CFS patients have vasculitis. A few years later when I saw a gastroenterologist, I mentioned the vasculitis, and he burst out laughing: "You don't have vasculitis!" What did I know?

I have often wondered about that pain in my blood vessels, which I have felt most often in my throat and face on the right side. I have also wondered if the all-over achiness is blood vessel pain.

I don't recall hearing other patients complain of pain in the blood vessels, nor have I often seen blood vessels mentioned by ME/CFS experts. I would like to know more. Perhaps someone can direct me to a summary of the hypothesis that ME/CFS may be an autoimmune disorder that attacks the blood vessels? Thank you.

I just think the blood vessels must be involved. Time will tell.

I am eagerly awaiting Fluge/Mella's paper explaining their autoimmune/blood vessel hypothesis.

 

[JennyJenny]

On one visit to the doctor who diagnosed my CFS (1990), I mentioned the pain in my blood vessels.

I think this is why we have pain throughout our body. I thought for a couple of years now that a lot of our pain involves the vascular system. My BP went down to 80/50 and STAYED THERE. I have had ME/CFS since age 17 (1979) and always had a "low normal" 110/70 and around age 32 or so fainted during a table tilt test.

I was put on Fludrocortisone when I dropped to 80/50 which is an off label treatment for ME/CFS as well as another BP medication for those with high BP and ME/CFS.

In the mini doc on youtube (I am sure you have seen it but you can search on youtube "Invisible Illness Palo Alto" to view) the woman says she feels as though all her blood has been removed and replaced with cement. I always said I felt like my veins were full of white glue and my muscles felt prettified.

Lately research is saying we do not have heart problems but cardio vascular problems but due to immobility this leads to congestive heart failure.

I think they may be on to something here, I really do.

I was thinking about the cluster outbreaks and the issue with that is, many recovered from the outbreak in a couple of months not all remained ill. But those genetically disposed it may lead to the autoimmune system going on the attack and them now being ME/CFS patients. And when you are genetically disposed to something it can be any bad virus or toxic mold or chemical exposure or bacterial infection that can set it off. So I am thinking a cluster outbreak or not it is a matter of time for the genetically disposed patient.

There is the theory that Fibro involves the vascular system also.

 

[Merry]

Interesting, @JennyJenny. I have seen the video and remember the woman's comment that she feels like she has cement in her veins. I focused on the cement rather than cement in the veins and thought she meant she feels heavy and slow, nearly immobile. You describe your veins as being filled with glue. I think about mine as being on fire.

Sorry to hear you've been ill since you were a teenager. Same for me. What a life.

I might give genetics more emphasis if it hadn't happened that health problems in my family seem to have been passed to another family that we were connected to socially. I don't mean that the two families were part of an outbreak. I'm left wondering about a persistent pathogen.

All a mystery. I'm sure I'm not going to figure it out.

 

[JennyJenny]

I might give genetics more emphasis if it hadn't happened that health problems in my family seem to have been passed to another family that we were connected to socially. I don't mean that the two families were part of an outbreak. I'm left wondering about a persistent pathogen.

I know my friend's sister and her daughter have it so I thought that was interesting. Not exactly immediate family members and onset at different times. Yet how come all there numerous friends didn't get it. And what about all my numerous friends or other ME/CFS patients with numerous friends and spouses and boy/girlfriends and on and on. Yet, many will say they have a family member immediate or cousin or aunt that has it.

I really do lean towards a genetic component. But until there is a huge study where the DNA has the life crunched out of thousands of patients and their family members, we might not know. Thankfully DNA is getting cheaper to run and research but we still don't have that kind of money.

 

[Cort]

I think this is why we have pain throughout our body. I thought for a couple of years now that a lot of our pain involves the vascular system. My BP went down to 80/50 and STAYED THERE. I have had ME/CFS since age 17 (1979) and always had a "low normal" 110/70 and around age 32 or so fainted during a table tilt test.

I was put on Fludrocortisone when I dropped to 80/50 which is an off label treatment for ME/CFS as well as another BP medication for those with high BP and ME/CFS.

In the mini doc on youtube (I am sure you have seen it but you can search on youtube "Invisible Illness Palo Alto" to view) the woman says she feels as though all her blood has been removed and replaced with cement. I always said I felt like my veins were full of white glue and my muscles felt prettified.

Lately research is saying we do not have heart problems but cardio vascular problems but due to immobility this leads to congestive heart failure.

I think they may be on to something here, I really do.

I was thinking about the cluster outbreaks and the issue with that is, many recovered from the outbreak in a couple of months not all remained ill. But those genetically disposed it may lead to the autoimmune system going on the attack and them now being ME/CFS patients. And when you are genetically disposed to something it can be any bad virus or toxic mold or chemical exposure or bacterial infection that can set it off. So I am thinking a cluster outbreak or not it is a matter of time for the genetically disposed patient.

There is the theory that Fibro involves the vascular system also.

80/50!

I can relate to this.....

she feels as though all her blood has been removed and replaced with cement. I always said I felt like my veins were full of white glue and my muscles felt petriified

It would be a good poll question...Do you feel like your blood has been removed and replaced with cement or do your muscles feel petrified?

I get it about the autoimmunity....that is a great explanation. I never thought of that before....

 

[Cort]

Interesting, @JennyJenny. I have seen the video and remember the woman's comment that she feels like she has cement in her veins. I focused on the cement rather than cement in the veins and thought she meant she feels heavy and slow, nearly immobile. You describe your veins as being filled with glue. I think about mine as being on fire.

Sorry to hear you've been ill since you were a teenager. Same for me. What a life.

I might give genetics more emphasis if it hadn't happened that health problems in my family seem to have been passed to another family that we were connected to socially. I don't mean that the two families were part of an outbreak. I'm left wondering about a persistent pathogen.

All a mystery. I'm sure I'm not going to figure it out.

Well, one of my chief complaints has been muscles and skin that feel like they're burning. Is that similar to what you experience Merry or something different?

 

[JennyJenny]

80/50!

I can relate to this.....

It would be a good poll question...Do you feel like your blood has been removed and replaced with cement or do your muscles feel petrified?

I get it about the autoimmunity....that is a great explanation. I never thought of that before....

Well, I also said that my tendons felt like old rotting rubber bands, so don't forget that as part of the poll. lol

 

[Merry]

Well, one of my chief complaints has been muscles and skin that feel like they're burning. Is that similar to what you experience Merry or something different?

I have experienced, Cort, that burning on the skin and in the muscles. But the fire in the blood vessels I feel just in the blood vessels. They hurt, are tender to the touch, and I think of them as inflamed. I wouldn't say it is a burning sensation, but, rather, that the word "fire" equals "inflammation."

I also said that my tendons felt like old rotting rubber bands

I may know what you mean, @JennyJenny, about the tendons. They feel like they are going to give, no longer hold in properly what they are supposed to hold in.

@JennyJenny, you could collect a list of descriptive terms like "old rotting rubber bands" for symptoms and put together a funny poll.

 

[JennyJenny]

@JennyJenny, you could collect a list of descriptive terms like "old rotting rubber bands" for symptoms and put together a funny poll.

I just might. If anyone wants to list their symptoms and what things felt like such as: "My hair hurts" or "A steel curved x-shaped beam through my skull" (another two of mine) that feel free. Because I know since being in medical forums the last few years I am not the only one stuck expressing my symptoms like this. Brain burning and feeling like it is full of mold too.

Don't get me started on the pictures I have drawn of my fact and body and the dozen different types of pain I feel and then I give a copy to each of my doctors.

 

[Merry]

Hey, @JennyJenny. I like the idea that you draw pictures of your pain for your doctors. Dare I ask how doctors have reacted to the pictures?

I believe that the most distressing pain I experience -- and fortunately I don't experience it often -- is the feeling that the flesh of my forearms is coming off the bone.

 

[JennyJenny]

@Merry

They look at them and read what I wrote next to them with a straight face. I don't think they mind. The pictures are awful that is for sure but it gets the point across.

Only last month did I feel pain as if the flesh were coming off on my right upper arm underneath. If felt like fire, nerve pain and as if I might have a rash all rolled into one. It lasted a few days, maybe a week I can't remember. And where that came from I don't know as I never had that before.

 

[Cort]

Ewwwwww......

Hey, @JennyJenny. I like the idea that you draw pictures of your pain for your doctors. Dare I ask how doctors have reacted to the pictures?

I believe that the most distressing pain I experience -- and fortunately I don't experience it often -- is the feeling that the flesh of my forearms is coming off the bone.

 

[Cort]

I have experienced, Cort, that burning on the skin and in the muscles. But the fire in the blood vessels I feel just in the blood vessels. They hurt, are tender to the touch, and I think of them as inflamed. I wouldn't say it is a burning sensation, but, rather, that the word "fire" equals "inflammation."



I may know what you mean, @JennyJenny, about the tendons. They feel like they are going to give, no longer hold in properly what they are supposed to hold in.

@JennyJenny, you could collect a list of descriptive terms like "old rotting rubber bands" for symptoms and put together a funny poll.

Just created a symptom description thread -

• http://www.cortjohnson.org/forums/t...fibromyalgia-symptom-description-thread.2845/

If it picks up it will be interesting to see what people experience. I imagine the descriptions will be Shakespearean in their depth and variety...

 

[Cort]

@Merry

They look at them and read what I wrote next to them with a straight face. I don't think they mind. The pictures are awful that is for sure but it gets the point across.

Only last month did I feel pain as if the flesh were coming off on my right upper arm underneath. If felt like fire, nerve pain and as if I might have a rash all rolled into one. It lasted a few days, maybe a week I can't remember. And where that came from I don't know as I never had that before.

Just created a symptom description thread...This could get very evocative...

• http://www.cortjohnson.org/forums/t...fibromyalgia-symptom-description-thread.2845/

 

[ShyestofFlies]

I don't recall hearing other patients complain of pain in the blood vessels, nor have I often seen blood vessels mentioned by ME/CFS experts. I would like to know more. Perhaps someone can direct me to a summary of the hypothesis that ME/CFS may be an autoimmune disorder that attacks the blood vessels? Thank you.

I don't know if anyone has ever done a comprehensive analysis of how many people with ME/CFS or FM have Raynaud's, but I can't imagine it would be lower than the general population at least.

I don't have pain I can definately tell is in my blood vessels daily (its more generic so to speak then that location wise it just feels like my nerves are always on edge and painful all the time)...

Needles possibly related possibly not?----

But when getting blood draws and IV, any type of blood or needle procedure I experience extreme amounts of pain. It's a type of hyperalgesia though to find info on it you have to look into "needle phobia" and vasovagal reactions. It appears as an example when talking about types of pain but rarely information beyond that is provided outside of the 1 needle phobia resource.

Though the hyperalgesic pain related to needles is not related to fear. Sure I have a low level fear of needles - more so if it was near my eyes or face then my arm! But the pain itself made me vomit, passout, I turn white, I sweat, I cry, it hurts for hours, days or weeks and it feels extremely painful. I'm normally around a 6-8/10 on a daily basis, a blood draw feels like an 11/10!

For example: I had my blood drawn on Tuesday without my numbing cream for the first time in a while, it still hurts- it's the end of Sunday and the technitian was not bad! She didn't hit anything she wasn't supposed to hit, it's just extremely painful. My hands are normally the best place for me to do blood without my cream but this time it was the opposite.

For the record the cream is called "EMLA" or a generic version is just a lidocaine/prilocaine cream suspension. It's messy and it can't help you if the vein is deep.

There is also a patch version that works deeper, but is more expensive, and harder to convince insurance of letting you get called Synera. There is an OTC version of the cream people say is almost as good in some countries.

[My pcp prescribed the cream but told me my insurance would fight her over the patch despite them saying they will allow its prescription. She told me to try a specialist to prescribe it when I run out of cream.]

From the "experiment" with the cream I know the actual penetration of the skin is a part of my needle pain, but the vessel itself being penetrated is. It also continues to hurt the entire time the needle is in the vein and a lot when it is removed.

I have asked many technitians and they always say "it's not supposed to do that." I thought I was jsut a wimp with pain but it turns out hyperalgesia realted to this is a thing. Most people suck it up and power through, but I can't spend an hour in the blood draw lab letting the reaction pass.

It's not psychological because with the cream I can tell jokes and not even notice the procedure. The worst that happens when the cream works is I get lightheaded from dysautonomia issues.

 

[ShyestofFlies]

Hey, @JennyJenny. I like the idea that you draw pictures of your pain for your doctors. Dare I ask how doctors have reacted to the pictures?

I believe that the most distressing pain I experience -- and fortunately I don't experience it often -- is the feeling that the flesh of my forearms is coming off the bone.

Sorry to multi-post, though not flesh per se with my connective tissue disease I regularly feel as though my tissues are ripping from my bones, like tendons/ligaments/possibly muscles? I'm not great with internal anatomy so forgive me if that sounds very inaccurate.

Though it probably lends some credibility having a connective disease, doctors do not seem concerned nor do they do anything about the ripping/tearing sensations even though they are supposed to at least recomend you to PT depending on the disease at work.

Even a "RICE it!" would be more useful then "huh that's weird" "tell me about how that medication is working" or "How is this other symptom that I'm in charge of but isn't that big of a deal?"

 

[ShyestofFlies]

@Merry

They look at them and read what I wrote next to them with a straight face. I don't think they mind. The pictures are awful that is for sure but it gets the point across.

The charts you make there are apps now including some free ones for this! One I've tried recently is "nanolume" it is the easiest one because it lets you do lasso loops for your pain areas and have multiple layers.

It is free but some features require purchase. I never got into this one because I want them to have a female body to draw on rather than just a male body.

As some other women who use these apps mentioned, it uhh gets a little weird when you are describing reproductive organ pain in your uterus but your diagram is a dude.

I used to use another one but it required you to paint with your finger everywhere, and by that point I could do easier with paper and highlighters. That one was free but I lost the name, I can find if anyone is interested.