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Rituximab study in norway. An application to The Research Council of Norway

IreneF

Senior Member
Messages
1,552
Location
San Francisco
Thank you, DanielBR. When's the exam?

I don't see how vascular effects can explain all the symptoms we experience. Some of them, maybe, but I think they are downstream effects consequent to something else.

I wish someone could explain why we have problems with NK cells.
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
@Jonathan Edwards, thank you so much for contributing. Are we sure that Viagra/Cialis have no effect at all? They should increase NO, shouldn't they?

Do we want to increase NO?

There was a placebo-controlled trial of Viagra in CFS patients starting like 4 years ago or something (in the USA), but the results have not been published to date, I think the trial may have ended early or something.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
It sounds from DanielBR's excellent trawling that viagra does increase NO, but only locally maybe - perhaps including lungs.

For what it's worth my suspicion is that NO in the lungs is not going to make people feel too good. Having had a prostate cancer taken out I have used viagra. On one occasion I made the mistake of using it while on a week's high altitude off piste ski-ing trip (3000M). That day I felt short of breath, nauseous and my legs wouldn't work. I had to go home to rest. Maybe what is needed is more NO somewhere else!
 

deleder2k

Senior Member
Messages
1,129
Does Cialis work in the same way? I have 30 pills. My GP said it was safe to combine it with propranolol, so I might give it a try.
 

deleder2k

Senior Member
Messages
1,129
Aha.. Ok. Looks like there was a Viagra study in the planning called "CLINICAL TRIAL: USE OF SILDENAFIL (VIAGRA) TO ALTER FATIGUE". Looks like it is postponed or cancelled. Not sure why that is.
 

Forbin

Senior Member
Messages
966
Its not an unreasonable hypothesis about B cell interaction with endothelial layers, giving rise to NOS irregularities. Indeed the Tenth Paradigm stuff from Martin L. Pall is about this kind of thing, though he emphases feedback loops.

Do we want to increase NO?

Not that I pretend to really understand this stuff, but Dr. Martin Pall's hypothesis seems to be that high levels of NO "initiate" ME/CFS and are then maintained by various loops. It doesn't sound like you would want to increase NO under that hypothesis.

It can be seen, from the above, that the pattern of evidence implicating elevated nitric oxide synthesis activity in the initiation of CFS/ME cases is quite striking. How can nitric oxide act to initiate these illnesses? By acting mainly through its oxidant product peroxynitrite to initiate the vicious cycle mechanism (1), the NO/ONOO- cycle, that is responsible for chronic illness.

http://www.thetenthparadigm.org/cfsweb.htm
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I am fairly sure that blanket increases in NO production are not what we want. What we want is to restore normal NO regulation and function. In particular, we want to prevent production of peroxynitrite, while maintaining normal NO. Nobody said this would be easy. I suspect adenosyl cobalamin might have a role there.
 

Sasha

Fine, thank you
Messages
17,863
Location
UK
I am fairly sure that blanket increases in NO production are not what we want. What we want is to restore normal NO regulation and function. In particular, we want to prevent production of peroxynitrite, while maintaining normal NO. Nobody said this would be easy. I suspect adenosyl cobalamin might have a role there.

I took some sublingual adenosyl cobalamin at an early point in Fred's methylation protocol and it was as though my batteries were suddenly being charged. I could actually feel it happening within about 30 seconds. I continued taking it (of course!) and had more energy than normal for a few days, could walk much further than before, and then it all started to go into reverse and I ended up getting very debilitated over the subsequent weeks, despite taking plenty of potassium. I've tried two different methylation protocols since then and got the same severe debilitation. I tried the cobalamin again, of course, but no effect.

It was a strange experience. Usually nothing has any effect on me, and I've tried loads of things. However, given what happened, I'd certainly buy the idea that adenosyl cobalamin has some kind of role to play, at least at some point.
 

deleder2k

Senior Member
Messages
1,129
Yes, if autoimmune plasma cells and useful plasma cells had the same half life then rituximab would be not much use for those diseases where it has to be given repeatedly. For those diseases that can go into long term remission with rituximab (because the signals to generate a new lot of autoimmune cells seem to have been cleared out) it would still work very well.

@Jonathan Edwards, I found something more on plasma exchange. This is from Fluge and Mellas application for the study KTS-3-2010, B-lymphocyte depletion with very severe chronic fatigue syndrome, which ended in 2013.

Our hypothesis is that chronic fatigue syndrome is an autoimmune disease, often triggered by infections. After treatment with Rituximab, patients experience fast B-cell depletion, yet it takes 2-8 months before the signs of clinical response to ME symptoms. The time course of response, delayed in relation to the B-cell reduction is best compatible with the gradual elimination of autoantibodies from the plasma. For the poorest group of patients in KTS-3-2010 with significantly reduced functional level, we believe it may take a long time (up to one year) before they see responses after Rituximab treatment alone, if there is a correlation between the level of presumptive autoantibodies and disease severity. It causes a strain for patients to travel to hospital (or from elsewhere in the country) for treatment every three months. Based on the hypothesis of disease-specific autoantibodies, it is a logical to try plasma exchange as initial therapy for this group, followed by Rituximab treatment as outlined in the minutes of KTS-3-2010. The hypothesis is that a faster removal of autoantibodies by a series of plasma replacements (in this case five treatments) followed by an immunosuppressive maintenance therapy, may result in a faster clinical response such as is known in certain immunological disorders with varying systemic manifestations (such as Wegener's granulomatosis , Goodpasture's syndrome, Guillain Barré). We therefore wish to apply for amendment to the study KTS-3-2010, as we want to expand the study to 5 patients, and 3-5 of the poorest patients in the study treated with initial plasma exchange (by Division of Kidney Diseases, Department of Medicine, Haukeland University) followed by B-cell depletion, as outlined in the protocol for the study. Objectives of the amendment (addition) to the Protocol is to shorten the interval from study entry to the response experienced by patients, as well as evaluating tolerance for this procedure in severely ill ME patients. It will also help to shed light on disease mechanisms in severe chronic fatigue syndrome. For 3-5 patients in the study KTS-3-2010, with very severe chronic fatigue syndrome. We will conduct initial standard plasma exchange with albumin-Ringer solution (one plasma volume, up to 5 treatments) by temporary dialysis catheter in the groin or internal jugular vein, the 1-2 weeks. 3 weeks after plasma exchange initiation of B-cell depletion as indicated in the protocol for KTS-3-2010: Rituximab 500 mg/m2 (1000 mg) twice two weeks apart, followed by maintenance therapy with Rituximab (500 mg/m2 , max 1000 mg) after 3, 6, 10 and 15 months. Otherwise identical to the protocol for KTS-3-2010 as it is stated in the previous application.
For patients who have plasma exchange before initiation of rituximab treatment:
This appendix describes plasma exchange we will give you at the start, three weeks before starting treatment with Rituximab as outlined in the general patient information for the study. Our theory is that chronic fatigue syndrome is a so-called autoimmune diseases, and that the autoantibodies in the plasma produced from cells based on B-lymphocytes, that is, antibodies that react against the body itself, instead of reacting to foreign substances in the environment. When a patient is treated with rituximab it depletes B cells rapidly but autoantibodies already present degrade slowly. For the most severely ill ME patients, it is possible that the amount of such autoantibodies in plasma is very high, and it may take a long time before patients achieve an improvement of symptoms by Rituximab treatment alone. It may be difficult for very sick ME patients having to wait up to one year of recovery, with several trips to the hospital for Rituximab infusions. We therefore believe it would be beneficial with plasma exchange before initiation of rituximab treatment aiming to rapidly reduce the amount of autoantibody so the patient can get improvement in symptoms earlier. Plasma replacement is an established procedure that takes place at the Renal Section, Department of Medicine, Haukeland University Hospital, under the leadership of Chief Einar Svarstad. The department has broad expertise and extensive experience with such a procedure from other diseases, including other autoimmune diseases where there is a need for rapid reduction of pathogenic autoantibody from the patient's blood (plasma). Before the procedure must be inserted a catheter into a vein either on the neck or groin, this is done with local anesthesia. During the procedure given a small dose of blood-thinning medication (heparin). The treatment usually takes about 2-3 hours each time, and usually repeated five times in one week. During the procedure carried blood through a filter that separates blood cells from blood plasma. Plasma containing the pathogenic autoantibodies removed and replaced with egg white solution (albumin), salts and water. Side effects you may experience during plasma exchange may be anxiety, nausea and dizziness. Serious complications are seen very rarely.
 

optimist

Senior Member
Messages
434
Location
Norway
I have no idea about this, but what about dialysis? Could that make a difference? If the issue is stuff in the blood, can't it just be replaced? Perhaps just with temporary effect?
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Thanks Deleder2K. I was aware that Oystein Fluge had treated some cases but I did not want to mention something discussed in conversation. I think I am allowed to say that we agreed that the results so far are hard to interpret either way. Neurologists in the UK, and probably elsewhere, are using plasma exchange to tackle distressing autoimmune neurological disease that needs tackling urgently, for which rituximab is slow. But to be of value that almost certainly needs to be followed up with other things like steroids and immunosuppressives. I constantly ask myself why ME does not seem to be so 'urgent'? There are probably three answers. One is that some of the other conditions include movement disorders that prevent any normal activity or even standing up or sleep. More tellingly though, we come back to the absence of an autoantibody marker in ME that would make theoretical justification solid and we do not have objective signs to measure, at least not consistently across a population. What I think is encouraging is that at least one neurological colleague, expert in this field, is ready to take the issue of autoimmunity and immunotherapy in ME seriously and share thoughts.

With regards to dialysis, Optimist, plasmapheresis is really just dialysis but at a different molecular size level. Dialysis gets rid of small molecules like urea. To get rid of antibody you need a filter that just saves cells and gets rid of proteins, replacing them with healthy plasma. In fact this is best done with a centrifuge. It is more complicated than dialysis because of the need to replace with donor plasma and because (at least in the past) it requires bigger shifts in and out of volume at any one time, which can cause problems for people with heart disease. Various specialised forms of '-pheresis' are now used in haematological disorders and it may be that the technique is now so much slicker than it was when most used in autoimmunity about thirty years ago that it should be considered more often. Having to use plasma is always an issue, however, since there is not an endless supply and it has its own potential unwanted effects.
 

NK17

Senior Member
Messages
592
I really like the direction this thread is taking and I'd like to thank @deleder2k for uploading resources that otherwise would be out of reach for most of us patients and clinicians/researchers alike.

I'd also like to thank @Jonathan Edwards for all his invaluable opinions, critical insight and say that he really gets all the nuances of our truly horrible disease. A disease that apparently doesn't kill, apparently does not paralyze. Apparently is not urgent.

To the untrained eye many of us look normal, but our daily realities are very much different. Many can't drive anymore, many can't leave their homes, or their beds and sofas, many can't stand up for a decent amount of time, many can't shower as frequently as they used to, many can't do all the things that normal human beings do. Some people with other very serious chronic diseases are able to do what PWME can't do.

Please keep up the urgent and much needed work.
 

NK17

Senior Member
Messages
592
@NK17, I think our main issue is that ME is not lethal. If all of me patients live a few years at the most, we would have seen research aimed at the disease decades ago.
Totally agree with you @deleder2k .
We have a serious medical problem that mainly impacts the quality of life.
One day we'll also have serious studies, done on strict cohorts of PWME, that will show that the quantity, or length of life span, can be impacted too.
 

DanME

Senior Member
Messages
289
@Jonathan Edwards Thank you so much for the incredible insight and information about plasma exchange. I am thrilled to hear, that Fluge and Mella thought about the possibility of eliminating antibodies in order to speed things up. Hopefully, they will get better data.
I remember, that MS patients sometimes get a round of plasma exchange during an active attack, if the high dose corticosteroid treatment fails to stop new symptoms.

A month ago I read a story about a ME patient in a German magazine, who had a benign brain tumor (I think vestibular schwannoma). Preparing the surgery, the doctors gave her cortisone infusions. She reported afterwards a relief of all her symptoms and never feeling better than after her brain surgery! The improvement lasted one month. I found the story quite remarkable and similar to the first patient of Fluge and Mella. Sadly she didn't get further treatment.

@deleder2k Did you try the Cialis pills and the betablocker? Arginine could help as well, but oral arginine is not very efficient in rising blood levels.