| The NO! OH NOO! Theory and Suggestions For Treatment |
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by Martin Pall Ph.D
(Posted by Martin Pall on the CFSFMResearch chat group at Yahoogroups.com on March 27th, 2006)
"This is going to be long post. It contains the most important information on the cause of [chronic fatigue syndrome] CFS, [fibromyalgia] FM, [multiple chemical sensaitivity] MCS and related illnesses and how to effectively treat them.
I have been working to the cause of these illnesses for almost 8 years and will have a book coming out on this and many related topics from Haworth Medical Press that will provide much more information than is in this post. Cases of each of these illnesses are initiated by short term stressors, but instead of recovering after exposure, people become ill with one or more these chronic illnesses. The stressors implicated include viral, bacterial and in a few cases, protozoan infections, physical trauma (most commonly to the head and neck but also including physical trauma to other regions of the body), chemical exposure to such chemicals a volatile organic solvents or such pesticides as organophosphorus/carbamates, organochlorine pesticides or pyrethroid pesticides, carbon monoxide exposure, severe psychological stress, certain mold toxins or ciguatoxin exposure. Each of these diverse stressors can initiate a process leading to increased nitric oxide levels. In some cases (infection) the iNOS form of nitric oxide synthase is involved but in most others, excessive NMDA activity is involved leading to increased nNOS activity. It follows that no single form of nitric oxide synthase is involved, but rather the common factor is nitric oxide. I have argued that the most important consequences of this are mediated not through nitric oxide itself but rather through the action of the oxidant product of nitric oxide, peroxynitrite.
Peroxynitrite synthesis
NO. + OO.- -------> ONOO-
How does this initiate these chronic illnesses? They act by initiating a biochemical vicious cycle which is responsible for these chronic illnesses: These arrows represent 22 distinct biochemical mechanisms whereby one of the parameters listed stimulate the next parameter connected by an arrow. Of these 19 are very well documented in the biochemical literature and the remaining three appear to be correct but are less well documented. This vicious cycle, which we are now calling the NO/ONOO- cycle (based on the structures of nitric oxide and peroxynitrite (but pronounced, no, oh no!) is responsible for the chronic nature of these illnesses.
The NO/ONOO- cycle is based on five distinct principles, two of which I have already described. These principles are as follows:
The NO/ONOO- cycle mechanism, can be summarized in five different principles:
1. Short-term stressors that initiate cases of multisystem illnesses act by stimulating nitric oxide synthase (NOS) activity and consequently produce increased levels of nitric oxide and its oxidant product peroxynitrite.
2. Initiation is converted into a chronic illness through the action of vicious cycle mechanisms, through which chronic elevation of nitric oxide and peroxynitrite is produced and maintained.
3. Symptoms and signs of these illnesses are generated by elevated levels of nitric oxide and/or other important consequences of the proposed mechanism, i.e. elevated levels of peroxynitrite or inflammatory cytokines, oxidative stress and elevated NMDA and vanilloid receptor activity.
4. Because the compounds involved, nitric oxide, superoxide and peroxynitrite have quite limited diffusion distances in biologicaltissues and because most of the mechanisms involved in maintaining the NO/ONOO- cycle act at the level of individual cells, the fundamental mechanisms are local. The consequence of this is that one tissue may be impacted by this underlying biochemistry while an adjacent tissue may be largely unaffected. The tissue distribution may be propagated indefinitely over time by these local vicious cycle mechanisms. This can lead to many differences in symptoms, depending on the tissue distribution variation, from one case to another. This is such an important principle that I have devoted an entire chapter to it (Chapter 4).
5. Therapy should focus on down-regulating elements of the NO/ONOO- cycle, rather than on just on providing symptomatic relief.
Let me comment on principles 4 and 5. The local nature of the NO/ONOO- cycle means that impact of the cycle on different tissues may be largely independent of each other. Because of this, the symptoms and signs shown by different sufferers of these illnesses are highly variable, depending on which tissues are impacted in which individuals. This variation has been a source of much concern in trying to understand these illnesses but is easily understood as being a consequence of the NO/ONOO- cycle mechanism.
Principle 5 states that therapy should focus on down-regulating NO/ONOO- cycle biochemistry, rather than on symptomatic therapy. The difficulty in doing so can be seen from the complexity of the cycle (Figure 1). Because the cycle has such high level complexity and because scavengers for peroxynitrite, the most central compound in the cycle are inefficient, the approach that may have the most traction is to use multiple agents, particularly well-tolerated nutritional agents, to down-regulate NO/ONOO- cycle biochemistry. This is likely to be the most promising approach to such therapy.
In Chapter 15 of my book, the longest chapter in the book, I discuss 30 different agents or classes of agents that are available today and are predicted to down-regulate NO/ONOO- cycle biochemistry. These are summarized in the table below. I follow with descriptions of treatment protocols independently developed by five different physicians, each of whom use from 14 to 18 agents or classes of agents predicted to down-regulate this biochemistry. While some of these use additional agents, not linked or less obviously linked to NO/ONOO- cvcle biochemistry, I would argue that this pattern is not coincidental. In other words, I argue that:
1. These protocols are largely effective because so many agents in them down-regulate NO/ONOO- cycle biochemistry.
Thirty agents or classes of agents predicted to down-regulate NO/ONOO cycle biochemistry:
Agent or Class of Agents Clinical Trial Data or Clinical Observation/Anecdotal Reports
Vitamin C (ascorbic acid) - Clinical Trial Data
You will note that there is clinical trial data on the efficacy of 12 of these agents or classes of agents, and there are clinical observations and/or anecdotal evidence of efficacy of six others. Nonetheless, each of these individually, have limited efficacy, suggesting that combinations may be more effective than are individual agents.
Treatment protocols of five different physicians
The comments after some of these agents are mine, not those of the physicians involved: These are listed in no particular order.
Agents from Cheney Protocol Predicted to Down-Regulate NO/ONOO- Cycle Biochemistry
High dose hydroxocobalamin (B12) injections - nitric oxide scavenger
Agents from Teitelbaum Protocol Predicted to Down-Regulate NO/ONOO Cycle Biochemistry
Agents from Nicolson Protocol Predicted to Down-Regulate NO/ONOO- Cycle Biochemistry
Agents from Petrovic Protocol Predicted to Down-Regulate NO/ONOO- Cycle Biochemistry
Agents from Pall/Ziem Protocol Predicted to Down-Regulate NO/ONOO- Cycle Biochemistry
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 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. In other words these are true diseases, with a defined morbid process and etiology, albeit ones with unusual variation from case to case due to the local nature of the underlying biochemistry. This is a major new paradigm of human disease, and there are other diseases/illnesses that are candidates for inclusion under this paradigm."
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Comments (6)
  written by paranovelgirl, March 12, 2009
It would be much simpler for 'we' who suffer from the illness if the lists were put in laymen's terms.
Thank you
written by g_mrrsn, January 24, 2010
Dr. Pall, thank you so much for your research and exlanation of MCS, GWS, PTSD, CF and FM. I have suffered from MCS since Oct 1997. I lost my job, my family, my friends, my church, and my savings have been depleted trying to fight and live with MCS. I found it to be the most debilitating disease on the planet.I call it the disease from Hell. Most, if not all, of us need to live in a bubble or glass enclosure.
I have researched and studied this malady and yours is the best explanation I have seen. I have been doing a number of the supplements you recommended, but how does one conquer the stress of this illness? I do not know. Chemicals permeate every area of society. Everything now seems to have to smell good, even Walmart bags. Since you have this disease, an article on how you manage daily living would be nice. For example what products have you found okay, clothing( I wear only old stuff washed over and over in soda and vinegar). I clean with soda and vinegar. I can't fix my hair or go to a beauty shoppe. Public places especially churches are full of perfume. How are you able to work? I found that oxygen helps after an exposure or would help avoid exposures, but can't get it because my COPD is not low enough. I have heard this called poor perfusion whereby carbon dioxide accumulates in the brain overriding the oxygen level and I need oxygen to flush the CO out and alleviate this perfusion problem. I sure hope you continue your research and that people and the medical field will finally stop calling us crazy and we can get relief. I have been told I was a universal reactor and nothing could help, but I believe as long as I am breathing there will be help eventually. I first began to understand this illnes from the book "Is This Your Child's World?" by Dr. Doris Rapp Buffalo NY. Thank you again and please keep searching for all of us. May God bestow his richest blesings on you. 
written by scrapladyandmore, April 19, 2010
Oh my...if I'm taking L-arginine and L-citrulline to control blood pressure ... "Some doctors report that elevating nitric oxide in hypertensive patients can lower blood pressure by 10 to 60 points." then I may be making my MCS symptoms worse?
Am I interpreting this correctly? Thanks
 written by Maff, June 28, 2010
This would seem to be the implications of Professor Pall's theory of NO's involvement in MCS - which has now been confirmed by independent researchers. I am afraid at this point I am not sure how to proceed in a situation such as yours. I will do some research into this. For the time-being please follow your doctor's advice and certainly do not stop any of your anti-hypertensive treatments without their recommendation to do so.
Take care, Maff
written by Newly Minted Cougar Fan, July 28, 2010
I was diagnosed with PTSD many years ago and suspect MCS given my hypersensitivity to chemicals (headaches,nausea). It seems to have worsened greatly since I moved from Western WA to the burbs surrounding one of the most polluted cities in the country a number of years ago. It makes sense.
When I've been asked to describe the PTSD, I've always said, "It's like walking around peeled or in a very "loud" environment with no way to turn down the volume" (the 'volume' included all sensory input, not just sound). I never realized there was a name for the olfactory overload aspect of this condition, if you can call it that. After reading several of your papers, it occurs to me that my relatively recent anecdotal find regarding GABA's ability to "turn down the volume" for the anxiety may similarly apply to the MCS symptomology given your theory on the role of Nitric Oxide. I may experiment with this and keep you posted, should you be interested. Otherwise, please know that your work has brought me a great deal of peace just knowing that I am not alone in this---that someone else out there cares about finding a solution to these maddening conditions. Thanks again--- a newly minted Cougar fan
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Anyway, meanwhile, you have a long list of product which might help but, as a layman, I'm not sure I could just go to the pharmacy and ask for one of them.
What can I do?
I'm not sure going to see a physician can help as this is such a new result it might not be widely known / accepted yet (after isn't MCS controversial?)