Nitric Oxide Cycle & ‘Unexplained’ Illnesses

[Guest guest]

See also next Help ME Circle:

*Nitric Oxide Cycle & Therapy*

~jvr

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http://www.immunesupport.com/library/showarticle.cfm?id=8071 & T=CFIDS_FM & B1=EM061\

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Nitric Oxide Cycle Theory: Will It Explain CFS, FM, and

Other 'Unexplained' Illnesses? - Q & A with L. Pall, PhD

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ImmuneSupport.com

06-11-2007

L. Pall, PhD, is generating excitement in scientific

communities worldwide with his theory that a " stressor-initiated "

biochemical mechanism - the nitric oxide/peroxynitrite

(NO/ONOO-) cycle - may be responsible for CFS, FM, and other

syndromes.

The attention began with publication of his new book:

*Explaining 'Unexplained Illnesses': Disease Paradigm for

Chronic Fatigue Syndrome, Multiple Chemical Sensitivity,

Fibromyalgia, Post-Traumatic Stress Disorder, Gulf War

Syndrome and Others.*

http://www.amazon.com/Explaining-Unexplained-Illnesses-Fibromyalgia-Post-Traumat\

ic/dp/078902389X/ref=sr_1_1/103-6953908-9698264?ie=UTF8 & s=books & qid=1181681200 & s\

r=8-1

In the following Q & A, Dr. Pall, Professor of Biochemistry and

Basic Medical Sciences at Washington State University,

explains his theory in lay terms especially for our readers. Simply

put, Dr. Pall proposes that the complex NO/ONOO- cycle he

describes may result in high levels of oxidants, which affect

different tissues in different individuals, accounting for a

" stunning " variety of symptoms. Dr. Pall also believes a regimen

of antioxidant supplementation may help the body

" downregulate " the NO/ONOO- cycle biochemistry.

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Q: Dr. Pall, you suggest that cases of chronic fatigue syndrome

(CFS), fibromyalgia (FM), multiple chemical sensitivity (MCS)

and post-traumatic stress disorder (PTSD) may all get started

(get " initiated " ) by similar mechanisms. What led you to that

conclusion?

Dr. Pall: Cases of each of these are initiated by certain

short-term stressors. These include both bacterial and viral

infections in CFS and FM, exposure to three types of pesticides

or to organic solvents, in MCS, to physical trauma in FM or

PTSD, or to severe psychological stress for PTSD or any of

these others. There are others, totalling 12 or 13 such stressors.

Each of these diverse stressors can increase levels of a

chemical compound called nitric oxide in the body. So I

proposed that nitric oxide is likely to have a role in the initiation

of chronic illness.

* * * *

Q: So how can nitric oxide act to initiate chronic illness?

Dr. Pall: That is a very important question. I proposed that nitric

oxide, acting via its product peroxynitrite, a potent oxidant, acts

to initiate a biochemical vicious cycle which is the cause of

illness.

This cycle, which we now call the NO/ONOO- (pronounced no, oh

no!) after the structure of nitric oxide (NO) and peroxynitrite

(ONOO-) is based on many well documented biochemical

mechanisms, and the combination of such mechanisms is a

complex vicious cycle which can propagate itself over time,

producing chronic illness.

So for each of these cases of illness, we have an initial cause,

one or more stressors, and an ongoing cause, the NO/ONOO-

cycle mechanism. The pronunciation no, oh no reflects both the

role of these two chemicals and the way people who suffer from

these illnesses feel.

* * * *

Q: What else can you explain about these illnesses?

Dr. Pall: Almost everything:

* How many of the symptoms are generated,

* Why these symptoms are variable from one individual to

another,

* Why these illnesses often occur together in the same

individuals,

* Why they also often occur with such diseases as asthma,

migraine headache, tinnitus, lupus or rheumatoid arthritis,

* And how they should be treated.

* * * *

Q: You have described five principles that summarize the

NO/ONOO- cycle mechanism as a model of disease. Please

describe these.

Dr. Pall:

* The first principle, which we have discussed, is that

NO/ONOO- cycle illnesses are initiated by stressors that can

raise levels of nitric oxide or other cycle elements.

* The second principle is that the chronic illness is caused by the

NO/ONOO- cycle and that ill people will, therefore, have raised

levels of various cycle elements.

* The third is that the symptoms and signs of illness must be

generated by the elements of the cycle.

* The fourth is that the basic mechanism is local. This local

nature is caused by the fact that the three chemicals that have

central role in the NO/ONOO- cycle, nitric oxide, peroxynitrite,

and a third chemical – superoxide – all have relatively short half

lives in biological tissues, so that they don't travel very far from

where they are produced to where they are destroyed. And the

mechanisms of the cycle act at the level of individual cells of the

body.

The consequences of these are that one person may have

certain tissues of their body impacted by this local NO/ONOO-

cycle biochemistry, but others may have different tissues

impacted, leading, in turn, to much variation in symptoms and

signs from one individual to another.

This variation in symptoms and signs of illness have been one of

the greatest puzzles of this group of illnesses, and this can be

explained easily with the current model.

* The fifth principle, the one that most sufferers as well as most

physicians should find of the most interest, is how to treat these

illnesses.

We should treat these by lowering (down-regulating) the

NO/ONOO- cycle biochemistry. In other words we need to treat

the cause of illness, not just the symptoms.

* * * *

Q: We'll get back to therapy shortly. You suggest that the

complexity of the cycle is the most difficult aspect in the effective

treatment of these illnesses. Why is that?

Dr. Pall: The cycle involves at least 22 different mechanisms, by

which one element of the cycle leads to an increase in another

element of the cycle. It is the combination of these mechanisms,

diagrammed by arrows in Figure 1 on my website and in my

book.

Figure 1 - see:

http://www.immunesupport.com/library/showarticle.cfm?id=8071 & T=CFIDS_FM & B1=EM061\

307F

The cycle involves many such mechanisms, as stated here, and

also such variables as the activity of a " transciption factor " called

NF-kappa B, which turns on the inflammatory cytokine genes

and a gene that encodes the inducible nitric oxide synthase

(iNOS), the levels of superoxide, the levels of calcium in the

cytoplasm of cells, and the levels of two receptor systems that

act mainly in the nervous system, the vanilloid receptors and the

NMDA receptors.

The cycle also involves decreased ability to make energy in the

form of ATP, due to the attacks of peroxynitrite on proteins and

other components in the mitochondria.

* * * *

Q: So how does this explain what we need to do for effective

therapy?

Dr. Pall: It is the complexity of the cycle that makes treatment

such a challenge.

I discuss many " agents " that are predicted to lower the

NO/ONOO- cycle biochemistry in the chapter of my book on

therapy (the longest chapter in the book). Twelve or 13 classes

of such agents that have been reported to produce significant

improvement in CFS, FM, or MCS in clinical trial studies and

others may also be useful, albeit with less evidence.

However, individual agents produce only modest improvements.

Five physicians have produced complex treatment protocols

having 14 or more agents predicted to down-regulate the

NO/ONOO- cycle biochemistry, and these complex protocols

appear to be much more effective than are the individual agents.

It is these complex combinations of agents that have the most

promise in the treatment of these illnesses. Most of these agents

are nutritional, but some are conventional pharmaceuticals and

some are " herbals. " [Dr. Pall refers to protocols developed by

Dr. Cheney, Dr. Garth Nicolson, Dr. Noboysa (Nash)

Petrovic, and Dr. Teitelbaum, as well as Dr. Grace Ziem -

with whom Dr. Pall has cooperated in his own efforts to evolve a

protocol.]

* * * *

Q: This treatment approach seems to the almost the opposite of

that usually used in modern medicine. Is that so?

Dr. Pall: You are quite right – this approach is opposite to the

predominant current approach to treatment. That predominant

approach dates from the development of wide spectrum

antibiotics in the 1940's and 1950's. That " magic bullet "

approach is still very effective in the treatment of many acute

bacterial infections. But it has been a failure with most chronic

diseases, which are rarely cured; and often one cannot even

greatly slow their progression.

The evidence of these five physicians suggests that we may be

able to get a good clinical response with our group of four

illnesses. Our goal should, in my view, be to get a substantial

number of cures and it is my hope that by improving this

approach, we will be able to do so.

* * * *

Q: We understand you have designed a protocol that is available

over-the-counter, is that right?

Dr. Pall: Yes, I have designed...an approach to down-regulating

the NO/ONOO- cycle biochemistry that involves only

over-the-counter supplements. [see " Antioxidant Suggestions

for Down-Regulation of the NO/ONOO- Cycle from Dr.

Pall, PhD " .]

Let me just caution that I am a PhD, not an MD, and none of this

should be viewed as medical advice, and that the supplements

included in the protocol are not sold as a treatment or cure for

any disease.

* * * *

Q: You argue, we take it from the title of the book, that these four

illnesses are true diseases and that the NO/ONOO- cycle is a

disease mechanism.

Dr. Pall: Exactly. I propose that the NO/ONOO- cycle is the tenth

paradigm of human disease, adding it to the nine well-accepted

disease paradigms described in Chapter 14 of my book.

It is unusual, however, primarily because the local nature of the

cycle leads to much variation of symptoms of illness, depending

on which tissues are impacted by the cycle and how severely

they are impacted. What we are dealing with here with CFS,

MCS, FM and PTSD is a huge spectrum of disease, with

stunning variations in different individuals.

* * * *

Q: Are there any other important breakthroughs proposed in your

book?

Dr. Pall: One very important breakthrough is that there are other

diseases that are good candidates for NO/ONOO- cycle

diseases. I suggest 14 additional diseases/illnesses that appear

to be good candidates for NO/ONOO- cycle diseases, including

such diseases as multiple sclerosis, tinnitus, Alzheimer's,

Parkinson's, amyotrophic lateral sclerosis, and asthma.

Each of these six has the apparent involvement of the

NO/ONOO- cycle in different tissues. Another disease that is a

candidate as a NO/ONOO- cycle disease is autism, where the

early onset and the impact of the cycle on the developing brain

may produce the characteristic properties of autism. Autism also

has a huge spectrum of disease, the autistic spectrum

disorders.

The criteria for other diseases/illnesses being candidates for

inclusion under the NO/ONOO- cycle paradigm are their fit with

the five principles we discussed earlier.

The possibility that this single mechanism may explain many

different diseases is truly stunning. But it should not be

completely surprising. There are dozens of diseases that are

chronic inflammatory diseases, and the NO/ONOO- cycle

involves inflammatory biochemistry, much the same

biochemistry that occurs in inflammation. Thus the NO/ONOO-

cycle may explain many of the diseases that are so predominant

in medicine.

* * * *

Q: What response has the scientific community given to your

theory?

Dr. Pall: The response has been truly amazing. I have just

returned from giving five talks in Europe, two in Britain, and three

in Spain. And the response at each of these talks has been

extraordinary. I have already been invited back to both countries

to give more talks. I am scheduled to give a talk in Mexico and

five others in the U.S. this year. My book sold out within a week,

with a second printing scheduled. I have had nine radio

interviews to date and still more will occur fairly shortly.

I have to say that I am amazed at how positive the responses

have been to date, especially when you consider how

conservative science tends to be and how difficult it usually is to

get acceptance of new scientific paradigms.

* * * *

Thank you very much, Professor Pall, for your responses to our

questions, and we hope to hear more about your ongoing work

in the future.

For More Information

If you are interested in reading a more detailed synopsis of Dr.

Pall's NO/ONOO- cycle concept - including a chart detailing

" plausible mechanisms " for the different signs and symptoms

associated with multisystem illnesses, from fatigue and memory

dysfunction to chronic pain and IBS - visit Dr. Pall's website at

http://molecular.biosciences.wsu.edu/Faculty/pall/pall_main.htm

___

* Dr. Pall's book, Explaining 'Unexplained Illnesses': Disease

Paradigm for Chronic Fatigue Syndrome, Multiple Chemical

Sensitivity, Fibromyalgia, Posttraumatic Stress Disorder, Gulf

War Syndrome and Others (Haworth Press, 2007) is available

through Amazon.com and may be ordered at your local

bookstore.

Note: This information has not been evaluated by the FDA. It is

not meant to prevent, diagnose, treat, or cure any illness,

condition, or disease. It is very important that you make no

change in your healthcare plan or regimen without researching

and discussing it in collaboration with your professional

healthcare team.