The NO! OH NOO! Theory and Suggestions For Treatment by Martin Pall

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The NO! OH NOO!

Theory and Suggestions For Treatment by Martin Pall Ph.D

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(http://phoenix-cfs.org/NO%20ONOO%20Theory%20Treatment%20Pall%2006.htm)

(Posted by Martin Pall on the CFSFMResearch chat group at .com on

March 27th, 2006)

" This is going to be long post. It contains the most important information

on the cause of CFS, FM, 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-

nitric superoxide peroxynitrite

oxide

 

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 biological tissues 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 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-

cycle 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.

2. The NO/ONOO_ cycle makes useful predictions in terms of therapy and this

helps confirm its role as the central cause of these chronic illnesses.

 

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

Tocopherols/Tocotrienols Anecdotal Reports

Selenium - None

Carotenoids - None

Flavonoids - Clinical Trial Data

Reductive stress relieving agents - Clinical Trial Data

Mitochondrial regeneration agents - Clinical Trial Data

L-Carnitine/Acetyl-L-carnitine - Clinical Trial Data

Hydroxocobalamin/B12 - Clinical Trial Data

Folic acid - Clinical Trial Data

Vitamin B6/pyridoxal phosphate - Anecdotal Reports

Riboflavin - None

Other B vitamins - None

Glutathione/glutathione precursors - Clinical Observations

alpha-Lipoic acid - None

Magnesium - Clinical Trial Data

SOD minerals/zinc, manganese, copper - None

NMDA antagonists - Clinical Trial Data

Riluzole - None

Taurine - None

Inosine/uric acid - None

Long chain omega-3 fatty acids - Clinical Trial Data

Agents that lower NF-kappa B activity - Anecdotal Reports

Curcumin - None

Algal supplements - Clinical Trial Data

Hyperbaric oxygen - Clinical Trial Data

Minocycline and Other Tetracyclines - Clinical Observations

Creatine - None

Lowered vanilloid activity - None

Carnosine - None

TRH - Clinical Observations

 

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

Whey protein-glutathione precursor

Guaifenesin-vanilloid antagonist?

NMDA blockers

Magnesium-lowers NMDA activity

Taurine-antioxidant and acts to lower excitotoxicity including NMDA activity

GABA agonists-GABA acts as an inhibitory neurotransmitter to lower NMDA

activity-these include the drug

neurotin (gabapentin)

Histamine blockers-mast cells which release histamine are activated by both

nitric oxide and vanilloid

stimulation and may therefore be part of the

cycle mechanism

Betaine hydrochloride (HCl)-Betaine lowers reductive stress, the

hydrochloride form should only be used in

those with low stomach acid.

Betaine (trimethylglycine) is also listed separately

in the protocol description

Flavonoids, including " bioflavonoids, " olive leaf extract, organic

botanicals, hawthorn extract

Vitamin E (forms not listed)

Coenzyme Q10 - acts both as antioxidant and to stimulate mitochondrial

function

A-lipoic acid

Selenium

Omega-3 and -6 fatty acids

Melatonin - as an antioxidant

Pyridoxal phosphate-improves glutamate/GABA ratio

Folic acid-lowers uncoupling of nitric oxide synthases

 

Agents from Teitelbaum Protocol Predicted to Down-Regulate NO/ONOO Cycle

Biochemistry

Daily energy B-complex-B vitamins including high dose B6, riboflavin,

thiamine, niacin and also folic acid.

These fall into four categories that I

have listed earlier in the chapter.

Betaine hydrochloride (HCl)-lowers reductive stress, hydrochloride -form

should only be taken by those

deficient in stomach acid

Magnesium as magnesium glycinate and magnesium malate-lowers NMDA

activity-often uses magnesium

 

injections

A-Lipoic acid-important antioxidant helps regenerate reduced glutathione

Vitamin B12 IM injections, 3 mg injections (does not state whether this is

hydroxocobalamin)-may act as

potent nitric oxide scavenger

Eskimo fish oil-excellent source of long chain omega-3 fatty acids. Lowers

iNOS induction, anti-inflammatory

Vitamin C

Grape seed extract (flavonoid)

Vitamin E, natural-does not state whether this includes g-tocopherol or

tocotrienols

Physician's protein formula, used as glutathione precursor

Zinc-antioxidant properties and copper/zinc superoxide dysmutase precursor

Acetyl-L-carnitine-important for restoring mitochondrial function

Coenzyme Q10-both important antioxidant properties and stimulates

mitochondrial function

 

Agents from Nicolson Protocol Predicted to Down-Regulate NO/ONOO- Cycle

Biochemistry

Other phosphatidyl polyunsaturated lipids-this and the phosphatidyl choline

are predicted to help restore

the

oxidatively damaged mitochondrial inner membrane

Magnesium-lowers NMDA activity, may aid in energy metabolism

Taurine-antioxidant activity and lowers excitoxicity including NMDA activity

Artichoke extract-as flavonoid source?

Spirulina-blue-green alga is a concentrated antioxidant source

Natural vitamin E-does not tell us whether this includes g-tocopherol or

tocotrienols

Calcium ascorbate-vitamin C

a-Lipoic acid-important antioxidant, key role in regeneration of reduced

glutathione, but also has role in

energy metabolism

Vitamin B6-balance glutamate and GABA levels, lowers excitotoxicity

Niacin-role in energy metabolism

Riboflavin-important in reduction of oxidized glutathione back to reduced

glutathione; also has important

role in mitochondrial function

Thiamin-role in energy metabolism

Vitamin B12-as nitric oxide scavenger?

Folic acid-lowers nitric oxide synthase uncoupling

 

Agents from Petrovic Protocol Predicted to Down-Regulate NO/ONOO- Cycle

Biochemistry

Valine and isoleucine-branched chain amino acids known to be involved in

energy metabolism in

mitochondria, and may be expected, therefore,

to stimulate energy metabolism;

modest levels may also lower excitotoxicity

Pyridoxine (B6)-improves balance between glutamate and GABA, lowers

excitotoxicity

Vitamin B12 in the form of cyanocobalamin-cyanocobalamin is converted to

hydroxocobalamin in the human

body but the latter form will be more active as a nitric

oxide scavenger, since it does not

require such conversion

Riboflavin-helps reduce oxidized glutathione back to reduced glutathione

Carotenoids (alpha-carotene, bixin, zeaxanthin and lutein)-lipid (fat)

soluble peroxynitrite scavengers

Flavonoids (flavones, rutin, hesperetin and others)

Ascorbic acid (vitamin C)

Tocotrienols-forms of vitamin E reported to have special roles in lowering

effects of excitotoxicity

Thiamine (aneurin)-B vitamin involved in energy metabolism

Magnesium-lowers NMDA activity; may aid energy metabolism

Zinc-precursor of SOD

Betaine hydrochloride (HCl)-lowers reductive stress, hydrochloride form

should only be used by those

deficient in stomach acid

Essential fatty acids including long chain omega-3 fatty acids

Phosphatidyl serine-reported to lower iNOS induction

 

Agents from Pall/Ziem Protocol Predicted to Down-Regulate NO/ONOO- Cycle

Biochemistry

Nebulized, inhaled reduced glutathione

Nebulized, inhaled hydroxocobalamin (some use sublingual)

Mixed, natural tocopherols including g-tocopherol

Buffered vitamin C

Magnesium as malate

Four different flavonoid sources: Ginkgo biloba extract, cranberry extract,

silymarin, and bilberry extract

Selenium as selenium-grown yeast

Coenzyme Q10

Folic acid

Carotenoids including lycopene, lutein and b-carotene

a-Lipoic acid

Zinc (modest dose), manganese (low dose) and copper (low dose)

Vitamin B6 in the form of pyridoxal phosphate

Riboflavin 5'-phosphate (FMN)

Betaine (trimethylglycine)

Dr. Ziem has recently added two additional agents: green tea extract

(flanonoids) and acetyl L-carnitine.

 

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. "

--

Martin L. (Marty) Pall

Professor of Biochemistry and Basic Medical Sciences

Washington State University

phone 509-335-1246

fax 509-335-9688