Novel Disease Paradigm Produces Explanations for a Whole Group of Illnesses

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Novel Disease Paradigm Produces Explanations for a Whole Group of Illnesses

_http://molecular.biosciences.wsu.edu/Faculty/pall/pall_main.htm_

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

A Common Causal (Etiologic) Mechanism for Chronic Fatigue Syndrome, Multiple

Chemical Sensitivity, Fibromyalgia and Posttraumatic Stress Disorder

Martin L. Pall, Professor of Biochemistry and Basic Medical Sciences

Washington State University

_martin_pall_ (martin_pall)

509-335-1246

Specific web pages:

_Multiple Chemical Sensitivity_

(http://molecular.biosciences.wsu.edu/Faculty/pall/pall_mcs.htm)

_Chronic Fatigue Syndrome_

(http://molecular.biosciences.wsu.edu/Faculty/pall/pall_cfs.htm)

_Fibromyalgia _

(http://molecular.biosciences.wsu.edu/Faculty/pall/pall_fibro.htm)

These four illnesses, chronic fatigue syndrome (CFS), multiple chemical

sensitivity (MCS), fibromyalgia (FM) and post-traumatic stress disorder (PTSD)

often occur together in the same individuals (they are comorbid) and share many

symptoms in common (1-15). Gulf War syndrome is a combination of all four

(16-20). These four illnesses also share a common pattern of case initiation

(15,21): Each is often initiated (that is started) by a short-term stressor

only to be followed by chronic illness that typically lasts for years and often

for life. These various similarities and overlaps among these four have led

many scientists to suggest that they may share a common etiology (cause),

however they have been uncertain what the cause may be. I will call these four

illnesses multisystem illnesses, following the lead of some others, and will

challenge here the claims they are unexplained and that even their symptoms are

unexplained. Indeed my goal for this web page is to provide a detailed

explanation for their overall mechanism and provide a proposed mechanism for

many

of the symptoms and signs that they share. Therapy should be based on

down-regulating the overall mechanism. In web pages linked to this one, I will

discuss some specific features of each of these illnesses and how each of these

specific features may be generated by this same basic mechanism.

This web site outlines the understanding of these illnesses that is

documented in great detail in my forthcoming book (21).

Short-Term Stressors and the Cycle They Initiate

The stressors implicated in the initiation of these illnesses (21) are

summarized in Table 1.

Table 1 Illnesses Initiated by Short Term Stressors

IllnessStressors

Chronic fatigue syndrome

Viral infections, bacterial infections, physical trauma, severe

psychological stress, carbon monoxide exposure, organophosphorus pesticide

exposure,

ciguatoxin exposure, toxoplasmosis (protozoan) infection

Multiple chemical sensitivity

Volatile organic solvent exposure, organophosphorus/carbamate pesticide

exposure, organochlorine pesticide exposure, pyrethroid pesticide exposure

Fibromyalgia

Physical trauma (particularly head and neck trauma), viral infections,

bacterial infections, autoimmune diseases (secondary fibromyalgia), severe

psychological stress

Post-traumatic stress disorder

Severe psychological stress; physical (head) trauma

The stressors most commonly involved in the initiation of each type of

illness are indicated in bold face.

These 12 diverse stressors can all act to increase the levels of the

compound nitric oxide in the body (15,21-27). Eight of these have been shown to

increase nitric oxide in animal models and/or in humans. The other four,

ciguatoxin, severe psychological stress, organochlorine pesticides and

pyrethroid

pesticides, have all been shown to initiate a response that leads to increased

NMDA receptor activity and it is known that increased NMDA receptor activity

produces increased levels of nitric oxide and its oxidant product,

peroxynitrite. Thus, all 12 can produce a common biochemical response and the

consequent

increase in nitric oxide may explain the common roles of these stressors in

initiating cases of these chronic illnesses. How can a short-term increase in

nitric oxide produce chronic illness that typically lasts for years and

often for life? It may be argued that it may act through its oxidant product,

peroxynitrite, to initiate a vicious cycle mechanism which is responsible for

the chronic illness. In other words, we have an initial cause (one or more

short-term stressors) and then an ongoing cause of chronic illness (vicious

cycle). The cycle that is proposed to be responsible is diagrammed in Figure 1

(15,21-28).

 

Fig. 1 legend. Vicious (NO/ONOO-) cycle diagram.

Each arrow represents one or more mechanisms by which the variable at the

foot of the arrow can stimulate the level of the variable at the head of the

arrow. It can be seen that these arrows form a series of loops that can

potentially continue to stimulate each other. An example of this would be that

nitric oxide can increase peroxynitrite which can stimulate oxidative stress

which

can stimulate NF- kB which can increase the production of iNOS which can, in

turn increase nitric oxide. This loop alone constitutes a potential vicious

cycle and there are a number of other loops, diagrammed in the figure that

can collectively make up a much larger vicious cycle. The challenge, according

to this view, in these illnesses is to lower this whole pattern of elevations

to get back into a normal range. You will note that the cycle not only

includes the compounds nitric oxide, superoxide and peroxynitrite but a series

of

other elements, including the transcription factor NF- kB, oxidative stress,

five inflammatory cytokines (in box, upper right), all three different forms

of nitric oxide synthases (iNOS, nNOS and eNOS), and two neurological

receptors the vanilloid receptor and the NMDA receptor.

We are now calling this cycle the NO/ONOO- cycle, based on the structures of

nitric oxide (NO) and peroxynitrite (ONOO-), but pronounced no, oh no!

One of the features of the NO/ONOO- cycle that may not be obvious from Fig.

1, is that mitochondrial (energy metabolism) dysfunction is an integral part

of the cycle. It is known that peroxynitrite attacks a number of the

components of mitochondria, inhibiting their ability to generate energy in the

form

of ATP (21,23,25). Several of these components are certain proteins known as

iron-sulfur proteins and have key roles in the generation of energy in

mitochondria and are inactivated by peroxynitrite. Nitric oxide and superoxide

can

also inhibit energy metabolism in mitochondria, as well (21,25). The lowered

energy metabolism has important roles in the NO/ONOO- cycle, leading to

increased NMDA activity and increased levels of intracellular calcium (Ca 2+).

Lowered energy metabolism may also lead to lowered ability of the impacted cells

to recover from the impact of other elements of the cycle.

There are 22 different mechanisms represented by the arrows in the NO/ONOO-

cycle, of which 19 are well-accepted biochemistry (21). The other 3 are less

well documented, but have been reported in apparently reliable studies.

Overall, there is extensive evidence supporting the individual mechanisms of the

NO/ONOO- cycle and what needs to be questioned is its physiological relevance

to these multisystem illnesses.

Five Principles

There are five principles underlying the NO/ONOO- cycle as an explanatory

model of these illnesses (21), the first two of which we have already

discussed:

1. Short term stressors that initiate cases of multisystem illnesses

act by raising nitric oxide synthesis and consequent 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 and other cycle elements 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 the mechanisms involved in the cycle act at the level of individual

cells,

the fundamental mechanisms are local.

5. Therapy should focus on down-regulating NO/ONOO- cycle biochemistry.

I’ll discuss examples of principle 3 later on this web page as well on the

specific pages dedicated to three of these illnesses, multiple chemical

sensitivity, chronic fatigue syndrome and fibromyalgia.

The fourth principle is a very important one. Because the compounds

involved, nitric oxide, peroxynitrite and superoxide have relatively short half

lives

in biological tissues and because the mechanisms of the cycle act at the

cellular level, the basic mechanism of the cycle is local. Consequently, the

cycle may severely impact one tissue of the body but an adjacent tissue may be

largely unimpacted. Thus because the tissues impacted by the cycle may vary

from one patient to another, this easily explains why the symptoms and signs of

illness vary so much from one patient to another. This variability in

symptoms and signs has been one of the great puzzles of these multisystem

illnesses

and it is easily resolved by the NO/ONOO- cycle mechanism. I am not saying

that there are no systemic changes in these illnesses, but rather that the

main changes are local.

The fifth principle is the most important one for the sufferers of these

illnesses and for the dedicated physicians and other health care providers who

are trying to effectively treat them. We need to lower the NO/ONOO- cycle

biochemistry for effective treatment; treating symptoms will never be very

effective because symptomatic treatment does not get at the basic cause of

illness.

I will argue below that we do have five effective treatment protocols, each

using multiple agents that down-regulate NO/ONOO- cycle biochemistry.

Elevation of NO/ONOO- Cycle Elements in the Chronic Phase of Illness

The chronic phase of these multisystem illnesses, the only phase that can

usually be studied in humans, is typically studied years or decades after the

initiation of illness. Nevertheless, where NO/ONOO- cycle elements have been

studied, they have been reported to be elevated. Clearly one needs to explain

how these may be elevated years after the initiation of illness, and the

NO/ONOO- cycle mechanism provides such an explanation. Among the cycle elements

that have been studied are oxidative stress, nitric oxide synthesis,

inflammatory cytokine levels, lower mitochondrial/energy metabolism, NMDA

activity and

vanilloid activity. Peroxynitrite itself has not been studied but its

elevation can be inferred from the elevation of nitric oxide synthesis and of

oxidative stress. Some of these elements have only been studied in some

multisystem illnesses. For example, vanilloid activity has only been studied, to

my

knowledge, in FM and in MCS, being apparently elevated in both. Inflammatory

cytokines have only been studied in CFS, FM and in PTSD, but not in MCS; however

it is reported that chemical exposure can increase such cytokine levels.

In general, where data are available, elements of the NO/ONOO- cycle appear

to be elevated in the chronic phase of multisystem illnesses (15,21-28).

Three Generic Types of Evidence for the Existence of the NO/ONOO- Cycle

There are three generic types of evidence – that is evidence not linked to

any specific disease--supporting the existence of the NO/ONOO- cycle (reviewed

in my book, ref 21). One is a series of studies showing that treatment with

two drugs known to act to increase nitric oxide levels can produce increases

in nitric oxide synthesis. These two drugs, nitroglycerine and nitroprusside,

are both known to chemically break down and one of the break down products

is nitric oxide. They are reported to lead to increased nitric oxide synthesis

in the body due to the action of all three nitric oxide synthases. This

provides evidence for a vicious cycle leading to increased nitric oxide

synthesis

via all three synthases, but does not provide evidence for any of the other

elements of the NO/ONOO- cycle.

A second type of generic evidence is from studies of hyperalgesia, the

process that produces excessive perception of pain. It has been shown that all

of

the elements of the NO/ONOO- cycle are involved in the generation of

excessive pain hyperalgesia. It is difficult to see how all of these elements

can be

involved here unless they are linked together by such a cycle as the NO/ONOO-

cycle. What is surprising is that cycle elements are elevated both in the

painful tissues and also in that region of the spinal cord that is involved in

pain processing – the dorsal horn region(s) of the spinal cord. Thus two

types of regions of the body appear to have NO/ONOO- cycle elevation in

hyperalgesia. One of the consequences of these mechanisms is that it provides a

simple

explanation for the excessive pain in these multisystem illnesses – NO/ONOO-

cycle elevation produces chronic pain through the same mechanisms previously

documented in hyperalgesia.

The third type of generic evidence for the cycle reviewed in my book is the

finding that NMDA stimulation leads to increased activity for essentially all

of the elements of the NO/ONOO- cycle. NMDA stimulation is known to allow

the flow of calcium ions (Ca 2+) into the cytoplasm of the cell, leading, in

turn to stimulation of the two nitric oxide synthases that are

calcium-dependent, nNOS and eNOS. Thus two cycle elements are elevated

initially,

intracellular calcium and nitric oxide but this leads to elevation of the other

cycle

elements, as well. All the major elements of the NO/ONOO- cycle are reported to

be elevated following NMDA stimulation (21). This provides evidence that the

NO/ONOO- cycle or something very similar to it can act in living cells in

response to NMDA stimulation.

Shared Symptoms and Signs Found in Multisystem Illnesses

In Chapter 3 in my book (21), I look at a 17 distinct symptoms and signs

that are found in several of these multisystem illnesses and several of these

were discussed in an earlier paper (23). Most of these are often found in all

four of these illnesses, although there are some which have only been studied

in two or three of them. Most of these only occur in some patients,

reflecting the high variability of symptoms and signs that was discussed above.

Many

people have repeatedly claimed that these symptoms and signs are unexplained,

but that is no longer true. In my book and, in some cases, in an earlier

paper (23), I present a number of plausible mechanisms by which these symptoms

and signs can be generated by NO/ONOO- cycle elements. These are presented as

plausible mechanisms, not as established mechanisms in these illnesses.

Several of these are listed in Table 2:

Table 2 Plausible Mechanisms for Symptoms and Signs of Multisystem Illnesses

 

Symptom or sign Plausible mechanism

Learning and memory dysfunction

Excessive levels of nitric oxide in brain; energy metabolism dysfunction in

brain due to peroxynitrite, nitric oxide and superoxide

Fatigue

Energy metabolism dysfunction in brain due to peroxynitrite, nitric oxide

and superoxide

Chronic excessive pain

Hyperalgesia mechanisms due to all of the elements of the NO/ONOO- cycle

Anxiety/panic attack

Excessive NMDA activity in the amygdala of the brain

Brain PET scan abnormalities

Energy metabolism dysfunction leading to lowered fluorodeoxyglucose

transport in the brain; changes in blood flow produced by nitric oxide,

peroxynitrite

and isoprostanes

Brain SPECT scan abnormalities

Changes in accumulation of probe molecule due to lowered reduced glutathione

in brain (which is produce, in turn, by peroxynitrite-caused oxidative

stress)

Immune (NK-cell) dysfunction

Produced by oxidant damage and specifically by elevated levels of superoxide

 

Depression

Increased nitric oxide in brain

Sleep disturbance

Produced by elevated levels of inflammatory cytokines, increased nitric

oxide and increased NF- kB activity

Orthostatic intolerance

Two possible mechanisms, both involving nitric oxide: nitric oxide effects

on autonomic nervous system activity and also local nitric oxide-mediated

vasodilation

Irritable bowel syndrome

Nitric oxide and vanilloid effects on GI tract function

Food allergies

Peroxynitrite-mediated intestinal hyperpermeability, leading to increased

food antigen absorption and immune response to such antigens

Evidence for each of these is presented in my book (21).

It can be seen from Table 2, that a diverse group of shared symptoms and

signs can be generated via known mechanisms from elements of the NO/ONOO-

cycle,

providing plausible mechanisms for such symptom generation. Thus these

symptoms and signs should no longer be considered to be unexplained. I will

consider how what are viewed as unique symptoms of signs of MCS, CFS or FM may

be

generated on the web pages dedicated to each of these individual illnesses.

Therapy

The fifth principle of the NO/ONOO- cycle is that therapy should focus on

down-regulating NO/ONOO- cycle biochemistry. In other words, lower the cause of

illness. Let me state at the outset that I am a Ph.D., not an M.D. and

nothing here should be viewed as medical advice.

There are several challenges to therapies aimed at lowering NO/ONOO- cycle

biochemistry.

* The first of these is that we need to stop doing things that

up-regulate this biochemistry and there are various stressors that up-regulate

this

biochemistry therefore are of obvious concern.

* The second is that the complexity of the NO/ONOO- cycle makes it

difficult to down-regulate and makes it likely that we will need to use

multiple

agents in order to be effective in such down-regulation. We don’t have a

magic bullet to treat these illnesses and may have to rely, therefore, on

complex combinations of agents each of which may produce an incremental

improvement

by lowering aspects of the cycle mechanism.

* The third is that peroxynitrite, the most central element in the

NO/ONOO- cycle is difficult to effectively scavenge in vivo and therefore

approaches based solely on scavenging peroxynitrite may not be expected to be

effective.

Let’s consider the first of these challenges. Such stressors as chemical

exposure in MCS, excessive exercise in CFS and psychological stress, especially

in PTSD, should be avoided to have any expectation of effective therapy. Each

of these stressors are expected to up-regulated NO/ONOO- cycle activity in

these individual illnesses. Foods to which individuals have developed food

allergies should be avoided, as antibody-antigen reactions cause tissues to

increase nitric oxide synthesis. Excitotoxins can stimulate NMDA activity and

up-regulate NO/ONOO- cycle biochemistry and should therefore be avoided.

Excitoxins include monosodium glutamate, aspartame and possibly certain other

flavorings such as hydrolyzed vegetable proteins.

In Chapter 15 of my book, I consider 30 different agents or classes of

agents that are available today and are predicted to down-regulate NO/ONOO-

cycle

biochemistry and are predicted, therefore, to be potentially useful

therapeutic agents. I will add a 31 st such agent that was suggested to me by

Dr.

Jacob Teitelbaum. Each of these are listed in the long table that follows.

Table 3

Agents Predicted to Down-Regulate NO/ONOO Cycle Biochemistry

Agent (or class) Mechanism(s) Evidence

Tocopherols/

tocotrienols

Chain breaking antioxidants. Gamma-tocopherol may have special role in

peroxynitrite scavenging and tocotrienols are reported to have special roles in

protecting from excitoxicity

Ascorbate

Chain breaking antioxidant; may also scavenge peroxynitrite; helps to

regenerate other antixoxidants

CT

Coenzyme Q10

Stimulates mitochondrial function, scavenges peroxynitrite, lowers NMDA

activity

CT

selenium

Antioxidant properties, selenium compounds are peroxynitrite scavengers,

replete deficiencies

carotenoids

Scavenge peroxynitrite in membranes

flavonoids

Complex group of phenolic antioxidants with multiple and variable functions;

chain breaking antioxidants, lower NF- kB activity, scavenge peroxynitrite,

superoxide and nitric oxide, allow regeneration of other antioxidants

CT

TMG, choline, SAMe, others

Compounds with methyl groups attached to positively charged nitrogens or

sulfurs act to relieve reductive stress

CT

Carnitine/ acetyl carnitine

Improved transport of fatty acids into mitochondrion for energy metabolism

and regeneration of mitochondrial inner membrane; others?

CT

phospholipids

May allow regeneration of oxidized mitochondrial inner membrane lipids;

phosphatidyl choline may act to lower reductive stress

CT?

Hydroxocobalamin (B 12)

Potent nitric oxide scavenger; limited uptake when taken orally; other forms

of B 12 may act as precursor but with probable lower efficacy.

CT

Vitamin B 6; pyridoxal phosphate

Lowers excitoxicity by improving balance between glutamate and GABA

CO/A

Riboflavin and also 5’-phosphate

May increase glutathione reductase activity and thus increase reduction of

oxidized glutathione

Other B vitamins

Improve energy metabolism, replete deficiencies

Reduced glutathione and precursors

Reduced glutathione not effective taken orally; precursors should probably

be limited in dosage used. Most important antioxidant synthesized in body,

many functions.

CO/A

a-lipoic acid

Helps restore reduced glutathione, antioxidant activity, regenerate other

antioxidants, lowers NF- kB activity ; quality of supplements seems to be quite

variable

Mg 2+

Magnesium acts to lower NMDA activity, improve energy metabolism, replete

deficiencies

CT

Zn 2+, Mn 2+, Cu 2+

Precursors of superoxide dismutases, antioxidant activity, replete

deficiencies; doses should be modest

riluzole

Lowers glutamate release, excitoxicity

taurine

Lowers excitoxicity, NF- kB activity, iNOS induction, Ca 2+

NMDA antagonists; gabapentin

Lower excessive NMDA activity, lower response to chemical exposure in MCS

CT

Inosine

Increases uric acid pools which scavenges, in turn, peroxynitrite breakdown

products; may also act to speed recovery of ATP pools; possible down-side may

include increased mast cell activity

Long chain omega-

3 fatty acids

Lower iNOS induction, lower NF- kB activity, replete deficiencies

CT

Agents that lower NF- kB activity

Lower NF- kB activity

CO/A?

Curcumin

Similar of flavonoids in actions

Algal supplements

Rich in antioxidants

CT

Hyperbaric O 2 treatment

May act via hydrogen peroxide to induce synthesis of tetrahydrobiopterin and

therefore decrease NOS uncoupling

CT

Minocycline/ tetracyclines

Lowers iNOS induction, NMDA activity

creatine

Lowers excitotoxicity

Lowers vanilloid activity, Panax ginseng? Guaifenesin?

Expected to lower vanilloid activity

CO/A?

carnosine

Reported peroxynitrite scavenger, unusual antioxidant

TRH

Lowers NMDA activity

D-ribose

Increases recovery of ATP pools after energy metabolism dysfunction; may

increase reduction of oxidized glutathione

CO/A

Evidence is listed as being clinical trial evidence (CT) or clinical

observations/anecdotal evidence (CO/A) or none, based solely on studies of CFS,

MCS,

FM or closely related illnesses.

It can be seen from Table 3 that there are many different agents that are

promising candidates for therapy. Most of them are nutritional supplements.

There is some evidence for efficacy of individual agents based on clinical

trials (CT) or from clinical observations and/or anecdotal evidence (CO/A) but

in

most cases, the individual agents where they seem to be effective, have

relatively modest effectiveness. The suggestion is that combinations of these

agents may be much more effective than individual agents. This combination

therapy has been the approach taken by five different physicians in developing

their treatment protocols and such combination therapy approaches appear to be

the most promising of all therapeutic approaches for treatment of these

illnesses.

Five physicians have developed complex treatment protocols for these

multisystem illnesses. Three of these have focused on the treatment of chronic

fatigue syndrome or closely related fatiguing illness, one on both chronic

fatigue

syndrome and fibromyalgia and one on chemically sensitive patients. Each of

these protocols uses from 14 to 18 different agents or classes of agents that

are predicted to down-regulate NO/ONOO- cycle biochemistry! While two of

these protocols (Teitelbaum’s and Cheney’s) contain substantial numbers of

agents not obviously related to the NO/ONOO- cycle, each contains many agents

predicted to down-regulate the cycle. The treatment protocols are outlined in

the lists that follow:

Dr. Paul Cheney has developed his treatment protocol based on clinical

observations and has honed it over the past two decades of treatment of chronic

fatigue syndrome patients. He advises trying to avoid things that exacerbate

the NO/ONOO- cycle mechanism, some of the same things that I discussed above.

Specifically he suggests attenuating GI tract problems by such strategies as

going on a low food allergen diet, minimizing environmental chemical exposure

and also minimizing inflammatory diseases, such as around the teeth. The

agents that I list are followed, in some cases, by comments on how they may

act—

those comments are mine, not Cheney’s.

* High dose hydroxocobalamin (B12) injections— potent 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 neurontin (gabapentin)

* Histamine blockers—mast cells which release histamine are activated

by both nitric oxide and vanilloid stimulation (Chapter 7) 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

Antioxidants listed as follows:

* 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 that may act in the brain

* Pyridoxal phosphate—improves glutamate/GABA ratio

* Folic acid—lowers uncoupling of nitric oxide synthases

Cheney prescribes for his patients a total of 18 distinct agents or classes

of agents, each of which can be viewed as down-regulating aspects of the

NO/ONOO- cycle. I would argue that this in not just coincidental, that it

argues

in support of the NO/ONOO- cycle mechanism.

Dr. Jacob Teitelbaum has published placebo-controlled trial data supporting

the efficacy of one version of his protocol (29,30), something none of these

other physicians has done. It seems to be effective on both chronic fatigue

syndrome and fibromyalgia patients. I am going to describe a recent version of

his complex protocol, focusing on what may be the central parts of the

protocol, the parts described as “nutritional treatments†and

“mitochondrial

energy treatments.†The last agent in the list, D-ribose, was added to the

protocol recently (personal communication).

* Daily energy B-complex—B vitamins including high dose B 6,

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 B 12 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

* D-ribose—acts to increase rate of ATP and reduced glutathione

regeneration

If you consider that the oral B vitamins fall into four categories listed

earlier in the chapter, Teitelbaum uses a total of 18 agents or classes of

agents that are predicted to down-regulate the NO/ONOO- cycle, in the core part

of his treatment protocol.

Dr. Garth Nicolson started his scientific career developing the famous

Singer/Nicolson, fluid mosaic model of biological membranes, a model that is

described in essentially all of the standard biochemistry textbooks. He and his

colleagues have published on open label trials of a complex proprietary mixture

known as NT factor TM, apparently designed to improve mitochondrial and thus

energy metabolism function. The trials have been on a group of older

patients with unexplained chronic fatigue, and consequently there is some

question

whether these patients have CFS. Nevertheless, Nicolson and coworkers (31-33)

report statistically significant improvements in fatigue and in several other

changes often found in multisystem disease patients, affective/meaning,

sensory and cognitive/mood. Many of the NT factor components are predicted to

lower much of the NO/ONOO- cycle biochemistry. Unfortunately, there is no

detailed description of the concentrations of the components of the NT factor

proprietary mixture. The mixture contains the following components that are

predicted to lower NO/ONOO- cycle biochemistry:

* Polyunsaturated phosphatidyl choline—predicted to lower reductive

stress

* 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 highly 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 B 6—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 B 12—as nitric oxide scavenger?

* Folic acid—lowers nitric oxide synthase uncoupling

The way I have categorized these earlier on this site and in Chapter 15 of

my book, these agents fall into 15 distinct classes of agents expected to

lower NO/ONOO- cycle biochemistry.

Dr. Neboysa (Nash) Petrovic is a South African physician who, I believe,

also has a clinic in England. His CFS treatment protocol (34) has been

described

as follows (I am unsure how current this is):

* 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 (B 6)—improves balance between glutamate and GABA, lowers

excitotoxicity

* Vitamin B 12 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

* Zinc

* 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 (35,36)

According to the way I have listed these agents, his protocol contains 14

agents or classes of agents predicted to down-regulate NO/ONOO- cycle

biochemistry.

My Own Effort to Develop a Treatment Protocol

My effort to apply the NO/ONOO- cycle mechanism to the treatment of these

multisystem illnesses was in cooperation with Dr. Grace Ziem in Maryland. The

history of this collaboration and our respective roles are described in my

book. The protocol was developed to try to effectively treat Dr. Ziem’s

chemically sensitive, chemically injured patients, patients that she does not

consider to be MCS patients. Her views on this are described in my book (21)

and on

her web site (37).

The protocol described below is only effective, according to Dr. Ziem when

her patients minimize chemical exposure, consistent with the view that we need

to avoid up-regulating the NO/ONOO- cycle for these agents to be effective.

The protocol as described in my book contains the following agents:

* 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 B 6 in the form of pyridoxal phosphate

* Riboflavin 5’-phosphate (FMN)

* Betaine (trimethylglycine)

Patients are advised to use environmental controls to reduce exposure to

volatile organic solvents, pesticides and other irritant chemicals wherever

possible. Dr. Ziem finds that her most severely chemically injured patients

need

to be started on much lower doses of the glutathione and a -lipoic acid,

increasing exposure as they see initial improvement. The therapeutic agents

were

compounded by Key Pharmacy in Kent, Washington which has been calling it

their “neural sensitization protocol.†Key Pharmacy has a web site that

lists

their email address and phone number and consequently further information can

be easily obtained.

Dr. Ziem reports four distinct observations about her patients (21):

* The majority of her patients suffering from reactive airways were

placed on this protocol during the first half of 2004 and almost all of them

were on it or most of it by spring 2005. Patients coming back to see her report

consistent improvement of their symptoms, including respiratory symptoms,

fatigue, cognitive function and usually migraine. Improvements were well above

those seen with her previous treatment approach.

* Historically, Dr. Ziem has gotten many emergency calls each summer

from patients who have become very ill from nearby pesticide spraying. In the

summer of 2004 she did not receive any such calls from her patients on the

protocol. In the summer of 2005 she received only one such call, from a patient

on the protocol who was directly exposed to pesticide spray.

* Two of her patients reported being completely asymptomatic,

something she had not seen before. These were, however, still controlling their

environment to minimize exposure and still on the protocol.

* Patients seem to be improving at such a rapid rate that many are no

longer coming in regularly to see her. She is now able to take new patients

at 10 to 15 times the previous rate. In order to assess the progress of the

patients who are no longer coming in, Mr. Jim Seymour has contacted 30 such

patients and all 30 report substantial improvement in their symptoms. However,

the majority of them are not on the complete protocol, reporting that they are

unable to afford it. Seymour’s subjective assessment is that those on the

complete protocol have seen much greater improvement than have those on only

part.

As of the beginning of 2006, two additional agents are being added to the

oral part of the protocol, acetyl-L-carnitine and taurine. We are considering

adding one or two flavonoid-containing extracts that scavenge superoxide. The

current protocol, then contains 17 different agents or classes of agents that

are predicted to down-regulate NO/ONOO- cycle biochemistry.

Dr. Ziem states, in a personal communication (21) that “I consider the

protocol to be the most significant medical advance ever for chemical injury,

but

it is not a substitute for environmental controls. It does gradually allow

patients to be in social environments with fewer symptoms and less severe

exacerbation.â€

I have talked with other physicians who have used this protocol with

apparent favorable response in their CFS and FM patients. It may be effective,

therefore, in a variety of NO/ONOO- cycle diseases.

The Tenth Paradigm of Human Disease

What we have been describing here is an etiologic mechanism centered on

certain morbid processes which explain the four multisystem illnesses and

possibly other diseases/illnesses both prominent and obscure. It argues that

the

multisystem illnesses are true diseases caused by this mechanism, albeit

diseases that are highly variable from one individual to another because of the

variation of tissue distribution of the underlying biochemistry. They

constitute,

in other words, a disease spectrum.

The NO/ONOO- cycle mechanism fits into the history of diseases (21, Chapter

14) as shown in Table 4:

Table 4 Ten Paradigms of Human Disease

Infectious disease

1. Nutritional deficiency disease, such as beri beri or scurvy

2. Genetic disease—those whose predominant cause is mutation of a

specific gene

3. Hormone dysfunction disease, including those with too much or too

little hormone function

Serial somatic mutation and selection—various types of cancer

Ischemic cardiovascular disease

1. Allergies

2. Autoimmune disease

3. Amyloid diseases including prion diseases

NO/ONOO- cycle diseases

The reported prevalences of multisystem illnesses have been fairly

well-studied in the U.S. at least, and they are comparable with the prevalences

of the

other major disease paradigms, shown in bold face. It can be argued that the

tenth paradigm, NO/ONOO- cycle diseases, may well be one of the top four

disease paradigms in terms of its overall impact on human health.

Could It Be Wrong?

Could the NO/ONOO- cycle explanation of multisystem illnesses be wrong?

Could this tenth paradigm of human disease be fictional?

There are certainly many areas where there are little or no data to support

predictions of the cycle model and many others where the data that is

available is inadequate to support current standards of evidence. In addition,

the

cycle as outlined in Figure 1 may be oversimplified both because certain

aspects of it may be missing in certain tissues and because additional cycle

elements are likely to be involved in certain tissues, as well. Nevertheless the

therapy discussion strongly suggests that the cycle makes very useful

predictions in terms of therapy and therefore is sufficiently comprehensive to

be a

useful, predictive model.

Let me focus on two important features. Firstly it is the only explanatory

model that explains not just one but all of these multisystem illnesses.

Consequently it is the only available model to fit the prediction that many

scientists have made that these must share a common etiologic mechanism.

Secondly,

the cycle mechanism itself as diagrammed in Figure 1 is based almost entirely

on well-established biochemical mechanisms. The only thing that is new about

it is the assumption that the elements of the cycle fit together as

predicted by these mechanisms and constitute, therefore, a vicious cycle. It is

that

simple prediction that underlies all of the explanatory power of the model.

In the last chapter of my book, I list 12 puzzling features of these

illnesses that are explained by the NO/ONOO- cycle mechanism, including its

five

underlying principles. None of these had been previously explained and this

lack

of explanation has been what has led, in part, to the repeated claims that

these are unexplained illnesses. The 12 features explained by the NO/ONOO-

cycle are as follows:

It provides explanations for the etiology of not just one but all four of

these multisystem diseases.

1. It explains their chronic nature.

2. It explains how cases can be initiated by 12 diverse and distinct

stressors.

3. It explains the diverse biochemical and physiological properties of

the chronic phase of these diseases.

4. It explains how 18 different agents or groups of agents may

individually produce reported improvements and how the complex treatment

protocols of

five different physicians may lead to major improvements in sufferers.

5. It explains 16 of the shared symptoms and signs of these diseases,

symptoms and signs that have repeatedly been described as being previously

unexplained.

6. It explains the symptoms that are specific for each type of disease,

symptoms that can be explained by the influence of the NO/ONOO- cycle on

specific tissues.

7. It explains their high comorbidity with each other.

8. It explains their high comorbidity with such well-accepted diseases

as tinnitus, asthma, migraine, lupus and rheumatoid arthritis.

9. It explains 11 distinct puzzling feature of MCS, only one of which

was adequately explained previously.

10. It explains the properties of animal models of CFS, MCS and PTSD,

each of which provides evidence, in turn, supporting a NO/ONOO- cycle etiology.

 

11. It explains the stunning qualitative and quantitative variation in

symptoms from one patient to another.

If you take away the central mechanism of the NO/ONOO- cycle as it is

described in Figure 1, all of these explanations disappear and we are left with

an

unstructured list of unexplained observations. It is this stunning fit

between observation and prediction that tells us that the basic features of the

NO/ONOO- cycle explanatory model cannot be wrong! The NO/ONOO- cycle explanatory

model is like an arch, where the basic cycle mechanism is the keystone. If

you remove the keystone, the whole arch collapses into a rubble of scattered

stones and it is the complete collapse that tells us how the arch is organized

to make a compelling structure. The cycle mechanism, which is based on a

simple and evident assumption, is the keystone that is essential for

understanding these multisystem illnesses.

Richard Feynman, the great 20 th century scientist was called by Omni

magazine “the smartest man in the world†and has also been considered to be

a

great skeptic. Feynman wrote that “It is possible to know when you are right,

way

ahead of checking all the consequences. You can recognize truth by its

beauty and simplicity.†It is that beauty and simplicity and comprehensiveness

that tells us that the NO/ONOO- cycle model is fundamentally right.

Specific web pages:

_Multiple Chemical Sensitivity_

(http://molecular.biosciences.wsu.edu/Faculty/pall/pall_mcs.htm)

_Chronic Fatigue Syndrome_

(http://molecular.biosciences.wsu.edu/Faculty/pall/pall_cfs.htm)

_Fibromyalgia_

(http://molecular.biosciences.wsu.edu/Faculty/pall/pall_fibro.htm)

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