Therapy

Martin L. Pall

Professor Emeritus of Biochemistry and Basic Medical Sciences, Washington State University and Research Director, The Tenth Paradigm Research  Group

 

Other web pages:

Main Web Page

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Multiple Chemical Sensitivity

Fibromyalgia

Additional Possible NO/ONOO- Cycle Diseases

Five Principles

Allergy Research  Group Nutritional Support Protocol

 

The fifth principle of the NO/ONOO- cycle explanatory model is that therapy should focus on down-regulating NO/ONOO- cycle biochemistry, rather than on treatment of symptoms.  In Chapter 15 of my book (1) and elsewhere (2), I listed 30 distinct currently available agents or classes of agents that are predicted to down-regulate this biochemistry.  A 31^st was suggested to me by Dr. Jacob Teitelbaum, D-ribose, and is listed here as well.  A 32^nd, Ecklonia cava extract, is also listed.  Some of these have individually been found in clinical trial studies to provide significant improvement in one or more of the multisystem illnesses (1).  Efficacy of others is supported by clinical observations and/or anecdotal evidence whereas still other there is no such evidence available.  Generally, where efficacy of a single such agent, has been reported, it is modest.  We have no “magic bullet” treatment, but the complexity of the NO/ONOO- cycle suggests that these may act additively or synergistically with each other, so that complex treatment protocols may be much more effective than are single treatments.  The 32 agents or classes of agents described earlier in this paragraph, are listed in Table 1 below.  There may be additional agents not listed here that may be potentially useful, as well.

 

It is important to note that I am a Ph.D., not an M.D., and nothing on my web site should be viewed as medical advice.

 

Table 1.          NO/ONOO- Cycle Summary of Individual Agents or Classes of Agents

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
a-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-kB 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 Observation
D-ribose	Clinical Trial Data
Ecklonia cava extract	Clinical Trial Data

 

The mechanisms predicting that these agents may be expected to down-regulate NO/ONOO- cycle biochemistry are presented in my book, as are the clinical trial, clinical observation and anecdotal evidence relating to one or more of these multisystem illnesses.

 

Five Complex Treatment Protocols

 

 Five physicians/scientists have developed complex treatment protocols containing from 14 to 18 different agents or classes of agents predicted to down-regulate NO/ONOO- cycle biochemistry.  These each appear to be effective in the treatment of multisystem illnesses based on clinical observations and, in two cases (Jacob Teitelbaum’s and Garth Nicolson’s), clinical trial studies.  Two other protocols are those of Dr. Paul Cheney and Dr. Nash Petrovic.  I have been involved with the development of the Pall/Ziem protocol, working with Dr. Grace Ziem on its development.  The Pall/Ziem protocol has been used to treat chemically injured, chemically sensitive patients.  The others have been used to treat CFS patients with Teitelbaum’s being used to treat FM patients as well.  Each of these are discussed elsewhere (1,2).  The lists provided below were current when my book was being written but may no longer be current.  And there are additional agents in two of these protocols which may not obviously act to lower the NO/ONOO- cycle biochemistry.

 

One important caution:  To be effective, these various treatments require, in my view, that individuals avoid stressors that may be expected to up-regulate NO/ONOO- cycle biochemistry.  Those include:

 

1. Chemical exposure in MCS patients
2. Food antigens in those who have developed food allergies
3. Excitotoxins such as MSG and aspartame that may be expected to increase NMDA activity
4. Excessive exercise leading to post-exertional malaise in CFS patients
5. Psychological stress, especially in PTSD patients

 

The comments following some of the agents listed are mine, not those of the physicians involved and reflect some of the expected mechanisms of action of these agents.

 

Table 2-1  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

D-ribose—increased regeneration of adenine nucleotides (including ATP) after energy metabolism dysfunction and may also help restore reduced glutathione pools

 

Table 2-2  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

 

Table 2-3  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 (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

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

 

Table 2-4  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

 

Table 2-5  Agents from Pall/Ziem Protocol Predicted to Down-Regulate NO/ONOO- Cycle Biochemistry

Nebulized, inhaled reduced glutathione

Nebulized, inhaled hydroxocobalamin (sometime also 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 also added three additional agents:  green tea extract, hawthorn extract and acetyl L-carnitine.  The detailed clinical observations of Dr. Ziem on responses to this protocol are described in Chapter 15, of my book (1).

 

I argue that the fact that so many agents predicted to down-regulate NO/ONOO- cycle biochemistry are components in these treatment protocols is not likely to be coincidental.  It suggests that the NO/ONOO- cycle makes useful predictions in terms of therapy.  Conversely, the apparent efficacy of both individual and complex combinations of such agents provides important support for a NO/ONOO- cycle etiology of these illnesses.

 

A sixth protocol that involves multiple agents predicted to down-regulate the NO/ONOO- cycle is described on a separate web page (Allergy Research Group Nutritional Support Protocol).  It is entirely over-the-counter, composed of nutritional supplements and contains 23 different agents or classes of agents predicted to down-regulate various aspects of the NO/ONOO- cycle.  I have been receiving both clinical observations from medical care providers and also anecdotal reports that it provides substantial improvements in something like 80 to 85% of people with these multisystem illnesses (3,4).  I return below to this issue of how one might be able to get still better clinical responses to these complex protocols.

 

What the Mechanisms of Action of Agents Reported to Be Helpful in the Treatment of CFS/ME and/or FM Tell Us about the Etiology of These Diseases

 

As discussed in the first part of this web page, there are a number of agents that have been reported in clinical trials to produce substantial improvements in patients, most commonly those suffering from CFS/ME and/or FM.  The apparent mechanism of action of these agents provides important evidence on the apparent disease mechanism.  So one question that should be raised is whether the action of these agents is compatible with the NO/ONOO- cycle and specifically what parts of the cycle may be inferred from their mechanisms of action.  The apparent efficacy of these agents provides support for several parts of the NO/ONOO- cycle.

 

For example, the agents carnitine/acetyl carnitine and coenzyme Q10 are reported to be helpful and these probably act to improve mitochondrial function, suggesting that mitochondrial dysfunction has an important role in the disease mechanism.  In addition the Nicolson protocol described above is essentially aimed as restoring mitochondrial function, although I argue in Chapter 15, ref. 1 that many of these agents can act in other ways to lower the NO/ONOO- cycle.  Nevertheless, the role of unoxidized phospholipids in that protocol will help restore the cardiolipin in the inner mitochondrial membrane, an important issue given the predicted role of cardiolipin oxidation in leading to mitochondrial dysfunction.   So we see a number of these studies all provide evidence for mitochondrial dysfunction, an important part of the NO/ONOO- cycle.

 

There is also evidence from clinical trials for a role of excessive NMDA activity in FM.  Four different NMDA antagonists have been studied in FM patients and found to produce substantial improvements (1).  We only have clinical observations for roles of these NMDA antagonists in CFS/ME and in MCS (1).  The drug pregabalin that acts indirectly to lower excitotoxicity including NMDA activity has also been reported in clinical trials of FM patients to produce improvements and is approved for use as a drug to treat FM patients.  Magnesium which acts to lower NMDA activity is probably the most widely reported agent for producing improvements in the multisystem illnesses, although magnesium may also act to improve energy metabolism and may have other effects, as well.  In general we have substantial evidence for roles of excessive NMDA activity, an important NO/ONOO- cycle element, from these clinical trial and clinical observation studies.

 

The polyphenolic antioxidants, flavonoids and Ecklonia cava extract, have been reported to produce improvements in clinical trials, suggesting a role for oxidative stress.  Algal supplements may also act primarily by providing substantial doses of antioxidants and again are reported to produce improvements in clinical trials.  High dose IV ascorbate (vitamin C) has been studied in four clinical trial studies in Japan to be helpful, as well, but here I think the primary role may be a different one than simply acting as a chain breaking antioxidant (I’ll discuss this in more detail below).  In any case, we do have substantial evidence for a causal role of oxidative stress from these studies, another important NO/ONOO- cycle element.

 

High dose hydroxocobalamin, a form of vitamin B12 that is a potent nitric oxide scavenger (5), was reported in a placebo-controlled trial to produce statistically significant improvements in a group of CFS/ME-like patients (6).  Vitamin B12 has been used for over 60 years to treat CFS/ME-like patients and has also been used to treat FM and MCS patients (Chapters 6 and 14, ref. 1).  It appears that cyanocobalamin is less effective than is hydroxocobalamin, presumably because the conversion of cyanocobalamin to hydroxocobalamin in the body is only partial.  Hydroxocobalamin has been used experimentally as a test for a role on nitric oxide (5), so its potent role as a nitric oxide scavenger  is extensively recognized in the scientific literature.

 

There are several types of evidence that suggest that hydroxocobalamin is acting here primarily as a nitric oxide scavenger rather than primarily by allaying a B12 deficiency.  There was no correlation between the initial B12 blood levels and the effectiveness of the treatment in the only placebo-controlled trial (6).  Secondly, it appears that a much higher dose is needed to get a good clinical response than is needed to allay such a deficiency (Chapter 6, ref. 1).  Generally, the hydroxocobalamin is given by IM or subcutaneous injection, by nasal spray or occasionally, as a nebulized inhalant.  Each of these are expected to give much higher blood levels than one can get from an oral supplement, because of the limited absorption of oral B12 due to limited availability of intrinsic factor, a glycoprotein that has an important role in the absorption of B12. 

 

Fish oil supplements have been shown in clinical trials to be helpful with these multisystem illnesses and fish oil supplements are known to have antiinflammatory effects (Chapter 15, ref. 1).  This is the most probable mode of action here, providing some support for an important inflammatory aspect to these multisystem illnesses.

 

Folic acid supplements have been reported to be helpful in clinical trial studies as well and these may be expected to help restore BH4 levels (7).  And high dose IV ascorbate (vitamin C) has been reported to produce substantial improvements in four CFS/ME studies in Japan and in one on MCS (reviewed in 3), and such high dose IV ascorbate should also act to help restore BH4 levels as well (discussed in more detail below).  These studies provide some evidence that BH4 depletion has a role in these multisystem illnesses, as well.  

 

We have then, from clinical trial studies alone, evidence for roles of oxidative stress, excessive NMDA activity, mitochondrial dysfunction, nitric oxide, inflammatory biochemistry and BH4 depletion in these multisystem illnesses.  There is also evidence of other types for such roles of each of these, including genetic, measured correlates in the chronic phase of illness, animal model studies and in CFS/ME, gene expression studies (1-4).  It is difficult to see how this pattern of evidence can occur unless the NO/ONOO- cycle or something similar to it is the central causal mechanism for these illnesses.

 

Is There a Way to Obtain Substantial Numbers of Cures in People Suffering From These Illnesses?

 

If we understand the central mechanism of these multisystem illnesses sufficiently well and if we are able to down-regulate it effectively, we should be able to start getting significant numbers of cures using these approaches.  As far as I can  determine, from the published information of the five protocols described above or from the Allergy Research Group (ARG) Nutritional Support protocol described on my other web page, none of these seem to be giving us any substantial numbers of cures. 

 

Clearly how to approach getting a better clinical response to these protocols will depend on the specific protocol one is starting with, so because I am most involved currently with the ARG Nutritional Support protocol, that is the one that I will consider here.

 

The ARG nutritional support protocol does not have any reduced glutathione in it, although it contains agents that may serve as precursors for reduced glutathione in the body.  I have gotten some feedback from sufferers that reduced glutathione, taken as an liposomal oral supplement or as a nasal spray or even nebulized inhalant is helpful for s substantial number of people.  However people with asthma symptoms tend to be sensitive to it and should, therefore, start on low doses.  We don’t have any agents that directly lower NF-kappa B activity, although we do have antioxidants that may indirectly lower such activity, so it is possible that such NF-kappa B lowering agents may be helpful. The only agent we have that lowers NMDA activity is magnesium and it is possible that drugs that lower such activity may be helpful additions. 

 

Having said that, it is my view that the basic problem in not obtaining cures may be that we are NOT adequately lowering the central couplet of the NO/ONOO- cycle.  Let me remind you that what I call the central couplet is the reciprocal relation between peroxynitrite and tetrahydrobiopterin (BH4).  Peroxynitrite oxidizes BH4 leading to partial uncoupling of the nitric oxide synthases, which acts in turn, to produce more peroxynitrite. 

                                               

 

 

We do have several agents that are in that protocol, in part, to lower either peroxynitrite levels or help restore BH4 levels, but it is not clear that they work very well at the levels that can be easily obtained in the body from such oral supplements.  So it may well be that the main reason for not getting substantial numbers of cures from this protocol, is that we have been unable to sufficiently lower this central couplet.  And I will argue in a paper that I plan to submit within days of this writing, that sauna therapy may well act primarily by helping increase BH4 availability in the body.  Having said that, it may well be that the best agent to lower this central couplet may be high dose, IV ascorbate, an agent which, as mentioned above has been shown to produce substantial improvements in CFS/ME and reported to produce such improvements in MCS.

 

High dose ascorbate is predicted to act in three ways to lower this central couplet:

 

1.      Ascorbate is a peroxynitrite scavenger, although all of the evidence available suggests that it does not work very well at the normal levels typically found in the body or easily obtainable via oral ascorbate.  However, IV ascorbate can generate levels 30 times or more higher and such levels should be much more effective in scavenging peroxynitrite.

2.      When BH4 is oxidized by peroxynitrite, the initial oxidation product designated BH3 (the one electron oxidation product) can be reduced back to BH4 by ascorbate.  However, the BH3 is itself unstable, so that efficient reduction may be expected to require relatively high levels of ascorbate.

3.      High dose ascorbate gets oxidized in the body, generating substantial amounts of hydrogen peroxide, and hydrogen peroxide is known to induce higher production of an enzyme called GTP cyclohydrolase I.  This enzyme is the first and rate limiting enzyme in the de novo pathway for the production of BH4.  It follows that high dose ascorbate is predicted to produce more BH4 in the body by this pathway, as well. 

 

One caution:  It is likely to be important to perform a test for iron binding saturation, to avoid giving high dose ascorbate to those who may have high free iron levels.  In individuals with high free iron, high dose ascorbate is dangerous because it can generate high levels of Fenton chemistry. 

 

I have discussed this approach in reference 3 and plan to write an independent paper on it shortly.  I think that it is quite possible, then, that a series of treatments with IV ascorbate, in addition to a wide ranging protocol such as the Allergy Research Group nutritional support protocol, may generate substantial numbers of cures of people suffering from multisystem illnesses or other NO/ONOO- cycle diseases.

 

References  Cited:

 

1.  Pall M.L.  (2007)  Explaining “Unexplained Illnesses”:  Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromylagia, Post-Traumatic Stress Disorder, Gulf War Syndrome and Others.  Harrington Park (Haworth) Press, New York.

2.  Pall M.L.  (2006)  The NO/ONOO- cycle as the cause of fibromyalgia and related illnesses:  Etiology, explanation and effective therapy.  In:  New Research in Fibromyalgia, John A. Pederson, Ed., pp 39-59, Nova Biomedical Publishers, Inc., New York.

3.  Pall M.L.  (2009)  The NO/ONOO- cycle mechanism as the cause chronic fatigue syndrome/myalgic encephalomyelitis.  In:  New Research in Chronic Fatigue Syndrome,  Nova Biomedical Publishers, Inc., New York, in Press.

4.  Pall M.L.  (2009)  Multiple chemical sensitivity:  toxicological questions and mechanisms.  Wiley & Sons, New York, in press.

5. Pall M. L.  (2001)  Cobalamin used in chronic fatigue syndrome therapy is a nitric oxide scavenger.  J Chronic Fatigue Syndr 8,39-45.

6. Ellis F. R., Nasser S.  (1973) A pilot study of vitamin B12 in the treatment of tiredness.  Br J Nutr 30,277-283.

7. .  Pall M.L.  (2007)  Nitric oxide synthase partial uncoupling as a key switching mechanism for the NO/ONOO- cycle.  Med Hypotheses 69,821-825.