Martin Pall, Ph.D

Martin Pall’s NO/ONOO Theory: Part II – Treatments Predicted to Assist in Chronic Fatigue Syndrome (ME/CFS)

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
  • Selenium – None
  • Tocopherols/Tocotrienols Anecdotal Reports
  • 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
  • Inosine/uric acid – None
  • Taurine – None
  • Riluzole – 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.”

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