Therapy

Allergy Research Group Nutritional Support Protocol
May Help Down-Regulate the NO/ONOO- Cycle

Martin L. Pall

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Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Multiple Chemical Sensitivity

Fibromylgia

Other NO/ONOO- Cycle Diseases

Five Principles

Therapy

Let me remind the reader that I am a PhD, not an MD and nothing I say or write should be viewed as medical advice. The over-the-counter supplements described here are not sold to treat or cure any disease. The statements here are not approved of by the FDA.

I designed a set of nutritional supplements with the Allergy Research Group that may be predicted to down-regulate the NO/ONOO- cycle biochemistry. Four of these products were designed explicitly for this purpose and three others were already being produced by the Allergy Research Group but fit well within the overall goals of the protocol. We are calling this that Allergy Research Group nutritional support protocol. I do receive a small royalty on sales from the Allergy Research Group and so do have a conflict of interest that the reader should be aware of. My recent suggestions for dosage regimen is as follows:

1. #75930 CoQ-Gamma E with Tocotrienols & Carotenoids: one capsule per day in the morning. Those with body weights over 100 lbs should add a second capsule at mid-day.

2. #75780 FlaviNox: one capsule, four times per day, three preferably with or after meals. Those with body weights over 120 lbs, should add a second capsule with each of three meals.

3. #75940 MVM-A Antioxidant Protocol, multivitamin mineral supplement with added N-acetyl carnitine: one capsule, four times per day, three preferably with or after meals. Those with body weights over 120 lbs, should add a second capsule, with breakfast and with dinner.

4. #75960 NAC Enhanced Antioxidant Formula: one each twice per day, with or after breakfast and supper.

5. #71250 & #73870 Super EPA (fish oil): one per day in the morning after breakfast. Those with body weights over 100 lbs, should add a second capsule at mid-day, taken with or after lunch.

6. #75910 FibroBoost (Ecklonia cava extract): one each twice per day, with or after breakfast and supper.

7. #70010 Buffered Vitamin C: one capsule, four times per day, preferably three with or after meals.

I am suggesting that the three products that are to be taken four times per day, be taken at the same times, with three being taken with or after the three meals of the day and the fourth taken at bedtime.

I suggest that for those intending to try all seven, that you start with the first, trying it alone for three days to see if it is well tolerated, adding second for three days, and so forth. By doing this you should find if there are any products that are not well tolerated, such that they can be eliminated for the time being and perhaps be tested later with either the same or possibly lower dosage. It will take 21 days, in this way, to get to the end of the initial period, into a period where all tolerated products are being taken.

You can get much more information about these products from the Allergy Research Group web site:

www.allergyresearchgroup.com

There are 23 distinct agents/classes of agents found in these products that are predicted to down-regulate the NO/ONOO- cycle biochemistry. Most of these predictions are discussed and documented in Chapter 15 of my book “Explaining ‘Unexplained Illnesses’”. All 23 of these are described in the following Table 1:

Table 1

Agent or class Mechanism Comments

Vitamin C (ascorbic acid)*	Chain breaking antioxidant; lowers NF-kappa B activity; reported to scavenge peroxynitrite and also help restore tetrahydrobiopterin (BH4) levels	May require high doses to be effective with the latter two mechanisms; this may be the basis of so called “megadose therapy” for vitamin C
Vitamin E including tocopherols and tocotrienols	Lipid soluble antioxidant; gamma-tocopherol may be particularly useful in scavenging breakdown products of peroxynitrite and in lowering chronic inflammatory responses; tocotrienols may be particularly important in protecting from excitotoxicity and protecting mitochondria; lowers NF-kappa B activity	High dose alpha-tocopherol, the most commonly used form of vitamin E induces an enzyme that degrades other forms of vitamin E; thus high dose alpha-tocopherol should be avoided, in my view, because it will produce a deficiency in other forms of vitamin E
Magnesium*	Lowers NMDA activity and may be useful in improving energy metabolism and ATP utilization	Magnesium is the agent that is most widely studied and found to be useful in the treatment of the multisystem illnesses
N-acetyl cysteine (NAC)	Precursor in the synthesis of reduced glutathione.	Some people with multisystem illnesses appear to be sensitive to this, possibly because of excitoxicity of the cysteine produced from it; we use a relatively modest dose here and suggest always taking it with meals
Fish oil (long chain omega-3 fatty acids)*	Lowers iNOS induction; important for brain function; alsolowers production of inflammatory protaglandins	Highly susceptible to lipid peroxidation and may, therefore be depleted
Flavonoids*	Chain breaking antioxidants; some scavenge peroxynitrite, some scavenge superoxide; some reported to induce SOD; All three types are found in FlaviNox; some flavonoids may also act to help restore BH4 levels; lower NF-kappa B activity	Flavonoids go up rapidly in the blood after consumption but also drop rapidly; taking them four times a day is an attempt to maintain higher blood levels over much of the day
Carotenoids, including beta-carotene, lycopene, lutein	These are all reported to scavenge peroxynitrite in lipids, such as biological membranes	Only natural forms are used here; the natural form of beta-carotene has substantial amounts of cis double bonds, whereas synthetic beta-carotene is predominantly all trans and largely inactive as a scavenger; the other carotenoids are very active, particularly in certain regions of the body and may be more active than even natural beta-carotene
Selenium in the form of seleno-methionine	Serves as a precursor for selenoproteins including three forms of the antioxidant enzyme glutathione peroxidase and also a selenoprotein reported to be a peroxynitrite scavenger	Peroxynitrite reacts with many selenium compounds; if this generates products that are not retained in the body this will lead to lowered selenium levels which have been found in the multisystem illnesses
Acetyl L-carnitine*	Helps transport fatty acids into mitochondria; may be important here not only directly for energy metabolism but also to restore the oxidized fatty acid residues that may be produced by superoxide in the cardiolipin of the inner mitochondrial membrane	May also help lower reductive stress
Ecklonia cava extract*	Polyphenolic chain breaking antioxidant; reported to help scavenge both peroxynitrite and superoxide; based on its reported properties, it may also help restore BH4 levels	Appears to stay in the body much longer than do the flavonoids, a useful property; reported to be helpful in a clinical trial study of fibromyalgia
Vitamin B6 including pyridoxal phosphate	Multiple functions; is present here primarily because of its activity in the enzyme glutamate decarboxylase (it can be rate-limiting)	May help restore balance between glutamate and GABA; lower excitotoxicity and excessive NMDA activity
Hydroxocobala-min form of vitamin B-12*	Potent nitric oxide scavenger, lowers nitric oxide levels	Taking this orally four times per day is an attempt to saturate the intrinsic factor mediated uptake over much of the day and thus get maximum oral uptake; still higher levels can be obtained by injection, inhalation or nasal spray
Folic acid*	Relatively high doses will lower the partial uncoupling of the nitric oxide synthases by helping to restore tetrahydrobiopterin	Reacts with oxidants and therefore may be depleted due to the NO/ONOO- cycle
Niacin	Helps restore NAD/NADH pools that can be depleted by peroxynitrite mediated poly ADP-ribosylation	This may be important, in turn for lowering mitochondrial/energy metabolism dysfunction
Riboflavin including 5’-phosphate	Multifunctional; main rationale for including it here is to stimulate glutathione reductase, a key enzyme for maintaining levels of reduced glutathione	One of four agents here that are important for maintaining reduced glutathione; reacts with oxidants and therefore may be depleted due to the NO/ONOO- cycle
Thiamine (vitamin B1)	Important in energy metabolism, including two steps in pentose phosphate shunt which generates NADPH	Critical for NADPH which can act to regenerate reduced glutathione; reacts with oxidants and therefore may be depleted due to the NO/ONOO- cycle
R-Alpha-lipoic acid	Important antioxidant; helps restore reduced glutathione levels; lowers NF-kappa B activity	Rapidly converted in the body to reduced lipoic acid and lipoamide, the most active forms; possibly one of the most important agents but not tested in clinical trials for multisystem illnesses
Other B vitamins	Biotin reported to be depleted with alpha-lipoic acid supplementation; pantothenic acid important for energy metabolism	Coenzyme A (produced from panthothenic acid) is a thiol compound which may be depleted under conditions of oxidative stress; this may be still another mechanism producing energy metabolism dysfunction
Trimethyl glycine (betaine)	Lowers reductive stress; also helps with the generation of S-adenosyl methionine (SAM)	While the main rationale for including this here is from the reductive stress concern, SAM generation may also be of concern; the enzyme methionine synthase is inhibited by nitric oxide and inactivated under conditions of oxidative stress, thus leading to lowered SAM and lowered methylation
Coenzyme Q10 (ubiquinone)	Important in mitochondrial function; important antioxidant; reported to scavenge peroxynitrite	Optimal dosage may vary considerably among different individuals; suggest taking in the morning as some report it can keep them up at night
Zinc, copper and manganese	These minerals are all precursors of the antixodant enzyme superoxide dismutase (SOD) and can be rate limiting for its synthesis under some circumstances	Dosage here is important as too high doses can all cause problems
RNA (another member of this group has been tested in a clinical trial)	Two important functions: Provides adenosine for restoring adenine nucleotide pools after energy metabolism dysfunction; when catabolized, the purine bases generate uric acid, a peroxynitrite scavenger	Two other agents can act similarly: D-ribose and inosine. Each of the three have their disadvantages, however. D-ribose is a potent glycating agent. Inosine acts to stimulate mast cells. And the commercial source of RNA is yeast and this may be a problem in those who have a yeast allergy.
Taurine	Lowers excitotoxicity including NMDA activity; helps restore balance between glutamate and GABA activity	Reported to be depleted in multisystem illnesses

It can be seen from the above-described combination of Allergy Research Group nutritional supplements supply nutrients that help down-regulate various aspects of the NO/ONOO- cycle. Many act as antioxidants, lowering oxidative stress, blocking oxidative chain reactions, and in some cases scavenging such oxidants as peroxynitrite and superoxide or acting to increase superoxide dysmutase activity. Some agents act to help restore tetrahydrobiopterin (BH4) levels and thus lower partial uncoupling of the nitric oxide synthases. Some agents lower nitric oxide levels. Some agents act in various ways to restore energy metabolism. Some act to lower excitotoxicity including excessive NMDA activity. Some act to lower certain inflammatory aspects including lowering NF-kappa B activity or lowering inflammatory prostaglandin synthesis. Thus all of the various aspects of the NO/ONOO- cycle mechanism as I have proposed it should be lowered to at least a certain extent.

The nutritional components are available in the EU as follows.

Dr. Michael Ash (in the UK)

at Nutri Link

info@nutri-linkltd.co.uk

+44(0) 8704 054 002

And in continental Europe:

Heinz Jurgen Albrecht
Delta Star Nutrients BV
Magalhaesweg 8-B
NL-5928
Venlo, Netherlands 5928
info@deltastar.nl

(+31) 77 396 9161

It does lower essentially all aspects of the NO/ONOO- cycle mechanism and I and others have received a large number of anecdotal reports and reports from physicians and other health care providers of apparent efficacy, some with dramatic apparent responses. These reports are from patients ME/CFS, MCS and fibromyalgia and other possibly related diseases as well, such as asthma. I would estimate (and this a very rough estimate) that about 85% of the patients who use these ideas for nutritional support get distinct improvements.

However, I received feedback from patients that higher doses than I suggested earlier were better for many people, leading me to increase the suggested doses. The dosage regimen suggested at the beginning of this article included such increasing doses.

People should, in general, consider their body weight in adjusting these suggested dosages further, either up or down, so that the amount of well tolerated supplements are maintained at approximately the levels per unit body weight given here.

There appears to be one group of individuals who respond very negatively to several of the capsules in this protocol. These are patients who have a high level of mercury stored in their bodies. They apparently react negatively because the alpha-lipoic acid mobilized stored mercury, allowing it to produce increased impact on areas the the body including the brain. Unfortunately, when we formulated this protocol, we placed alpha lipoic acid in four of the different capsules. Clearly those suffering from high levels of mercury in their bodies will have to undergo thorough mercury detoxification before they can take this or similar protocols. Mercury can up-regulate the NO/ONOO- cycle because its methyl mercury metabolite can increased NMDA activity.

Agents that are designed to lower the NO/ONOO- cycle biochemistry will only be effective if people taking them can avoid agents that will otherwise raise the cycle and thus exacerbate their symptoms. Such agents that raise the cycle will include chemicals in the MCS group, excessive exercise leading to post-exertional malaise in the ME/CFS group, chronic infections particularly in the ME/CFS and fibromyalgia group, food allergens in those with food allergies, and psychological stress in many but especially in those suffering from post-traumatic stress disorder.