Most studies involved CFS/ME and/or FM; however studies with sauna therapy and IV ascorbate have been published with MCS patients.
Multiagent Protocols and the Allergy Research Group Nutritional Support Protocol
IV buffered ascorbate
1. Acts as peroxynitrite scavenger; 2. reduces B back to BH4, helping restore BH4 levels; 3. the very high levels obtained by IV treatment can lead to increased levels of hydrogen peroxide, leading to induction of GTP cyclohydrolase I, thus leading to increased de novo synthesis of BH4.
circa 2–3 g, repeated daily
Blood levels obtained are substantially lower than for IV treatment, above. However such levels may be adequate to trigger the first two mechanisms outlined immediately above.
Induces GTP cyclohydrolase I, leading to increased de novo synthesis of BH4.
reduced glutathione, liposomal, time release, nasal spray, IV or inhalant
150–500 mg per day
Reduces BH2 back to BH4, thus helping restore normal BH4 levels and lowering the partial uncoupling of the nitric oxide synthases; some, particularly those with asthma-type symptoms, may have some difficulty tolerating this treatment, depending on dosage regimen.
Inosine, RNA, or D-ribose
Each of these has the capability of producing two responses: restoration of adenine nucleotide pools and increased uric acid levels in blood. The latter will lead to lowered levels of peroxynitrite breakdown products, NO2 radical and carbonate radical. Each of these agents have drawbacks (see text).
300 µg/day for 5-MTHF, higher doses for precursors
Acts as a potent peroxynitrite scavenger and will therefore help also restore BH4 pools; high dose folic or folinic acid will act to help raise 5-MTHF pools. 5-MTHF pools are depleted in CFS/ME, presumably due to peroxynitrite mediated oxidation.
circa 5 mg or less, oral daily
Helps restore BH4 pools; also acts as peroxynitrite scavenger. This would be an off-label use of BH4.
vasoactive intestinal peptide (VIP)
IV or inhalant
Induces GTP cyclohydrolase I, leading to increased de novo synthesis of BH4; this would be an off-label use.
flavonoids, ellagic acid, other phenolic antioxidants
Probably act to scavenge peroxynitrite and breakdown products and may also act more directly to help restore BH4; dosage and optimal sources are unclear.
IM injection, nasal spray or inhalant
Acts in the reduced form (cobalt II) as a potent nitric oxide scavenger; this will indirectly lower peroxynitrite because of the role of nitric oxide as a peroxynitrite scavenger.
Taken from the author's website with permission.
It follows that IV ascorbate may be able to favorably affect both sides of the central couplet, lowering peroxynitrite and its products and also, via two distinct mechanisms, increasing availability of BH4. This set of three mechanisms collectively produces a rationale for the use of IV ascorbate in the treatment of these multisystem illnesses. To my knowledge, there has been no previous rationale for such treatment, despite its reported effectiveness.
It will probably be important to determine that patients to be treated with such IV ascorbate do not have highly elevated levels of free iron, to avoid triggering extensive Fenton chemistry with the ascorbate treatment. Typically, this means that serum iron binding capacity should be no more than the upper limit of "normal"; that is, no more than 55% saturated.
In addition, those with a genetic glucose-6-phosphate dehydrogenase (G6PD) deficiency are susceptible to hemolysis caused by IV ascorbate because they are less able to detoxify the consequent hydrogen peroxide, so that treating such patients with IV ascorbate is contraindicated.38 Patients should therefore be tested for possible G6PD deficiency and for elevated free iron, and only those lacking both of these contraindications should be treated with high-dose IV ascorbate.
IV ascorbate used in such treatment should be buffered to the physiological pH of the blood (7.4) to avoid shifting the pH. Such buffering particularly important in those with kidney dysfunction who are less able to regulate the pH of the blood.
With the exception of cancer treatment, where IV ascorbate is thought to act mainly via increased production of hydrogen peroxide, there has been no widely applicable rationale for its reported effectiveness in the treatment of other diseases. The mechanisms described in this section are important, therefore, in providing such a rationale, one that makes important predictions about how IV ascorbate treatment may be useful and what strategies can maximize its efficacy.
It has been known for a number of years now that high-dose folic acid supplements can lower partial nitric oxide synthase uncoupling (this has been most studied with the eNOS nitric oxide synthase form), with much of this effect being due to increased availability of BH4.59-62 This response depends on the reduction of the folic acid by the enzyme dihydrofolate reductase, showing that a reduced form of folate probably has a role here. What has been unclear until recently is the reduced folate's mechanism of action.
It has been shown, however, that 5-methyltetrahydrofolate (5-MTHF) is an extremely potent peroxynitrite scavenger, so the probable mechanism of action is the lowering of peroxynitrite and its breakdown products.63,64 In other words, this is another situation in which the central couplet is involved, such that by lowering one end of the couplet (the peroxynitrite end), one also lowers the other end (increasing BH4). Another reduced folate, tetrahydrofolate, also acted as a peroxynitrite scavenger, although it was less active than was 5-MTHF.63
This action of 5-MTHF is also supported by its role in vivo and in vitro as an extremely active scavenger of singlet oxygen.65 Singlet oxygen is known to share chemical similarities to peroxynitrite because both molecules have very weak oxygen–oxygen bonds, so the similar scavenging of both molecules by 5-MTHF should not be surprising.
It has been shown that high-dose oral folic acid can lead to major increases in 5-MTHF. For example, Doshi et al. in their figure 5 showed that a single 5 mg folic acid supplement in humans led to roughly seven times the initial blood levels of 5-MTHF in 3 to 4 hours.66 They also showed that repeated daily 5 mg doses produced still higher 5-MTHF levels, roughly 15 times the initial levels, an effect that they attributed in part to an induction of the dihydrofolate reductase enzyme.
Jacobson et al. showed that levels of 5-MTHF in the sera from CFS patients were very low compared with normals and that other reduced folate pools were also depressed.67 I am aware of extensive unpublished data on CFS/ME patients, confirming these results. Gerwin reported that folate deficiency was one of the three most common systemic factors in myofascial pain syndrome, a condition closely linked to fibromyalgia.68 These studies strongly suggests that elevated peroxynitrite levels in CFS/ME and possibly other multisystem illnesses may produce a substantial loss of 5-MTHF, and that some of the products of 5-MTHF oxidation are lost to the folate pools, thus leading to an overall lowering of folates in the body. The lowering of 5-MTHF pools has also led in the unpublished data to a much more modest (circa 10% to 15%) lowering of S-adenosylmethionine levels.
It can be inferred from the studies discussed in this section that the reaction between 5-MTHF and peroxynitrite can have substantial impacts on both 5-MTHF levels and peroxynitrite-mediated responses in real physiological situations. With regard to the main focus of this article, raising the levels of 5-MTHF can significantly affect the central couplet by lowering the levels of peroxynitrite and its breakdown products. The practical question is whether this can be best accomplished by using high folic acid doses, which act as a precursor for 5-MTHF, or using 5-MTHF itself and/or other reduced folates that can serve as precursors of 5-MTHF, such as folinic acid. The answer is uncertain.
There are two important complications to this story. I have received information from two sources to the effect that using doses of 5-MTHF in substantial excess of 300 mcg leads to negative reactions in patients suffering from presumed NO/ONOO− cycle diseases. My guess is that this may be due to the toxicity of some of the oxidation products of peroxynitrite-mediated oxidation of 5-MTHF. If this interpretation is correct, it may be possible to increase the well-tolerated dose if one uses other agents that lower peroxynitrite at the same time.
The second complication is that there must be very rapid turnover of the methyl group on intracellular 5-MTHF. There are massive amounts of methylation going on in the body, and even though the great majority of that does not go through 5-MTHF, there still must be rapid turnover of the methyl group on 5-MTHF. It follows that the half-life of intracellular 5-MTHF is probably on the order of few seconds, and while the 5-MTHF can be regenerated after it acts as a methyl donor, the efficiency of that process is uncertain. Consequently, the effectiveness of an oral supplement of 5-MTHF on the scavenging of peroxynitrite may be expected to be greater in the extracellular space than it is intracellularly.
Folinic acid supplements were shown to produce major improvements in a group of CFS/ME patients.69 A number of other studies have reported major improvements in CFS/ME or FM patients with treatment protocols including high-dose folic acid or other folates, but it is difficult to determine the role of the folates themselves in such complex protocols.
Based on the compelling biochemistry, I think that folates, both folic acid and reduced folates, are among the most attractive agents in lowering the central couplet.
Perhaps the most obvious agent to use to lower the central couplet is BH4 itself, or alternatively precursors such as sepiapterin or biopterin. BH4 supplements have been reported to be helpful for the treatment of autism patients, and autism is one of the proposed NO/ONOO− cycle diseases.1,70-72 There are, however, some complications that need to be considered in using BH4 to lower the central couplet.
First, it is known that oral BH4 is largely oxidized and must therefore be reduced back to BH4 before it can function in target cells. Most of this reduction occurs intracellularly through enzymatic reduction. However, the rapid peroxidation of the BH4 leads to questions of whether this oxidation may produce peroxidative damage. For example, although Parkinson's disease is thought to involve BH4 depletion, an animal model study showed that high doses of BH4 produced Parkinson's-like symptoms and neuronal damage, providing some support for this view.73,74 In any case, it may be important to limit the dosage of BH4 if it is used directly to prevent any major consequences of BH4 peroxidation. It is possible that reducing agents such as high-dose ascorbate may minimize this peroxidation, and that using BH4 along with high-dose ascorbate may be helpful in constructing therapeutic strategies.
An alternative approach is to use precursors such as biopterin or sepiapterin as oral supplements to provide increased availability of BH4.
Vasoactive Intestinal Peptide (VIP)
VIP has been used by two physicians to treat CFS/ME patients or chemically sensitive patients (unpublished data), with apparently good responses in both. For example, Dr. William Rea has used VIP with his chemically sensitive patients with apparently good responses (personal communication). VIP is known to lower several parts of the NO/ONOO− cycle, and the most likely mechanism for this, in my view, is the reported role of VIP in inducing GTP cyclohydrolase I activity and consequently raising BH4 levels.75 This view is supported by the well-documented role of VIP in improving vasculature function. VIP is known to lower hypertension and vascular endothelial dysfunction, and both of these are caused in part by BH4 depletion.
Flavonoids, Ellagic Acid, and Other Phenolic Antioxidants
A number of flavonoids have been shown to act as scavengers of peroxynitrite, and also its precursor superoxide it has been suggested that they can be active in vivoin lowering peroxynitrite-mediated effects.76 Other phenolic antioxidants can also have important roles here, and perhaps one of the most important may be ellagic acid, which scavenges peroxynitrite.77 It is not clear to me which sources of these phenolics are the most likely to be useful here, but perhaps pomegranate extract, which contains substantial amounts of ellagic acid, and also several flavonoid-containing extracts that are reported to lower hypertension and improve vascular endothelial dysfunction.78-82 Ghosh and Scheepens list cocoa, wine, grape seed, berries, tea, tomatoes (polyphenolics and nonpolyphenolics), soy, hawthorn, and pomegranate as attractive possibilities for phenolic antioxidants that may lower hypertension and improve vascular endothelial dysfunction.80 Schmitt and Dirsch list cocoa, pomegranate, both green and black tea, olive oil, and soy among food sources. They also list ginkgo, hawthorn, and ginseng among herbal sources.81 Extracts of each of these should be considered as agents for possibly lowering the central couplet.
Hydroxocobalamin Form of Vitamin B12
Hydroxocobalamin has been used for over 70 years to decrease fatigue in people with chronic fatigue, long before CFS/ME was a well-defined illness. It was shown in a clinical trial of patients with a CFS/ME-like illness that 5 mg intramuscular (IM) injections twice a week produced statistically signficant improvements as compared with placebo.83 In this study, it was also shown that there was no correlation between initial B12 levels and response to hydroxocobalamin therapy, suggesting that the hydroxocobalamin was not acting primarily to allay a B12 deficiency. Lower doses of another form of B12 that were adequate to allay a possible B12 deficiency produce no clinical improvement, and other evidence also strongly suggests that high-dose hydroxocobalamin is not acting here to allay a B12 deficiency.84,85
Other uncontrolled studies have suggested that the hydroxocobalamin form of vitamin B12 produces clinical improvement in people with these multisystem diseases.1,86,87 It has been inferred that B12 is acting as a potent nitric oxide scavenger and that this is the probable mode of action in the treatment of these multisystem diseases. 1,87 People with these diseases report essentially across-the-board improvement in symptoms when treated with hydroxocobalamin, suggesting that it acts to lower the basic etiologic mechanism of these diseases, consistent with a nitric–oxide scavenging mechanism.
In order to act as a nitric oxide scavenger, hydroxocobalamin and the chemically similar aquacobalamin must have the cobalt at the center of the molecule reduced from the cobalt III form to cobalt II.88 Such reduction is a process that occurs in vivo and is necessary for all cobalamins to have vitamin B12 activity as well as for hydroxocobalamin to serve as a nitric oxide scavenger.
Nitric oxide does not have a direct role in the central couplet, but it does serve as a direct precursor of peroxynitrite, such that nitric oxide scavenging will inevitably lower peroxynitrite levels in vivo. It can be argued, therefore, that hydroxocobalamin will act to lower the peroxynitrite end of the central couplet by scavenging nitric oxide.
Summary and Overall Strategy
Of the 10 agents/classes of agents described above that are known or predicted to lower the central couplet, nine individually appear to produce substantial improvements in this group of diseases, based on clinical trial studies, clinical observations, or both. The only one of the nine for which this is not true is oral ascorbate. These observations make the central couplet an attractive part of the cycle to focus on in trying to obtain substantial numbers of cures for these diseases. The question being raised here is whether combinations of these ten, especially combinations designed to effectively lower the central couplet, when added to the strategy that I previously advocated for treatment of these diseases, will produce such cures.
That strategy suggested here is as follows: Avoid stressors that will otherwise upregulate the NO/ONOO− cycle while using multiple agents that each lower one or more aspects of the cycle and collectively should lower several of its aspects.1-3 There are multiple approaches, each using such a multiple agent strategy, although the one that I have most worked on is the Allergy Research Group nutritional support protocol, which appears to produce positive responses in 80% to 85% of such patients. In general, such multiple agent approaches seem to have been effective in producing clinical improvements in most such patients but have failed to give any substantial numbers of cures, based on published information (thetenthparadigm.org/arg.htm).2,3
I think that the basic problem has been the failure to effectively downregulate the central couplet of the NO/ONOO− cycle. The proposal here is that we should add a second phase to these previous therapeutic approaches, one aimed at lowering that central couplet. More specifically, this means using agents that lower peroxynitrite and/or its breakdown products on the one hand; it also means using agents that increase BH4 availability on the other. Increased BH4 availability can be produced by using agents that reduce oxidized products of BH4 back to BH4. Such increased BH4 availability can also be produced by agents that induce the enzyme GTP cyclohydrolase I, the first and rate-limiting enzyme in the de novo pathway for the synthesis of BH4. What I have provided, then, is an overall strategy for getting some cures and a description of ten agents/classes of agents that should be useful in carrying out such a strategy. I have not, however, provided a detailed protocol for getting such cures.
I do think that it is possible that IV buffered ascorbate alone, when added to one of these broad-ranging protocols lowering the NO/ONOO− cycle and avoiding stressors that will raise the cycle, may be effective in obtaining some cures. I suspect, however, that most of the other agents that lower the central couplet should be used as multiagent combinations. And it is quite possible that even repeated IV ascorbate will be improved by using some of the other agents/classes of agents. The general strategy is to lower both ends of the couplet simultaneously, and probably repeatedly to progressively lower the cycle into insignificance. There is predicted to be synergistic interactions when using agents that work simultaneously to lower both ends of the central couplet.
I would be delighted to work with physicians and other health-care providers who are interested in exploring this approach.
If the view proposed in this article can be shown to be correct, then we will be in a new era in medicine. That will be true even if the relevance of this approach is limited to such diseases as CFS/ME, MCS, and FM. If other proposed NO/ONOO− cycle diseases, such as tinnitus, Parkinson's, Alzheimers, ALS, asthma, autism, and MS, can also be cured by this approach, then the impact on medicine will be comparable to the previous biggest therapeutic breakthrough, the development of wide-spectrum antibiotics.
Is this all delusional optimism? Clearly, we won't know until we look. But what we do know is that all of these diseases are chronic diseases, with cases of each apparently initiated by stressors that should be able to initiate the cycle. And we have evidence with all of them for important roles of such cycle elements as oxidative stress, inflammatory biochemistry, mitochondrial dysfunction, and excessive NMDA activity. Where they have been looked at, we also have evidence for BH4 depletion and NF-κB elevation. It is difficult to see how these cycle elements could be involved unless the NO/ONOO− cycle or something very similar to it is not central to the etiology of these diseases.
Mechanisms have consequences. It is time, in my view, for the sufferers of these diseases to fully benefit from the predictions of the NO/ONOO− cycle mechanism.
Martin L. Pall, PhD
Professor emeritus of biochemistry and basic medical sciences, Washington State University, and research director, the Tenth Paradigm Research Group
638 NE 41st Ave.
Portland, OR 97232-3312
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The NO/ONOO− cycle is named for two of its many elements, nitric oxide (NO) and peroxynitrite (ONOO−) and is pronounced "no, oh no."
S-adenosylmethionine (SAMe) is the main direct methyl donor in living organisms, being produced by the methylation cycle and acting in turn to methylate many different substrates in the cell. There have been many claims that these illnesses are caused by lowered methylation cycle activity. I think that these claims not valid. There is a modest lowering of methylation activity caused by peroxynitrite-mediated 5-MTHF oxidation, but whether such modest lowering of methylation has any causal role is unclear. What should be clear is that such a modest methylation cycle lowering should be normalized by an effective downregulation of the NO/ONOO− cycle, including especially the central couplet. That is the treatment approach explored in this article is the approach that should be used to normalize various properties of these NO/ONOO− cycle diseases, including the modest lowering of methylation cycle activity.
Consult your doctor before using any of the treatments found within this site.
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