by Professor Martin Pall
Originally posted to The Tenth Paradigm Society Yahoo! Group - March 23, 2010
"I am copying a section of a paper recently published in the Townsend Letter for Doctors and Patients on how we may be able to start getting some cures of NO/ONOO- cycle diseases. The table will not format properly here, but I think you can figure it out.
I will add that we are planning to put out a second phase protocol, I think maybe in a couple of months or so, that can be used as a second phase and that I hope will start getting some cures. This is still hypothetical, of course, but the second phase will contain some agents that some of you have found to be helpful.
Of course, you all know that I am a PhD, not an MD and none of this should be viewed as medical advice.
How Can We Start Getting Substantial Numbers of Cures?
The use of multiple agent protocols where individual agents act to lower the NO/ONOO- cycle is an exciting and promising approach to therapy of these diseases. However, based on published evidence and to the extent I have access to it, unpublished evidence, none of these protocols produces any substantial numbers of cures. If we understand the NO/ONOO- cycle mechanism sufficiently and if we are effectively down-regulating it, we should start seeing substantial numbers of cures. Why has this not happened?
My own view, is that the part of the cycle that has been called the central couplet is insufficiently down-regulated in these protocols. The main argument that is being explored in this paper is that by more effectively lowering this central couplet mechanism, we may be able to extend these multiple agent protocols to obtain substantial numbers of cures. Let me remind you that the central couplet is the reciprocal relationship between peroxynitrite elevation on the one hand and BH4 depletion on the other. We need to focus, then on agents that lower peroxynitrite and its products at one end of the central couplet and also agents that raise BH4 availabliity on the other end of the central couplet.
There are at least ten available agents that are predicted to substantially lower the central couplet, summarized in Table 1 [Ed: contents below] and we will explore each of them one at a time.
Agents/Classes of Agents Predicted to Sustantially Lower the Central Couplet
Agent, Dosage and Presumed mechanism(s)
IV buffered ascorbate 7-50 g.,repeated
1. Acts as peroxynitrite scavenger 2. Reduces BH3 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
oral ascorbate circa 2-3g, 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.
Sauna Therapy, Repeated
Induces GTP cyclohydrolase I, leading to increased de novo synthesis of BH4 [Ed: "de novo" refers to the synthesis of a substance from its building blocks within the body].
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 thus 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 varies 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).
5-methyl tetrahydro-folate (5-MTHF) or Precursors Folic or Folinic Acid 300 micrograms/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.
Tetrahydro-biopterin (BH4) or Precursors of BH4 Biopterin or Sepiapterin Circa 5 mg, or Less, Oral Daily
Helps restore BH4 pools; also acts as peroxynitrite scavenger. This would be an off lable 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 lable use"
Flavonoids, Ellagic Acid, Other Phenolic Antioxidants, Oral
Probably act to scavenge peroxynitrite and breakdown products and may also act more directly to help restore BH4; dosage and optimal sources are unclear.
Hydroxocobalamin [Ed: vitamin B12] 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.
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