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Nitric oxide and its possible implication in ME/CFS (Part 2 of 2)
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Tetrahydrobiopterin (BH4) deficiency in CFS and the connection to folate metabolism

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by Joopiter76, Apr 13, 2011.

  1. dannybex

    dannybex Senior Member

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    There's now ample proof of the genetic issues involved -- talk to Rich Vank or any of his colleagues. That doesn't mean it's caused by genetics, but besides hormones, think about the pesticides, the solvents, the air "fresheners", the fact that nearly everything is either wrapped in plastic, or is sold in plastic bottles (compared to pre-1970) when most things came in glass bottles, the synthetic, artificial colors and flavors and the thousands of other chemicals we're exposed to that, due to the genetic polymorphisms, we have a much more difficult time detoxifying. These all lower glutathione, mess up methylation, which influences immune function, lowers the ability to fight infections, which keeps us sick when most of the population goes back to work after 2 weeks or so..................

    d.

    p.s. I can't believe this thread is over a year old! :)
  2. greenshots

    greenshots Senior Member

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    I couldn't have said it better myself, Danny, excellent synopsis of the whole damned mess!
    Angela



  3. JALAL1404

    JALAL1404

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    I have some suuggestion to lower NO ONOO- cycle, aminoguanidine is a very strong iNOS inhibitor (perhaps the strongest selecive inhibitor), it is saled as dietary suppement against glycation.
    http://en.wikipedia.org/wiki/Pimagedine
    http://www.ncbi.nlm.nih.gov/pubmed/8812641 (aminoguanidine iNOS)
    PARACTIN (andrographolide), is a strong inhibitor of nf kappa b and iNOS in part because of the later effect :
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1571992/ (for iNOS)
    This article is on Lupus sle but it speaks also about andrographolide being a good nf kappa b inhibitor
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753943
    I think nf kappa b and proinflamatory cytokines are negleged in peroxynitrite cycle but they are very important because cytokines strongly stimulate iNOS nadph oxidase and xanthine oxidase and nf kappa b (IL-1beta and tnf-alpha rise the latter), and because nf kappa b increases iNOS (directly) and increases pro-inflamatory cytokines.
    an article on andrographolide in lupus and it say it is a good nf kappa b inhibitor (the NO ONOO- cycle is also active in lupus), I know it because I have lupus since 2008.
    Moducare is perhaps a good product against proinflamatory cytokines :

    http://www.drhoffman.com/page.cfm/216
    Avenanthramide from avena sativa is a good proinflamatory cytokines inhibitor (by inhibiting phosphodiesterase).
    Does someone know if biopterin (BH4) from "living well today" contains l-biopterin or it actually contains tétrahydrobiopterin (wich one of the 2), thers is some différences betwenn the 2 !
  4. nandixon

    nandixon Senior Member

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    People who have 23andMe results can check their SNPs for the enzyme GTP cyclohydrolase I (GCH1), which is the rate-limiting step for production of tetrahydrobiopterin (BH4). Defects in the GCH1 gene can cause a deficiency of BH4, which in turn can cause dysregulation of nitric oxide synthase (NOS) with production of peroxynitrite and increased or sustained oxidative stress.

    I started a thread here which gives the normal alleles for a number of GCH1 SNPs so people can do a comparison:
    http://forums.phoenixrising.me/inde...imiting-enzyme-for-bh4-relation-to-nos.19570/
    Valentijn likes this.
  5. triffid113

    triffid113 Day of the Square Peg

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    I think DHEA fixes this. I have 3 genes which cause low BH4 levels and you know you have ONOO because it causes high blood pressure. When my hormones waned, I went from normal bp to stage 3 hypertension in one day (then back to normal after PMS over, etc). I fixed it by taking DHEA...it brought my bp down 30 points in 15 minutes and it stays
    down.
  6. Freddd

    Freddd Senior Member

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    Genetic combinations run into a very large number of combinations and permutations, just on the ones we know about. So let's keep it simple. Untitil the tests can say this person has padradoxical folare deficiency/insufficiency type 1, 2 , 3 or 4 to call deplin sized doses as "overdose" to be exceedingly incorrect and perjorative. I might as well say that to purposely underdose a vitamin keeping a person sick to fit a theory looks pretty strange to me. Titration to effect tells you the amount that a particular set of genes and expressions pf those genes come out. As feghoot said at the cannibal feast "One man's meat is another man's poi, son". And doing a rebalancing titration as one changes other things does pretty well keeping things in balance. It is not an arbtrary dose. And it appears that the major difference is how intolerant the person is of folic and folinic acids as there is competition. So to overcome the competition and bypass absorbtion problems including competition a larger dose works pretty well. Maybe in 50 years they will have the answers allowing the theoretical dose that should do the job if in balance with all other significant factors. However, we each get well by adjusting the doses of most everything for best benefit, not by taking a theoretical dose based on somebody's theory that doesn't work yet. It's a continual customizing. And you know, it takes a long time to gather exhaustive titration information onlots of people involving millions of genetic combinations.
  7. Freddd

    Freddd Senior Member

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    THIS IS TOTALLY RADICAL!

    In this paper she basically calls the accepted control of NO by hydroxycbl to be the starvation workaround for lacking adenosylb12.


    Hypotheses in the Life Sciences Volume 2 Issue 2 pp 31-54
    The Very Large Gorilla Sitting in the Room? Adenosylcobalamin is the Missing Link: its Radical and Tetrahydrobiopterin are the Principal in vivo Catalysts for Mammalian Nitric Oxide Synthases.

    Carmen Wheatley
    Orthomolecular Oncology, (registered charity no. 1078066), 4 Richmond Road, Oxford, OX1 2JJ, and St Catherine’s College, Oxford, OX1 3UJ, UK.

    Abstract
    Mammalian nitric oxide synthases (NOS) are a source of the universal second messenger, and pivotal biochemical molecule, nitric oxide (.NO). NOS are assumed to function catalytically in a haem-centred manner, by analogy with cytochrome P450. Yet, they differ significantly. Cobalamin, vitamin B12, is believed to function almost solely as an .NO scavenger and, latterly, as a direct, physiological inhibitor of the NOS. Yet, in pathology, associated to cobalamin deficiency, functional or otherwise, NOS over-produce superoxide, peroxynitrite (ONOO-), and other reactive nitrite species, rather than .NO (Figure 7). This paper offers a radical, new solution to the gaps and inconsistencies in the current understanding of the mechanism of haem-centred NOS catalysis, which also challenges the other existing paradigm of cobalamin as just an .NO mop. Examination of a wide diversity of NOS and cobalamin-dependent enzyme structure-function studies, as well as data from the .NO/cobalamin chemical, biochemical, immunological, genetic, and clinical literature, offers indications that cobalamin, specifically, in one of its active forms, adenosylcobalamin (AdoCbl), may have a third, eukaryotic coenzyme function as the principal cofactor of well-regulated NOS catalysis in vivo. The AdoCbl-centred NOS reaction is described in detail (Figure 5), and some existing evidence that, in vitro, without AdoCbl, NOS turnover activity is significantly slower than in in vivo AdoCbl-rich environments, is presented. AdoCbl, in conjunction with tetrahydrobiopterin, couples NOS oxygen binding/activation to L-arginine hydroxylation and .NO synthesis much more effectively than does haem, overcoming NOS spatial and redox problems, leading to productive catalysis, decreased radical formation/escape, with a consequent increased ratio of .NO to ONOO-, and prevention of pathology (Figures 5 & 7). In vivo, haem-centred NOS catalysis may, in fact, be the back-up NOS reaction, and it‟s predominance in the absence of AdoCbl, with a consequent lowering of the .NO/ONOO- ratio, is the real source of supposedly .NO derived pathology.

    You have to read the paper to find the Boron reference. Its in there somewhere in 25 pages. I found it the first time through but not again. This is her 4th paper on cobalamins and inflammation, the first three were the "Scarlet Pimpernel" papers. Again, this is a speculative paper advancing the edge of scientific understanding.



    DISCLAIMER

    I am a self taught systems analyst and consultant. I am not credentialed, certified or licensed to do anything besides drive a car. I have been disabled by the disease processes being discussed and affecting neurology in a multitude of ways for 10 years and impaired in a variety of ways and levels for 54 years before that. Everything I say is my opinion, synthesis, understanding or otherwise of my own creation except direct attributed quotes. Approximate paraphrases are also my interpretation of what I have read. All of this is at best my data analysis, understanding, synthesis and hypotheses and not to be construed as medical advice. I am not responsible for anything you do with any information provided in any way. Anything you do is your own responsibility and at your own risk. There are no published peer reviewed studies backing up my opinions or statements, except the incidental ones quoted or implicit in my synthesis or understanding, and then only in so far any reading of such papers may confer. Your interpretations, actions and variations of what I say are strictly at your own risk.
  8. Asklipia

    Asklipia Senior Member

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  9. Beefsterq

    Beefsterq

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  10. alex3619

    alex3619 Senior Member

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    It is presumed that most BH4 deficiency is genetic, and most of that is PKU. Aquired deficiency is rarely discussed.
  11. Asklipia

    Asklipia Senior Member

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    If that were true, then that deficiency would not play a role in a disease that appears a good few years after birth. Or would it?
    The alternative is : we use up too much BH4 at one point and cannot produce/recycle it fast enough.
    That could be a bad thing. It might also be a bad thing preferable to a worse thing. An adaptation of the body.
  12. alex3619

    alex3619 Senior Member

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    Our deficiency is clearly not the same as the genetic one, presuming we have one (which several theories suggest). Some of those theories, including Marty Pall's, suggest fixing BH4 might substantially improve our health. However I am not aware of any clinical trials on ME patients at all.
  13. alex3619

    alex3619 Senior Member

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    Emootje likes this.
  14. Emootje

    Emootje Senior Member

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    triffid113 and Crux like this.
  15. Vance

    Vance

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    > People who have 23andMe results can check their SNPs for the enzyme GTP cyclohydrolase I (GCH1),
    > which is the rate-limiting step for production of tetrahydrobiopterin (BH4).

    True. BH4 could also suffer from insufficient recycling (a few other genes/cofactors), excessive conversion to BH2 through oxidative stress and other mechanisms, or loss to urea via ammonia excess. The latter two are often mentioned for CFS/ME (and autism).

    Large amounts of 5-MTHF (which I believe is what it meant by "methyl folate") would seem to be useful with respect to BH4 for a couple reasons... Life Extension had an article that said 5-MTHF, in sufficient amounts, can sometimes substitute for BH4 in BH4's functions (which I believe was derived from a PubMed study). And there's also this idea that 5-MTHF, when present in sufficient amounts, can blow backwards through MTHFR to help recycle BH2 back into BH4. As i understand it, the A1298C MTHFR polymorphism (rs1801131) is specific to that function, rather than affecting the more typical conversion from 5,10-methylene-THF to 5-MTHF that C677T does. (Let me know if anyone needs references for this... I can try to dig them up.)

    With respect to clinical studies re: BH4 and CFS/ME... FWIW, Dr. Yasko mentioned in her 'Autism Pathways' book working with some Japanese doctors to use BH4 supplementation on autistic kids, where BH4 is also often said to be in short supply. And of course there seem to be similarities in the mechanism of autism. vs. CFS/ME. This was written a few years ago, so I'm not sure what the results were. And Dr. Yasko usually does things informally, so unless the Japanese doctors planned to publish, I doubt it will be. But maybe someone who follows her more closely would know what happened with this.
    triffid113 likes this.
  16. triffid113

    triffid113 Day of the Square Peg

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    Kuvan is very expensive. I can't afford it. You can get BH4 (1/4 dose of kuvan) from www.heartfixer.com. I have never noticed that a dose that low has any effect. But I keep it on hand for blood pressure emergencies. I guess I could swallow a bottle if I have to. I have noticed though that my blood pressure emergencies always mean that I have caught a urinary tract infection and probably no blood pressure med works until the infection is banished. The only thing that works then is not eating.
  17. triffid113

    triffid113 Day of the Square Peg

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    I made a typo above and it seems like no one understood...? Your hormones affect epigenetics. When they wane, your genetic defects come into play. Hence, you can have genes limiting BH4 production and never have noticed until your hormones wane in later life. It happens ALL THE TIME. So, for instance, I had normal blood pressure until I turned 50 despite 3 genes causing high blood pressure. I had normal BH4 despite 3 genes causing low production of BH4.

    I published before a list of things that raise BH4. I can't remember them all, but some of the things are:
    estrogen (this is why DHEA works)
    mfolate
    Vitamin C
    saunas

    That's all I remember, but there were more things. The 1st 3 above struck me as major. The 4th was a curiosity. The others were peripheral and I have forgotton them. I take 75mg DHEA, the Solgar mfolate, and 2 g. Vitamin C per day and I have normal BH4 despite 3 genes saying that I should not.

    What used to puzzle me is why I did not have high blood pressure as a kid, before my hormones came into play...but I discovered the answer...kids today DO have high blood pressure because they are being fed the same crap diets adults eat. When I was a kid we had stay-at-home moms cooking an extremely healthy diet for us...it was considered at that time that children had to eat exceptionally healthily. Somehow my generation lost sight of that ideal and the result has been an alarming increase in the serious chronic diseases f old age in children.
    ninauae likes this.
  18. triffid113

    triffid113 Day of the Square Peg

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    Um, just want to add my 2 cents...My Father tested as having NO detectable level of BH4 a month before his death on kidney dialysis (can't make urea w/o BH4). He did not have this problem his whole life, he did not have PKU his whole life. However we can all be sure that if he was not on dialysis he would have had PKU seizures. I wonder how many people on dialysis actually have PKU? There is a researcher at U of M studying this: http://clinicaltrials.gov/ct2/show/NCT00625820 This study says BH4 lowers inflammation (at least that caused by inability to pee): http://faculty.ksu.edu.sa/akorish/Documents/C-reactive protein- tetrahydropiopetrin.pdf

    I think, and this is just off the cuff, but unless you are very old (where the amount of glycation to your kidneys could be extreme) or you had a crisis with poison (like a ruptured appendix) that could actually destroy the kidney before its time, that if you cannot pee, you do not have enough or any BH4. So...since dialysis is in fact very common, whereas genetic defects are not so common (say 10%), then I would guess that you can become seriously BH4 deficient w/o genes to cause it. High blood sugar and free radicals destroy BH4, and my hunch is that that is a MUCH quicker route to dialysis than by glycation of the kidneys. Which means treatable and recoverable. However, WHO HAS THE GUTS TO TRY IT? Once you are in dialysis, if you consume anything that can't be dialyzed out, you die. So your options to try even normal vitamins are almost non-existant. It absolutely haunts me that I did not have the guts to try it on my father and he died. I was pursuing building up a case -- to figure out of it had been tried before, or if the molecular size could suggest it would be dialyzed, whatever I could find to raise the odds of success...but I did not have enough time. My father was MTHFR 1298 +/+, a genetic defect which is poo-poo'ed as being unimportant. IMHO this genetic defect all by itself has a damn good chance of killing you. BH4 is extremely important. Maybe we should all buy stock in BioMarin Pharmaceutical
  19. Freddd

    Freddd Senior Member

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    Hi Triffid,

    I'll clarify one thing. High serum level MeCbl tests were in uremic patiets to have a chance to maintain extreme serum levels for a few days before dialysis which does remove cobalamins from the blood which also have no known toxic level, at least other than CyCbl and that isn't toxic as long as it stays assembled as CyCbl and doesn't release cyanide.
  20. alcyone

    alcyone

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    Sauna: my top hypotheses about why it has helped me are:

    1: forces the body to sweat (toxin removal pathway.) This sauna treatment I approached with caution and under medical supervision. I could not sweat very much at all for 6 years after the chemo treatment that gave me full-blown ME. When I finally had a chance to try weekly steam sauna sessions, gradually progressing the time spent in sauna from 5 mins. to 20 mins., the first three months of that treatment produced sweat that smelled and tasted like the full mix of chemo drugs I had. The smell tapered off over time. Also, my body found itself able, progressively, to sweat again in normal heat conditions, not just in the sauna. The fundamental improvement in my functioning associated with this treatment has lasted for 14 years now.

    2: as is true for many others with ME/CFS I have a lowered "normal" body temperature. As in, almost 2% below standard "normal." I nearly always feel cold except in hot weather or for about an hour after aerobic exercise. Sauna treatment--I use a FIR at home now--heats up my body. I think this probably greatly improves the efficiency of enzyme reactions, speeding up the effective rate of my (genetically-reduced) capacity to turn out the stuff my cells need to function properly.

    Does anybody know if there is such a thing as a time-release biopterin formulation? I only have access to the 2.5 mg. capsules (mentioned above in this thread) and they last about 20-30 mins. for me. Long enough to break me out of a serious brain-fog but the "sun" of improved functioning goes behind the clouds way too soon. Thanks.

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