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Wednesday, 18 November 2015

The Hyperuricosuric Subtype of Autism, Uridine and Antipurinergic Therapy


A subtype of people with classic autism have uric acid excretion which is elevated (>2 Standard Deviations above the normal mean). 

According to the research these hyperuricosuric autistic individuals may comprise approximately 20% of the autistic population.

There is nothing new in these findings and the research goes back 15 years.  At that time nobody looked too deeply as why uric acid was elevated and the role of the purine metabolism in behaviour.

Dr Naviaux at the University of California is the researcher who is developing antipurinergic therapy.  I suspect his research is really at the root of what is going on and that high uric acid is just a consequence of an upstream metabolic dysfunction.

In the meantime, is there any benefit of treating people with autism and hyperuricemia?

It does seem that in some people doing just that does produce tangible benefits and not just in autism; there was even a study in bipolar disorder.  In bipolar, verapamil can also sometimes be effective.


Uric acid

Uric acid is a chemical created when the body breaks down substances called purines. Purines are found in some foods and drinks. These include liver, anchovies, mackerel, dried beans and peas, and beer.
Most uric acid dissolves in blood and travels to the kidneys. From there, it passes out in urine.  A high level of uric acid in the blood is called hyperuricemia,  the standard test though is to measure uric acid in urine.
  
Purine metabolism and autism

To learn about the purine metabolism and autism, I suggest you read the research by Naviaux, like the study below:




Autism spectrum disorders (ASDs) now affect 1–2% of the children born in the United States. Hundreds of genetic, metabolic and environmental factors are known to increase the risk of ASD. Similar factors are known to influence the risk of schizophrenia and bipolar disorder; however, a unifying mechanistic explanation has remained elusive. Here we used the maternal immune activation (MIA) mouse model of neurodevelopmental and neuropsychiatric disorders to study the effects of a single dose of the antipurinergic drug suramin on the behavior and metabolism of adult animals. We found that disturbances in social behavior, novelty preference and metabolism are not permanent but are treatable with antipurinergic therapy (APT) in this model of ASD and schizophrenia. A single dose of suramin (20mgkg−1 intraperitoneally (i.p.)) given to 6-month-old adults restored normal social behavior, novelty preference and metabolism. Comprehensive metabolomic analysis identified purine metabolism as the key regulatory pathway. Correction of purine metabolism normalized 17 of 18 metabolic pathways that were disturbed in the MIA model. Two days after treatment, the suramin concentration in the plasma and brainstem was 7.64μM pmolμl−1 (±0.50) and 5.15pmolmg−1 (±0.49), respectively. These data show good uptake of suramin into the central nervous system at the level of the brainstem. Most of the improvements associated with APT were lost after 5 weeks of drug washout, consistent with the 1-week plasma half-life of suramin in mice. Our results show that purine metabolism is a master regulator of behavior and metabolism in the MIA model, and that single-dose APT with suramin acutely reverses these abnormalities, even in adults.




Hyperuricemia
  
Purine synthesis is increased approximately 4-fold in hyperuricosuric autistic patients, so they have elevated levels in their blood and also excrete high levels.

Be aware that there is both Hyperuricemia and Hypouricemia.

It looks like things can easily get mixed up.

Some people have low levels of uric acid in their blood, because the excrete too much in their urine.

Causes of hyperuricemia can be classified into three functional types: increased production of uric acid, decreased excretion of uric acid, and mixed type. Causes of increased production include high levels of purine in the diet and increased purine metabolism.

In the case study below where hyperuricosuric autism was successfully treated, they actually used a therapy which is claimed for Hypouricemia

You will see reference below to this:-


Antiuricosuric drugs are useful for treatment of hypouricemia and perhaps also hyperuricosuria



This is very odd and please let me know if you think of a logical explanation.

It seems that the therapies for hypouricemia may treat hyperuricemia in autism.


Here is a summary from Wikipedia:-



Treatment

Idiopathic hypouricemia usually requires no treatment. In some cases, hypouricemia is a medical sign of an underlying condition that does require treatment. For example, if hypouricemia reflects high excretion of uric acid into the urine (hyperuricosuria) with its risk of uric acid nephrolithiasis, the hyperuricosuria may require treatment.

Drugs and dietary supplements that may be helpful

·         Inositol
·         Antiuricosurics
                          

Antiuricosurics

Antiuricosuric drugs raise serum uric acid levels and lower urine uric acid levels. These drugs include all diuretics, pyrazinoate, pyrazinamide, ethambutol, and aspirin.

Antiuricosuric drugs are useful for treatment of hypouricemia and perhaps also hyperuricosuria, but are contraindicated in persons with conditions including hyperuricemia and gout.

Dietary sources of uridine

Some foods that contain uridine in the form of RNA are listed below. Although claimed that virtually none of the uridine in this form is bioavailable "since - as shown by Handschumacher's Laboratory at Yale Medical School in 1981 - it is destroyed in the liver and gastrointestinal tract, and no food, when consumed, has ever been reliably shown to elevate blood uridine levels', this is contradicted by Yamamoto et al, plasma uridine levels rose 3.5 fold 30 minutes after beer ingestion, suggesting, at the very least, conflicting data. On the other hand, ethanol on its own (which is present in beer) increases uridine levels, which may explain the raise of uridine levels in the study by Yamamoto et al. In infants consuming mother's milk or commercial infant formulas, uridine is present as its monophosphate, UMP, and this source of uridine is indeed bioavailable and enters the blood.
·         Sugarcane extract
·         Tomatoes (0.5 to 1.0 g uridine per kilogram dry weight)
·         Brewer’s yeast (1.7% uridine by dry weight)
·         Beer
·         Broccoli
·         Offal (liver, pancreas, etc.)
Consumption of RNA-rich foods may lead to high levels of purines (adenosine and guanosine) in blood. High levels of purines are known to increase uric acid production and may aggravate or lead to conditions such as gout. Moderate consumption of yeast, about 5 grams per day, should provide adequate uridine for improved health with minimal side effects.



Hyperuricemia

Medications most often used to treat hyperuricemia are of two kinds: xanthine oxidase inhibitors and uricosurics. Xanthine oxidase inhibitors decrease the production of uric acid, by interfering with xanthine oxidase. Uricosurics increase the excretion of uric acid, by reducing the reabsorption of uric acid once the kidneys have filtered it out of the blood. Some of these medications are used as indicated, others are used off-label. Several other kinds of medications have potential for use in treating hyperuricemia. In people receiving hemodialysis, sevelamer can significantly reduce serum uric acid, apparently by adsorbing urate in the gut
Non-medication treatments for hyperuricemia include a low purine diet (see Gout) and a variety of dietary supplements. Treatment with lithium salts has been used as lithium improves uric acid solubility.

Decreased excretion

The principal drugs that contribute to hyperuricemia by decreased excretion are the primary antiuricosurics. Other drugs and agents include diuretics, salicylates, pyrazinamide, ethambutol, nicotinic acid, ciclosporin, 2-ethylamino-1,3,4-thiadiazole, and cytotoxic agents.
A ketogenic diet impairs the ability of the kidney to excrete uric acid, due to competition for transport between uric acid and ketones





Hyperuricosuric Autism




 Abstract
A subclass of patients with classic infantile autism have uric acid excretion which is >2 S.D.s above the normal mean. These hyperuricosuric autistic individuals may comprise approx. 20% of the autistic population. In order to determine the metabolic basis for urate overexcretion in these patients, de novo purine synthesis was measured in the cultured skin fibroblasts of these patients by quantification of the radiolabeled purine compounds produced by incubation with radiolabeled sodium formate. For comparison, de novo purine synthesis in normal controls, in normouricosuric autistic patients, and cells from patients with other disorders in which excessive uric acid excretion is seen was also measured. These experiments showed that de novo purine synthesis is increased approx. 4-fold in the hyperuricosuric autistic patients. This increase was less than that found in other hyperuricosuric disorders. No unusual radiolabeled compounds (such as adenylosuccinate) were detected in these experiments, and no gross deficiencies of radiolabeled nucleotides were seen. However, the ratio of adenine to guanine nucleotides produced by de novo synthesis was found to be lower in the cells of the hyperuricosuric autistic patients than in the normal controls or the cells from patients with other disorders. These results indicate that the hyperuricosuric subclass of autistic patients have increased de novo purine synthesis, and that the increase is approximately that expected for the degree of urate overexcretion when compared to other hyperuricosuric disorders. No particular enzyme defect was suggested by either gross deficiency of a radiolabeled compound or the appearance of an unusual radiolabeled compound, and no potentially neurotoxic metabolites were seen. Although an enzyme defect responsible for the accelerated purine synthesis was not identified, the abnormal ratio of adenine to guanine nucleotides suggests a defect in purine nucleotide interconversion.
                                    

Here is a case study regarding the successful treatment of hyperuricosuric autism with uridine supplementation.





Abstract

A single male subject with hyperuricosuric autism was treated for a period of 2 years with an oral dose of uridine, which increased from 50 to 500 mg/kg/day. This patient experienced dramatic social, cognitive, language, and motor improvements. These improvement decreased within 72 h of the discontinuation of uridine, but reappeared when uridine supplementation was resumed. Thus, it appears that patients with hyperuricosuric autism benefit from metabolic therapy with oral uridine therapy in a manner similar to that seen in other disorders of purine metabolism in which there is autistic symptomatology.



Uridine as a therapy in Bipolar Disorder


Here is a small trial using uridine to treat bipolar disorder in depressed adolescents:-





           Abstract
This report is an open-label case series of seven depressed adolescents with bipolar disorder treated with uridine for 6 weeks. Treatment response was measured with the Children's Depression Rating Scale-Revised and the Clinical Global Impressions scale. Uridine was associated with decreased depressive symptoms, and was well tolerated by study participants. Further systematic studies of uridine are warranted.




Conclusion
  
In people with autism and high levels of uric acid in urine and blood, there are some interesting avenues to pursue.  Very confusingly, they appear to be the therapies more commonly suggested for hypouricemia.

Uridine seems a good choice worth investigating for children with high levels of uric acid.

Beer is better reserved for adults with Asperger’s.


It may indeed turn out that high uric acid is a biomarker for people who will respond to Naviaux’s antipurinergic therapy.





29 comments:

  1. Peter congratulations on your new article!
    It looks very promising to a considerable number of autistic population.
    It will take quite a long time to be "digested", though.
    Peter, as I don't have instant access to uridine supplement and also begged my son to drink a couple of beers but he wouldn't, do you think I should try Suramin for a start?
    Petroula

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    1. Suramin is an old drug which can have some highly toxic side effects, so it is not available in many countries. There will be a trial in humans with autism, using a single dose. It is considered that a new drug without the side effects is needed, if that trial is positive.

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    2. University of California, San Diego (UCSD) Suramin Treatment Trial for Autism

      https://clinicaltrials.gov/ct2/show/NCT02508259?term=suramin&rank=6

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  2. Do you know if your uric acid needs to be elevated in both blood and/or urine or only one?

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    Replies
    1. All variants are possible, but do not mean the same thing.

      If you have low uric acid in your blood and high uric acid in urine, it would imply that you are excreting it too fast, rather than producing "too much".

      If you had high uric acid in the blood but low uric acid in the urine, it would imply a problem excreting it.

      The cluster identified in the research are producing abnormally high amounts of uric acid and then excreting correspondingly abnormally high amounts. So the odd thing is with the production of uric acid.

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  3. Anecdotally, I have found supplementing with Inosine (which is metabolized to urate in the body) has shown improvements in my son. It certainly has not made anything worse.

    Parkinsons disease is a neurodegenerative disease which among its symptoms is oxidative stress and researchers found that patients with higher urate levels were more protected from Parkinsons. The mechanism they believe for this is that the urate activated the nrf2 pathway and released glutathione from the surrounding astrocytes.

    http://www.sciencedaily.com/releases/2015/09/150901134946.htm

    High levels of uric acid may be a symptom of oxidative stress as uric acid is a potent antioxidant whose levels tend to rise with systemic oxidative stress in the body.

    http://www.ncbi.nlm.nih.gov/pubmed/16375736

    High levels of uric acid obviously cause gout (not something I want for my child), but the evidence I have seen is that exogenously and safely raising uric acid levels with inosine is neuroprotective, rather than the other way around. Here is some other Inosine links you may want to peruse:

    http://www.ncbi.nlm.nih.gov/pubmed/12440381
    http://brain.oxfordjournals.org/content/130/4/915
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC124418/
    http://www.jneurosci.org/content/29/25/8187.full

    Most of these studies deal with stroke and regrowing axons after brain injury, but if you see most forms of classic autism as a developmental form of brain damage (that may or may not be repairable) as I do, then you can probably see my point of view here in that long-term positive outcomes depend on favorably remodeling the brain after a developmental insult (which likely happens in utero).

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    1. Thanks Tyler for your very comprehensive comment.

      There is a big research effort to collect the genetic profiles of thousands of people with autism, it might be far more beneficial (in the short term) to collect metabolic profiles instead. Then you could quickly see things like the correlation between oxidative stress markers and high uric acid. When oxidative stress is treated does uric acid go down.

      What we normally have in the literature is data on 30 people, if we are lucky. It would not be such a big step to collect data on 10,000 children, even if it cost $500 per child. In the big world of autism research what is $5 million? Without data, everyone is just guessing, or just not bothering at all.

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    2. Agreed. I am just reiterating that everything we do as parents right now is a very gray area for those of us who have put in the time to making our best educated guesses as to what will work. There are plenty of blogs/self-proclaimed experts/psychiatrists/quack doctors/etc. who KNOW how to CURE autism because like anybody else they can find one or more correlations in some study and then assume there is a silver bullet approach to fixing the problem. Like diet advice quacks over the years, they all give simple solutions to complex and perhaps impossible to fully understand problems whether it be human metabolism or autism. The more we learn, the more questions are raised.

      As to what serious researchers are thinking right now with regards to autism at the moment:

      https://sfari.org/updates-and-events/sfari-blog/2014/what-we-know/autism-what-we-know-what-is-next

      Bumetanide is mentioned there which I also might add I started with my son a few days ago and am seeing some subtle cognitive improvements. Much thanks to you for suggestions on where to source this stuff from.

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    3. In many studies, uric acid is used as a marker of antioxidant capacity, a good thing. Though there is a difference between acute, transient hyperuricemia and chronic.
      http://www.ncbi.nlm.nih.gov/pubmed/17409313

      To get a spike in uric acid, some apples should probably do it:
      http://www.ncbi.nlm.nih.gov/pubmed/15203196

      Hormesis?
      http://www.ncbi.nlm.nih.gov/pubmed/17157175

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    4. This comment has been removed by the author.

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    5. RG, it is not entirely clear what is going on. The great majority of people with autism have oxidative stress and yet only a minority have high uric acid. It does seem that some people with autism feel better with even more uric acid. Clearly too much uric acid will be bad. So it is another case where some experimentation is needed to get at the answer. Uridine or inositol are among the choices. Inositol is known to help a wide variety of conditions, but, based on very small studies, not autism or schizophrenia. Inositol is very cheap and widely used, whereas uridine is expensive. Based on the above post, we know that at least on person benefited greatly from high dose uridine.

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  4. Does the role of inositol seem to be clear in the treatment of hyperuricosuric autism? If so, do you think that inositol is needed more or less?
    Thank you
    Petroula

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    1. Petroula, nothing is totally clear.

      Inositol does have some known benefits for certain conditions, including OCD. It also has properties unrelated to hypo/hypouricemia.


      "Some preliminary results of studies on high-dose inositol supplements show promising results for people suffering from problems such as bulimia, panic disorder, obsessive-compulsive disorder (OCD), agoraphobia, and unipolar and bipolar depression.[23][24][25]

      In a single double-blind study on 13 patients, myo-inositol (18 g daily) was found to reduce the symptoms of OCD significantly, with effectiveness equal to SSRIs and virtually without side effects.[26] In a double-blind, controlled trial, myo-inositol (18 grams daily) was superior to fluvoxamine for decreasing the number of panic attacks and other side effects.[23]

      Similarly large doses of inositol have been studied for treatment of depression. A 2004 meta-analysis by randomized controlled trials, with mixed results. The authors concluded the evidence is insufficient to determine whether inositol treatment can reduce depression symptoms, but no evidence of harm or negative side effects is seen.[27]"

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  5. Sorry Peter, I must have confused inositol with inosine.
    Now that I can see Tayler's comment I think I have the answer. Uric acid is high in some autism because it is an antioxidant. Uric acid also causes gout. We don't want the gout but we need the antioxidant properties, so we let inosine to regulate things.
    Petroula

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    1. Hi Petroula, insitol is interesting. It will increase uric acid and has similar antioxidant effects to NAC. It is very widely used for OCD and especially by women with PCOS (https://en.wikipedia.org/wiki/Polycystic_ovary_syndrome) and now people with type 2 diabetes. If you buy the powder it is quite cheap.

      If NAC helps, it may be worth trying inositol, regardless of its effect on uric acid. It is not working the same way as NAC, but seems to treat some of the same conditions.

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  6. Hello Peter, I am glad you approve inositol for a trial. I also find it interesting and of course it is on the list.
    My adult son doesn't like beer, powders, among with so many other things, but he likes tablets!
    Speaking of powders,the sulforaphane trial, from which I had mixed results, should be repeated with tablets this time.
    Meanwhile, I am expecting Double Wood Uridine from USA. It has been shipped.
    Now , as for Nac, we have an excellent base to start with. Nac gives self control together with awareness which leads to cognition. He repeatedly says" I have got rubbish in my mind" and I think that my next step is to address to that .
    Uridine is supposed to help make new neuro connections leading to "growth". So my expectation from Uridine is to help him out of the "rubbish".
    There is an experiment with a mouse mother who developed antibodies against her embryo and also had IL6 injections. Her offspring adult mouse was found disabled to inhibit thoughts and filter sensory input. This sounds familiar to me.
    Thanks for being so helpful
    Petroula

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  7. Hello Peter, You said that we needed large doses of inositol. Solgar Inositol is 500 mg/tb. How many tablets do you think I could start with? In Omnium there are 75 mg Inositol and 75 mg Choline and maybe they already give benefit, I have to trial and find out.
    Thank you
    Petroula

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    Replies
    1. Petroula, people seem to use Inositol powder. It is much cheaper than the tablets and does not taste bad.

      http://www.swansonvitamins.com/swanson-premium-pure-inositol-powder-8-oz-227-grams-pwdr

      As you see the suggested dose given is 6g a day. One scoop of the powder.

      There have been many small trials of Inositol in various neurological conditions. Some people it helped and others it did not. The trial in autism was tiny, but did not show a benefit. But given how many sub-types of autism exist, this does not really say a lot. It is simple to try it.

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    2. Hi Peter, thank you very much for your quick reply. I had time to cancel my order.
      Peter here is a scenario: Broccoli seems to be a "key word" in hyperuricosuric autism, too.
      1) Broccoli is supposed to produce uridine.
      2) Uric acid activates nrf2 pathway and so does sulforaphane.
      But " Is it certain 100% that SFN is the only bebeficial compound produced by eating broccoli?"
      In the case of hyperuricosuric autism broccoli may do just fine.
      A trial with broccoli extracts gave me some preliminary results.
      In twenty minutes time there was a huge laughter. It was relevant and occured from a top comment in a football blog. Then euphoria came. He was very talkative with relevant speech. He had a little stimming, though. Generally he seemed hyper in reciprocation and cognition.
      He agreed to add the broccoli in his daily supplementation.
      He only had 1500 mg of broccoli extracts, maybe it's too little.
      I think 3 days with it would give me a clearer conclusion.
      Thank you very much, your question is very inspiring!
      Petroula

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    3. I think the broccoli powder can really do no harm and it does indeed really help some people. That group are the ones with the laughter about 20-30 minutes after the first doses. I think it is good for long term use.

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    5. Sorry Peter, I send my reply twice by mistake. Could you please remove it?

      Also, trying to figure out why the supersprout SFN activated powder didn't work for us and the broccoli extracts tablets worked, always according to your checklist of expected results, I almost forgot the most important . I have to trial for at least 4 weeks.
      Thank you very much for kind reminder.
      The tablets we use contain the SFN amount of almost 4,5-5 mg total in three tablets.
      Petroula

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    6. Petroula, there are substances in broccoli sprouts other than the precursors to SFN. None of these supplements are reliable like prescription drugs, so it is a bit hit and miss and one jar may not contain what is on the label, or be the same as a jar from the previous batch.

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  8. Peter, just a few things about Bumetanide.
    In the case of hyperuricosuric autism, Bumetanide isn't mentioned among other diuretics. Do you think that it could be as effective as the other diuretics mentioned? Anyway I understand that Bumetanide applies to a greater autism population and the specific label of autism subtype doesn't really matter, so maybe just for the information.
    Also Bumetanide should go together with potassium and magnesium, right? I have the magnesium almost 150 mg with vitamin 6 but I can't find the right amount of potassium in Greece. There are pills in the pharmacy containing almost 700 mg per tablet. Is it ok to buy?
    One of my problems in my trials is the fact that I don't have instant access to supplements. Ordering them abroad can be a waste of time. For example I ordered Uridine from USA and although the company sent it at once, the parcel has been stuck in the customs for quite a lot of time.
    Peter, I don't suppose we could create the Bumetanide effect with something "natural", a herb or anything...couldn't we?
    Thanks a lot
    Petroula

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    1. I think you need the real drug, bumetanide. For the potassium supplement, just break it in half and then you have 2 x 350 mg.

      If you can check potassium levels before starting, this is best. Then check again 2 weeks after starting when level should have become stable.

      I think bumetanide will also have an effect on uric acid.

      Bumetanide is a key foundation to my son's therapy. It has a profound impact. Other things do indeed help, but most on a much lessor scale.

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  9. Hi Petroula,

    Have you tried the Uridine yet? What is the dose you are trying?

    I bought the Jarrow which is 250mg per capsule, and just realized that I have made a fundamental error in calculating dosage. I missed the /kg part which takes the recommended dosage for autism into the gms. At 150mg/kg, that would be about 7gms for my daughter. There appears to be only source for powder to dose at that level: a website called powder city.com.

    I also found this: a patent filing for uridine in autism, and at the very bottom a detailed case study.
    http://www.google.com/patents/CA2425593A1?cl=en

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    Replies
    1. Hi RG,

      Thanks for asking.

      As I have already posted to Peter, yes I've been trying it but for only 4 days now, starting low 300mg, then 600mg and yesterday 900mg. Today hopefully I'll reach 1200 mg.

      I use Double Wood Uridine capsules, 300 mg per capsule.
      I think I should stop at 1200 mg for a while, maybe the recommended dose is too much? I am not sure yet.

      Trials in young adult sons can be difficult to evaluate since my son has to face the music of his unexplained actions. I mean that there are many unpleasant concequences in his life and I have to evaluate his reasonable reaction according to that cotext. Considering that, anger and frustration would be expected but on the whole I can see more of himself.

      Thank you very much for the link, I'll have to check it before I go on with Uridine.

      We could talk about Uridine trials again when hopefully we have more results.

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    2. Thanks Petroula. Here is another report on four children:
      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC23552/

      I would appreciate it if you could keep me informed about your uridine experience, as I am planning on starting only after I find a reliable source for the powder.

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  10. I have a daughter with the 16p.11 chromosomal deletion. She's 11 years old and for years we've struggled to get her the help she needs to be successful in school. Can you put us in touch with someone who could give us some idea of we could try the blood pressure meds on her to see if the help? We'd greatly appreciate it.

    Thank you,

    Gregory Bonnette
    Gbonnette74@gmail.com

    ReplyDelete

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