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Tuesday, 13 June 2017

Eosinophilic Esophagitis – another Granulocyte Disorder Associated with Autism  


There are many comorbidities associated with autism.  I have long held the view that these comorbidities hold the key to understanding each particular case of autism.  In many cases this may be far more useful than genetic testing, which only seems to help in a minority of cases.

“Ringed esophagus” aka “Corrugated esophagus”


This then allows you to put people into sub-groups that may well respond to the same therapy.  This may all sound like common sense, but apparently is not.

Eosinophilic esophagitis (EoE) is a relatively new diagnosis and it is applies to a certain type of reflux/GERD/GORD that might be associated with a difficulty in swallowing and may not respond well to the standard stomach acid lowering therapies.

It is likely that most people with Eosinophilic esophagitis have never been correctly diagnosed. Many people have taken several years to get the correct diagnosis.

It is known that Eosinophilic esophagitis is much more common in autism than the general population. One study showed that EoE is four time more likely to be diagnosed in someone with autism. I suspect many people with autism never have their GI problems fully diagnosed.

We now have to add some new science to this blog


Granulocytes

There is a great deal already in this blog about mast cells.  Many readers have children who have allergies, mast cell activation, or even mastocytosis.  Mast cells are the ones (but not the only ones) that release histamine.

Mast cells are just one type of a class of cells called Granulocytes, that are produced in your bone marrow.

Granulocytes are a category of white blood cells characterized by the presence of granules, which release their contents when they degranulate.

The four types of granulocytes are:- 


·        mast cells

These have been well covered in the past. These are what cause problems for people with pollen allergy.


·        eosinophils

Eosinophils play a crucial part in the killing of parasites because their granules contain a unique, toxic basic protein and cationic protein. Eosinophils regulate other immune cell functions (e.g., CD4+ T cells, dendritic cells, B cells, mast cells, neutrophils, and basophils), they are involved in the destruction of tumor cells, and they promote the repair of damaged tissue. Interleukin-5 interacts with eosinophils and causes them to grow and differentiate; IL-5 is produced by basophils.

Note that some people with autism find that the TSO helminth parasites modify their immune system and improve their autism. This may relate to what is contained in the granules of eosinophils.  


·        basophils 

Basophils are similar to mast cells, in that they contain prestored histamine within their granules. Unlike mast cells they circulate in your blood . Basophils are the least common of the granulocytes, representing about 0.5 to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They can produce histamine and serotonin that induce inflammation, and heparin that prevents blood clotting.

There is research underway to try to develop basophil stabilizers.


·        neutrophils

Neutrophils are normally found in the bloodstream. During the beginning phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation.

Neutrophils are recruited to the site of injury within minutes following trauma, and are the hallmark of acute inflammation; however, due to some pathogens being indigestible, they can be unable to resolve certain infections without the assistance of other types of immune cells.

Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation. The contents of these granules have antimicrobial properties, and help combat infection.


An obvious question would be, if you know you have a problem with mast cells are you likely to have an issue with the other types of granulocytes?

One role of eosinophils is to regulate other immune cell functions (e.g., CD4+ T cells, dendritic cells, B cells, mast cells, neutrophils, and basophils).

The subject is highly complex and again not fully understood, but it is clear that granulocytes are all interrelated and so a problem with one may well be associated with a problem with others.

In the case of Eosinophilic esophagitis (EoE), both eosinophils and mast cell are directly involved.

Basophils, like mast cells, release histamine among other things when they degranulate.

Mast cells usually do not circulate in the blood stream, but instead are located in connective tissue.  Circulating granulocytes, like basophils can be recruited out of the blood into a tissue when needed.

So in addition to mast cell stabilizers perhaps, we might benefit from basophil and eosinophil stabilizers.

Surprisingly, the antihistamine cetirizine has Eosinophil-stabilizing properties, as does the asthma drug Montelukast. Both drugs are widely used in children.

Another substance, curine, also inhibits eosinophil influx and activation and is seen as a potential new treatment for asthma.  Interestingly the drug curine, is an alkaloid, that blocks L-type Ca²⁺ channels.

Regular readers may recall that I proposed the L-type calcium channel blocker Verapamil to control my son’s mast cell degranulation. Mast cells degranulate in a very complex fashion that involves the flow of Ca²⁺.

This may or may not be a coincidence. 

Fullerene nanomaterials are being developed as both mast cell and peripheral blood basophil stabilizers.



L-type calcium channels and GI disorders in Autism

There are many types of GI disorder in autism, however I suggest that a large group can be categorized as being broadly Granulocyte Disorders, which may well all respond to L-type calcium channel blockers, to some extent.

Indeed this may be a better solution than the widely used cromolyn sodium.

Perhaps people with autism, and their family members have certain calcium channels that are either overexpressed, or do not close fast enough, leading to a higher level of intracellular calcium.  This of course ties back in with Professor Gargus and his theories about IP3R and the calcium store inside the endoplasmic reticulum”.

This all gets extremely complex.

My rather simple suggestion would be that if you have autism and any GI problem from the esophagus downwards, a three day trial of verapamil just might change your life.  As is almost always the case, there are some people who do not tolerate verapamil.



Interleukin 5

Interleukin 5 (IL-5) is an inflammatory cytokine produced by type-2 T helper cells  (Th2), mast cells, basophils and eosinophils.

IL-5 interacts with eosinophils and causes them to grow and differentiate.

IL-5 has long been associated with the cause of several allergic diseases including allergic rhinitis and asthma, where a large increase in the number of circulating, airway tissue, and induced sputum eosinophils have been observed.

You might expect high levels of IL-5 in people with Eosinophilic esophagitis (EoE)



Anti–IL-5 therapy is associated with marked decreases in peripheral blood and esophageal eosinophilia (including the number of CCR3+ blood cells) in patients with EE and improved clinical outcomes.


Not surprisingly the same anti-IL-5 therapy has been approved to treat severe asthma.


Patients are given mepolizumab by injection every four weeks. It costs £840 per dose.



Mepolizumab for autism?

It is very expensive, so I doubt many people will think of Mepolizumab for autism.  If you have EoE, or severe asthma, you may be able to access this IL-5 therapy, my guess is that it would also reduce the severity of any comorbid autism.


Back to Eosinophilic Esophagitis

I was writing a while ago about food allergy in my book and came across the opinion that food allergy is no more common in autism than in typical people, but what is more common is Eosinophilic Esophagitis.

Eosinophilic esophagitis is a chronic immune system disease. It has been identified only in the past two decades, but is now considered a major cause of digestive system (gastrointestinal) illness.  In many cases it likely remains undiagnosed. If it continues, after a few years swallowing becomes difficult, in part because a “ringed esophagus” develops that impedes the passage of food.

As seems to be often the case there are plenty of contradictions in the diagnosis and treatment, as you will find as you read on.

The symptoms are broadly what would normally be diagnosed as reflux/GERD/GORD. This is very often found in people with autism and I expect in their relatives.

It is relevant to autism because it will be yet another comorbidity that when treated should improve autism, but it is also another marker of a particular sub-group of autism.

There are numerous other GI conditions comorbid with autism - colitis, IBD, IBS etc.  In the end I imagine that the molecular basis of some of these diagnoses is actually the same, so you will find the same therapies may be effective.

It looks like that one common factor is the mast cell and, just as in pollen allergy and asthma, stabilizing mast cells yields great benefit. Stabilizing mast cells is complex but involves the flow of calcium ions, Ca2+.  By modifying the flow of Ca2+ you can prevent mast cells degranulating.  This was one of my earlier discoveries, but there is now research showing the L type calcium channels “open” mast cells.  Keeping these channels closed is actually quite simple.

It would seem logical that the same approach could be therapeutic to other conditions that are, at least in part, mediated by mast cells.

According to the Mayo Clinic these are symptoms of eosinophilic-esophagitis


Adults:

·         Difficulty swallowing (dysphagia)

·         Food impaction

·         Chest pain that is often centrally located and does not respond to antacids

·         Persistent heartburn

·         Upper abdominal pain

·         No response to gastroesophageal reflux disease (GERD) medication

·         Backflow of undigested food (regurgitation)


Children:

·         Difficulty feeding

·         Vomiting

·         Abdominal pain

·         Difficulty swallowing (dysphagia)

·         Food impaction

·         No response to GERD medication

·         Failure to thrive (poor growth, malnutrition and weight loss)


The diagnosis of EoE is typically made on the combination of symptoms and findings of diagnostic testing.


Prior to the development of the EE Diagnostic Panel, EoE could only be diagnosed if gastroesophageal reflux did not respond to a six-week trial of twice-a-day high-dose proton-pump inhibitors (PPIs) or if a negative ambulatory pH study ruled out gastroesophageal reflux disease (GERD).

Treatment strategies include dietary modification to exclude food allergens, medical therapy, and mechanical dilatation of the esophagus.

The current recommendation for first line treatment is PPI in lieu of diet as a significant portion of EOE cases respond to this, and it is a low risk, low cost treatment.

The second and third line therapies are an elimination diet of either the 6 or 4 most common triggers, or topical corticosteroids, including both fluticasone, and topical viscous budesonide.

Elimination diets would be followed by re-introduction of foods under supervision if the first diet is successful. Allergy evaluation has not been found to be an effective means to determine what foods to eliminate.

  


MAST CELL STABILIZERS

In a small case series, Cromolyn sodium failed to show any clinical or histologic improvement in EoE patients

LEUKOTRIENE INHIBITORS

Montelukast is an eosinophil stabilizing agent. It improved clinical symptoms in EoE but there was no histological improvement

PROGNOSIS

As mentioned earlier, EoE is a chronic inflammatory disease of the esophagus. The inflammation leads to remodeling, fibrosis and stricture. Fortunately, no case of esophageal malignancy has been reported in EoE. Patients are generally diagnosed after several years of their symptoms. Although symptomatic improvement occurs after treatment, recurrence is common after discontinuation of treatment. So maintenance therapy is needed to prevent recurrences. At the present time there is no head to head study to suggest the best maintenance treatment. Continuation of swallowed corticosteroid and/or dietary therapy should be done in all EoE patients particularly in those with history of food impaction, dysphagia, esophageal stricture, and in those with rapid symptomatic and histologic relapse following initial treatment



Eosinophilic esophagitis and Mast Cells

Eosinophilic esophagitis is called Eosinophilic because it is mediated by Eosinophils, however it has been established that mast cells also play a role. 



Whereas prior studies have primarily focused on the role of eosinophils in disease diagnosis and pathogenesis, this study investigates the involvement of mast cells.

Herein we have identified local mastocytosis and mast cell degranulation in the esophagus of EE patients; identified an esophageal mast cell associated transcriptome that is significantly divergent from the eosinophil-associated transcriptome with CPA3 mRNA levels serving as the best mast cell surrogate marker; and provide evidence for the involvement of KIT ligand in the pathogenesis of EE.


One possible explanation for eosinophilic esophagitis:















A potential immunological mechanism involved in the pathogenesis of EoE. An uncontrolled TH2 immune response initiated by an allergic insult results in the transition of the esophagus from a normal (NL) to EoE phenotype through enhanced IL-13 production that induces highly elevated CCL26 (eotaxin-3) expression by esophageal epithelium. Dysregulated TH2 immune response and enhanced CCL26 secretion together promote the infiltration of CD4+TH2 cells, eosinophils, and mast cells, and potentially, type-2 innate lymphoid cells (ILC2) and CD4+TH9 cells; into the esophagus. TGF-β and IL-4 produced by the activated mast cells and CD4+TH2 cells may induce eosinophils, ILC2, and/or CD4+TH9 cells to produce IL-9, which in turn, promotes esophageal mastocytosis that contributes to the development of EoE pathophysiology.



Possible Eosinophil stabilizers


CONCLUSIONS Eosinophil-stabilizing properties and favorable safety profile make cetirizine an attractive add-on therapy for NMO. Thus far it has been well-tolerated in our patient population, with incoming data about efficacy expected over the coming months




·        Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum.

·        Curine inhibits eosinophil influx and activation and airway hyper-responsiveness.

·        Curine mechanisms involve inhibition of Ca2+ influx, and IL-13 and eotaxin secretion.

·        No significant toxicity was observed in mice orally treated with curine for 7 days.

·         Curine has the potential for the development of anti-asthmatic drugs.

  

Conclusion

Non conventional therapies for eosinophilic esophagitis might include:-


·        Cetirizine

·        Verapamil

·        Montelukast

·        Curine

The very expensive therapy is Mepolizumab.

If you have one type granulocyte causing a disorder, is seems almost inevitable that the other types of granulocyte are also involved.

Treating granulocyte disorders should improve autism and left untreated they may mask the effect of otherwise useful autism therapies. 

One reader did previously suggest a bone marrow transplant for autism. A rather radical solution, but if someone with autism was given donor bone marrow as part of another therapy, you might well see their autism improve.










47 comments:

  1. Verapamil does inhibit DAO - about 50% - so maybe it's best to use this one cautiously if low dao is suspected? I did have to stop verapamil for my son - maybe I was using it too much, and maybe only best for my son to use it when only in crisis level flare ups. Will have to test it again. He does have dao snps. One side effect I noticed when he was on it, he suddenly started reacting with hives after eating corn tortillas - his only hives reactions before were due to stress, never to foods. even though he is sensitive to certain foods, he never had hives reaction. More like the reactions closer to EoE. Recently, he did a really intense mountain hike and down a gorge to a waterfall - the pollen was very high that day and he also ate a high histamine food - avocado. That seemed to cause an intense flare. I thought maybe some bug in the water at first. Long story short, seems to have just been an intense mast cell flare up - and for first time we tried the cetirizine and zantac (ranitidine) combo that is often recommended by mast cell doctors, and what an amazing response! Cromolyn Sodium is a huge help for him, but the cet/zant combo will be his new go-to for flares. I also just learned that mast cell doctors like Dr Afrin often prescribe benzos like clonazepam due to their mast cell stabilizing properties. Had no idea! I will need to re-try low dose clonazepam, for flare ups, and see if it is a matter of finding the exact dose for his response.

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    1. You definately don't want to further inhibit DAO especially if you are eating a lot of foods with Amine groups and or you are taking probiotics. It contributes to a histamine response that is often no fun to deal with. BTW there is a shortage of DAO enzyme in the US. I found in my case it was the amines from biogenic amine increases in excess of my son's capacity to break them down. Once I cut back on the quantity the symptoms went away. He wasn't producing enough enzyme to break them down quick enough. I still give the amine foods but instead of giving water kefir with the amine foods I give the water kefir on days he is not eating so many amines and I give a small amount of water kefir. He has some epigenetic markers that make further complicate the issue. There are many problems with long term use of benzodiazepines----not to mention the effects I have witnessed with long term users. Here is one explanation: http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.1991.tb09781.x/pdf

      http://dc.uthsc.edu/cgi/viewcontent.cgi?article=1402&context=dissertations

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    2. I understand the point you make about benzo use, especially for an adolescent like my son. I just thought it was interesting that mast cell doctors rx it. I tried the *micro* dose of clonazepam, from the Catterall study information that Peter has written about - had it compounded so that micro dosage could be precise, and it only made my son sleepy - at such a miniscule dose. So we decided it is not for him. Same with my son and amines - he does best with lower protein, athough with other amines and glutamates histamines etc., it is just about threholds for him. The only food that immediately bothers him, theeshold or not, is high histamine tomato - his joints almost instantly ache and his kneecap has swollen before several times after eating. I can't find the DAO enzymes anymore either, but he seems to be doing well with small amounts of b6 and magensium with meals. Maybe his b6 levels have finally risen and helping the DAO enzyme. Also noticed the less I use antihistamines, the better his reactions have become. Seemed his allergy/histamine/mast cell was so bad for a while that his allergy medicine was "wearing off" and he needed more. Got me thinking- The bad reaction started happening same time every day - is this really about a medicine "wearing off"? made me wonder about a rebound effect with the allergy medicines - why not? It is possible with so many other drugs that affect neurotransmitters, and histamine is a neurotransmitter after all. So I stopped them and went back to supports I was using before our verapamil trial - he is so much better! I had to give allegra only once in last 2 weeks. And here we are in middle of grass pollen season and some molds due to recent heavy rain. So much improvement.

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    3. Re: probiotics - Over all, never had luck with those for my son (and ferments are very bad for him) - even the ones that are histamine degrading, and avoiding the histamine producing ones. I think my son's immune system is just too reactive to handle anything that stimulates it. And it could be what I was doing at the time, he was unable to handle probitiocs (for example, too many supplements and/or antihistamine use).. Especially in light of this information:

      http://www.nature.com/news/2008/080111/full/news.2008.436.html

      It does make me wonder.... We tried SLIT many years ago, and he was just too reactive to it then. If I started SLIT now, without using other immune system stimulants, a bunch of useless supplements or possible immune system suppressing anithistamines - I wonder if he is now ready for SLIT?

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    4. Go easy on the anti histamines if your kid on the spectrum is chronically battling bacterial infections/PANDAS issues???
      https://www.ncbi.nlm.nih.gov/pubmed/21346365

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  2. Some very interesting research on calcium channels came out today which may be tangentially related to the topic at hand:

    Press Release:

    https://www.sciencedaily.com/releases/2017/06/170613101941.htm

    Paper:

    http://www.pnas.org/content/early/2017/06/07/1704470114

    The claims by the authors are essentially that the number of vesicular docking sites are equal to the number of VGCC clusters, such that there is enough space at each VGCC cluster for one and only one vesicle to "dock" in any particular direction.

    Off the top of my head, if too many vesicles are released at a time (gumming up the works since only one can bind), or else if the calcium channel clusters are faulty such that they allow multiple vesicles to dock, then you will have significant problems either way. In autism, it seems you have too much LTP (Long-Term Potentiation) which is largely dependant on the rate of calcium entering a neuron, so in this regard just enough of the right type of calcium channel blocker (e.g. Verapamil) could help to rebalance this natural relation between vesicle release and calcium channel clusters (assuming my understanding is correct here) which is supposed to be 1:1. Of course, broadly acting calcium channel blockers like Verapamil are going to have a lot of side effects in the body (after all it is a blood pressure drug), but it is nevertheless interesting to think of calcium channel blockers as potentially being an end-run around other neurotransmitter problems via manipulating this relationship between vesicle docking sites and calcium channel clusters.

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    1. I think it will be a few decades before calcium channels in the brain are fully understood. I was surprised that verapamil has the effect it does in my son.

      If the same calcium channel dysfunction is present throughout the body, you might find rather than side effects, there are multiple benefits. So I see the presence of certain comorbidities as an indicator of who might benefit from this drug. It is definitely not for everyone and it may be best for occasional use in some people.

      It has other potential benefits such as upregulating autophagy.

      Based on the feedback todate, some people tolerate verapamil with no side effects at all, whereas others do have side effects. The drug is so widely used the list of even rare side effects is quite comprehensive.

      For example, some people use verapamil to treat/prevent cluster headaches and a small number develop gingival enlargement. Side effects were dose dependent.

      Verapamil induced gingival enlargement in cluster headache
      http://jnnp.bmj.com/content/76/1/124

      One reader of this blog found a similar side effect in her daughter.


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    2. Peter, I miss Verapamil so much. She was so calm, and willing to learn in that time... So many people, even pregnant women use it. My daughter couldn't. All nus effects have gone in a week after withdrawal of Verapamil (galactorrhoea and gingival hyperplasia).
      The major problem these days is changing of milk teeth and regression that follows it.
      Couple of days before the tooth begins to wobble she becomes dumb, foggy, with cramps in belly, and acnes on her forehead.
      Started montelukast yesterday to give a shot in small dose - 5mg. So far it is good.

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    3. Maja, did you consider Nimodipine as an alternative to Verapamil? Perhaps she will tolerate it better and the effects should be similar. For example both are used for cluster headaches.

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    4. Too strong (hypotension) - thank you...

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    5. Maja, surprisingly there is research into intranasal verapamil, some is from 2017. You wonder why nobody has trialled it for cluster headaches. For some reason calcium channel blockers and some other drugs accumulate in gum tissue. Intranasal might avoid this. Intranasal insulin does not reach your blood. The high tech intranasal verapamil is not much more potent than a basic spray.

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    6. It is a surprise! I will follow that, by all means. Really, Peter, you are serious explorer. Thanks for sharing.

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  3. Hi Peter, Cetirizine works well for my son's sneezing/rhinitis symptoms. It's not sedative and doesn't seem to cause side effects.

    For those who have eye allergy (conjunctivitis) and don't respond to dexamethasone, or have a rebound after stopping it, olopatadine might be a good option.
    When my son used dexamethasone for eye allergy, I noticed that it brought some negative behavioural effects and after discontinuation there was rebound.
    Then I found olopatadine eye drops which I think is a better alternative.
    Olopatadine is a Japanese antihistamine (selective H1 antagonist)/mast cell stabilizer found effective for treating the rebound phenomenon after discontinuation of topical steroids.
    I've read a paper saying that when you choose antihistamines you should keep in mind if you respond to tachykinins/Substance P inhibitors or not.
    Both cetirizine and olopatadine are SP inhibitors and I wanted to ask you if Substance P has something to do with autism allergies/inflammation.

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    1. Petra, this info on substance P is so interesting! Can you share your info. on cetirizine being a Substance P inhibitor? I found a paper describing substance P inhibitors being used with fibromyalgia patients and sub P antagonist affects stress response and emotion and antidepressant activity.

      http://www.psychiatrictimes.com/articles/substance-p-antagonist-relieves-depression
      "He noted that while substance P has been determined to be the most abundant neurokinin in the mammalian CNS, it is particularly concentrated in the amygdala and other regions thought critical for regulation of affective behavior and neurochemical responses to stress.

      Perhaps the effects of cetirizine on generalized pain helps certain sub groups of autism like my son's? He has responded to well to it I'm kicking myself for not trying it sooner. Very interesting info. Thanks for sharing Petra.

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  4. Hi Tanya, I am sure you can find several papers conclude that cetirizine can inhibit/modulate the expression of SP.

    Here is one:[Effect of cetirizine hydrochloride on the expression of substance P in ...
    https://www.ncbi.nlm.nih.gov/pubmed/16196274 -
    CONCLUSION:
    SP is considered to be involved in the pathogenesis of allergic dermatitis. Cetirizine hydrochloride can inhibit the expression of SP in IgE-dependent triphasic cutaneous reaction. It might be part of the mechanisms of anti-anaphylaxis of cetirizine.

    Tanya, my son was found negative to arthritis and Raynaud's syndrome. Thank you for your idea to check.

    I think tachykinin through SP inhibition, don't know to what extend, may be really helpful to strike nociception processing and pain responses. This pathway may be connected to anxiety like behavioural responses for some of our children.

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    1. Petra, I am no expert on SP, but I think you should follow up on your idea of saffron and P2X7.

      Here is a good paper on P2X7. (it mentions Naviaux and Suramin)

      The P2X7 Receptor Channel: Recent Developments and the Use of P2X7 Antagonists in Models of Disease

      http://pharmrev.aspetjournals.org/content/pharmrev/66/3/638.full.pdf

      Interestingly, Probenecid appears again. Recently we saw it is an OAT3 inhibitor that can improve the bioavailability of certain drugs. In the case of bumetanide and OAT3, it looks like Acetazolamide helps and even aspirin may help bioavailability.

      Probenecid is the most potent P2X7 inhibitor listed in that paper.

      Saffron is sold as an OTC P2X7 inhibitor for a very specific eye disorder. People seem to think it helps.

      We do not know which P2X or P2Y receptor gives Suramin its effect. If it is P2X7, there are clear alternatives.

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    2. Petra, in the study on P2X7 it mentions Colchicine as a therapeutic drug. Colchicine comes from Saffron. It is used to treat gout, as is Probenecid.

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    3. Hi Petra and Peter,

      In a recent search for new mast cell stabilizers because of ongoing flare-up in my son I found a paper comparing P2X7 antagonist activity of several H1 antihistamines:

      "Among the various agents tested, oxatomide significantly inhibited P2X7 receptor-mediated [Ca(2+)]i elevation in a concentration-dependent manner without affecting the P2Y2 receptor-mediated response in both N18TG2 and J774 cells. Consistently, oxatomide inhibited P2X7 receptor-mediated membrane current and downstream responses such as mitogen-activated protein kinase activation, inflammation-related gene induction, and cell death."

      https://www.ncbi.nlm.nih.gov/pubmed/26463039

      I wonder if anyone here is familiar with oxatomide as anti-allergic?

      It also seems to affect mast cells and other granulocytes.

      Peter, do you think that levocetirizine can stabilize eosinophils as cetirizine because of chemical similarity? Apparently levocetirizine was recommended as the most effective non-sedative H1 blocker for children with mast cell disorders by the immunologist that I once consulted here.

      And here is Ukrainian experience with L. reuteri for EoE (unfortunately the strain is not specified):
      http://www.vestnik-medicine.mgu.od.ua/archive/vip7_eng/4.pdf




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    4. Agnieszka, levoceterizine is the active enantiomer of cetirizine, so I think in theory it should stabilize eosinophils. I hope it does, because I am currently using it due to severe pollen conditions.

      I think tolerance is an issue with most, if not all, mast cell therapies. They seem to work best when you vary them.

      The Ukrainian trial was just one month, it would be interesting to see what happens after six months.

      I think L.reuteri has a role to play as part of the mix. I am currently using it.

      The first generation antihistamines seem much more potent, but make you drowsy.

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    5. Agnieszka, did you ever try one of higher bioavailability forms of curcumin? You may get at least a marginal benefit towards mast cell activation. I bought some a long time ago and now that it is very much allergy time, I am seeing if it helps. In theory it should help, but only a tiny amount gets absorbed.

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    6. Peter, thanks for this idea. I have some Longvida Curcumin - never used yet.
      I also thought about EGCG and theanine as an add-on, but I can't get them at once. It has been suggested that statins are mast cell stabilizing.

      Air is pollen-heavy here this year, I can see people suffering from allergic rhinits, who never experienced that before. This may contribute to the flare.

      But it seems like there was another trigger. To my surprise, analysis of symptoms and a series of withdrawals and exposure trials pointed to bumetanide and I've recently started new brand from the US. I found that it contains quinoline yellow (D&C Yellow No. 10 or E104 in Europe), which is histamine releasing additive. Apparently it is banned as food coloring in the US, but still can be used in medications.

      It's not the first time my son reacts to coloring additives in meds. Imagine I tried this bumetanide brand at first not realizing this.

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    7. Agnieszka, would you mind mentioning what brands of Bumetanide to avoid?

      /Ling

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    8. Ling, it was Sandoz 1 mg tablets from the US. The tablets are not bright yellow, they are slightly 'yellowish'. The best is to check summary of product characteristics or leaflet.

      I think that many people can tolerate this additive, but my son once reacted also to E124 in prescription effervescent potassium sold here. Why they need to have it bright pink is beyond my understanding.

      Also now he has a difficult time reacting to many things, this is mast cell activation related. Maybe few months ago he could use it without problems.

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    9. Thanks Agnieszka!
      Even though mast cell activation and additive intolerances may be scarce in the general population, it seems to be far more frequent in the ASD/ADHD population. So this is probably very useful information for the PolyPill audience.
      /Ling

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  5. Peter,after 15 days of using Miyairi 588, he started to clap almost permanently,beyond the last gains that he has aquired wich could be atributed to Diamox, the other new intervention, i think this probiotic causes him much stimming. He is in 8 tablets, only, but could this bacteria be causing more autistic behaviors? Another thing I wanted to ask you is why diamox alone is better than valproate low dose plus diamox low dose, 125 mg a day each,in the control of electrical activity.
    Valentina

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    1. Valentina, the effect of butyric acid (sodium butyrate/Miyaiari 588) seems to be dose dependent. One reader found 500mg of sodium butyrate had a good effect but 1000mg was not good. So it does look like you can have too much butyric acid. We know that too much propionic acid produces autistic behaviors. A smaller amount of butyric acid can be helpful, but you will have to experiment to find what dose of Miyairi is required.

      So maybe you need a lower dose and see if there is a positive effect. Maybe 4 or 5 tablets. It is a case of trial and error.

      Be careful to try too many things at once, otherwise you cannot know what is causing what effect.

      Diamox does help various very specific kinds of epilepsy. You need to establish was it Diamox or Miyairi that created the gains.

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    2. Valentina, I don't think you can assume that Miyari 588 is causing tics because of butyric acid as the most recent microbiome research suggests that interactions between various species are too complex to predict what particular metabolite is the root cause of some sort of effect/behavior in the body. The most sophisticated studies I have seen look at the whole change in the microbiome after the introduction of some variable whether that be a food, a probiotic, or just stressing an animal being studied.

      What you can say is that this strain is causing problems, but whether that is because of the Miyari 588 or else the result of an increase or decrease in another species because of the Miyari 588 or else a complex signaling cascade between the Miyari and some other species. You could even have a situation where you are getting both positive and negative symptoms at the same time.

      I would just take Peter's advice and try the sodium butyrate directly and see if you get the same acute problems at high doses. Then you will at least have a better gut feeling as to whether your issues with miyari are due to butyric acid or else some completely different reasons.

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    3. Ok Tyler, may be you are right and my son is not prepared to receive a costridium strain,even if it is a good clostridium strain,for its interactions in my son´s overactivated microbiome.May be only the short chain fatty acid,sodium butyrate is a better option for him.
      Valentina

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  6. Hi everyone,

    I'm actually excited about the finding that Saffron can be an anti-P2X7 therapy (I believe it was Petra who found this). I'm going to order a Saffron supplement and keep everyone posted.

    Speaking of P2X7, I've found something interesting that I wanted to share. It starts with this:

    https://www.ncbi.nlm.nih.gov/pubmed/28554875

    So basically, what this paper says is that CD39 scavenges extracellular ATP (eATP) which suppresses P2X7 activation.

    This really intrigued me because we've been really focused on blocking the P2X7 receptor, but this seems to offer an opportunity to clear up the ligand that activates P2X7, which should also be helpful as an additive therapy. So I then started looking for what can increase CD39 production and voila:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891436/

    Sesamin seems to be able to increase CD39 production, so I have just started adding it to my treatment regimen and will keep everyone posted.

    I hope this is helpful!

    AJ

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  7. I had the opportunity today to talk to a recently retired pediatrician specialized in allergy. I wasn't prepared for the topic to come up, else I would probably hade asked more of the "right" questions.
    However, what I learned was that in his practice, people with mast cell problems in the gut would be prescribed oral cromoglycinate (=sodium cromoglicate) and standard procedure for severe pollen allergy were double dose of medicine did not resolve the problem was to add singulair (montelukast).
    Though this does not add to our knowledge in the blog, I think it is very nice to have experts confirming the suggested treatments.
    I also stumbled on a case report (n=1) where addition of inhaled sodium cromoglicate to oral form added some benefits:
    "Sodium cromoglicate, a drug that reduces the release of mediators from mast cells, is effective in controlling gastrointestinal symptoms, but less effective in those affecting other body systems. In this case report we have shown that the addition of inhaled sodium cromoglicate controls the symptoms of bone pain, fatigue and headache and also that the doses have to be increased during the menstrual period."
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904792/

    /Ling

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  8. Hi Peter,
    As my son's skin is responding favorably to histidine, I wanted to re-try verapamil. Again, he quickly was escalated and agitated very easily.
    I don't know where to go next in terms of helping this mast cell issue. He takes supplement from Supreme Nutrition (which has quercitin) and of course, we continue the histidine. Memory/brain fog is not improving but overall mood and skin seem much better.
    I recently added Olive Leaf Oil for luteolin as well as artichoke extract.
    You mentioned Nimodipine recently. Might this as trial be a good idea to help the memory/brain fog piece?
    Thanks
    Nancy

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    1. Nancy, olive leaf oil is both an ACE inhibitor and a calcium channel blocker, in addition to other properties.

      Is your verapamil a yellow tablet? It seems that some people with mast cell issues are allergic to the yellow color they use in pills. This makes assessing the response rather complicated.

      Verapamil looks like the safest L type calcium channel blocker. Nimodipine has the same mode of action but has a bigger effect on lowering blood pressure. Have you checked your son's blood pressure?

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  9. The verapamil is not yellow. It is white.
    Not I have not checked his blood pressure recently but can have that done.
    Not sure what direction to go in at this point.

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    1. Nancy, it could be the combo of quercetin with the verapamil. Quercetin also lowers blood pressure. Maybe the combination caused his blood pressure to drop too much and his agitation was anxiety over that feeling? I can see how that sensation could be very unsettling for someone on the spectrum. My son has mast cell activation, histamine issues, allergies - the works. Colorings may be a problem for him - but if he will use something for a while, we usually err on side of caution and get a medicine compounded.

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  10. another thought: verapamil I have read can reduce DAO enzyme in gut by 50% - is it possible the combination of reduced DAO capacity and taking histidine is overwhelming him with histamine at that point? and then you get the agitated behavior? When he is agitated like this, have you ever tried a bit of baking soda in water (and with a bit of potassium bicarbonate, but not necessary) to see if that calms? It is a histamine antidote for gut.

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  11. Hi Peter and community,

    I've just found a very interesting paper and would really appreciate everyone's input on it - I think it may be very relevant to us. If this was recently addressed elsewhere, my apologies, I've been so busy lately I haven't had a chance to be as diligent as I would like.

    Here is the abstract of the paper:

    http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2017124a.html

    This paper shows that phosphorylated eIF2alpha could be responsible for some of the negative symptoms we see in our kids.

    The researchers used a small molecule inhibitor of eIF2a phosphorylation and some of the issues improved (in mice).

    I'm going to do a deep dive on this pathway (i.e. CAv1.2, Calcium channels, mTORc1,eIF4B, 4EBP1, and of course eIF2 (including phosphorylation of eIF2a), and ideally to see if there are any opportunities (natural, easy to access meds, etc.) to address what appears to be elevated phosphorylation of eIF2a, which may be very helpful to at least some of us.

    If anyone finds anything relevant, please post.

    Thanks in advance for your input!

    AJ

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    1. I researched this topic because I suspected the connection between PERK/eIF2alpha and autism after reading this article about new drug for Alzheimer's: http://www.nextbigfuture.com/2017/04/anti-dementia-drugs-will-soon-start-clinical-trials.html
      "Scientists hope they have found a drug to stop all neurodegenerative brain diseases, including dementia... When a virus hijacks a brain cell it leads to a build-up of viral proteins. Cells respond by shutting down nearly all protein production in order to halt the virus's spread. Many neurodegenerative diseases involve the production of faulty proteins that activate the same defenses, but with more severe consequences. The brain cells shut down production for so long that they eventually starve themselves to death... Prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival"

      It is interesting that "aluminum activates PERK-EIF2α signaling and inflammatory Proteins": https://www.ncbi.nlm.nih.gov/pubmed/26546554. A life-long accumulation of aluminum could be a probable cause of dementia.

      I quickly searched for natural supplements that would suppress the PERK/eIF2α signaling and found that alpha-linolenic acid does it: https://www.ncbi.nlm.nih.gov/pubmed/26399745. Flaxseed oil is probably the most common source of alpha-linolenic acid. My son has been taking a spoon of flaxseed oil every night after for the past month or so. Baclofen, a medication studied for autism and found to improve communication and socialization through activation of GABA_B raceptors, also suppresses the PERK pathway: http://journal.frontiersin.org/article/10.3389/fncel.2016.00255/full

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    2. Apigenin, Arctigenin and potentially Curcumin also appear to attenuate eIF2α according to this article:
      http://www.jbc.org/content/289/39/27118.full
      http://journal.frontiersin.org/article/10.3389/fnmol.2014.00022/full
      http://www.mdpi.com/1422-0067/18/6/1168/pdf

      Perhaps other Nrf2 activators also inhibit eIF2alpha signaling.

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    3. Hi Vladimir,

      Thanks so much for your response, and your great insights!

      The following paper will result in my adding ALA to my regimen:

      https://www.ncbi.nlm.nih.gov/pubmed/26399745

      And I have to say, I really think the following paper is outstanding:

      http://journal.frontiersin.org/article/10.3389/fnmol.2014.00022/full

      While it is intended for AD, it may be just as relevant to ASD because it details the relevant pathway we're looking at.

      One other way I'm going to look at this opportunity is to look for natural PERK or ATF4 inhibitors. PERK seems to lead to eIF2alpha phosphorylation, and this leads to ATF4 (and then CHOP) as per the following:

      http://journal.frontiersin.org/article/10.3389/fnins.2017.00152/full

      Still lots to read up on, but I'm excited about this pathway maybe leading to some improvements.

      Please keep up posted on your continued findings, and I will do the same.

      AJ

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  12. Actually I just checked out the verapamil tablets, and yes, they are yellow-orange in color. How do I go about getting some without the coloring?
    Nancy

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    1. Nancy, you need to ask a pharmacist. They must be used to this problem.

      In a comment from Agnieszka higher up the page you will see that her son will mast cell issues was allergic to quinoline yellow (D&C Yellow No. 10 or E104 in Europe), which is histamine releasing additive. This was used to color the bumetanide tablet.

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    2. Nancy, ask your son's doctor to send the rx to a compounding pharmacist. It is a bit more expensive but if your son has mast cell issues, it's best to err on side of caution if planning to use a medicine long term to have it compounded. What I have noticed with my son with mast cell activation, triggers can change. They can suddenly start reacting to things like colorings that they didn't react to before. With mast cell, figuring out the triggers is half the battle. Best of luck to you

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  13. I just read a pretty epic paper on Gulf War Illness which if you replace the words "Gulf War Illness" with autism, it would probably get published.

    Press Release:

    https://www.sciencedaily.com/releases/2017/06/170620114040.htm

    Paper:

    http://journal.frontiersin.org/article/10.3389/fnmol.2017.00182/full

    Pretty much the entire paper covers topics Peter has been blogging about in depth (how oxidative stress can lead to cognitive and emotive impairment) but the big takeaways for me with respect to autism are:

    (1) They show how a double hit from a compound used to give protection against nerve gas agents in battle which upregulates acetylcholine production while another compound found in pesticides that blocks and enzyme that degrades acetycholine (leading to increasing levels) can cause neuronal hyperactivity from excess acetylcholine signaling, leading to long-term upregulation of inflammatory genes that promote inflammation and don't downregulate once acetylcholine levels return to normal, thereby causing long-term oxidative stress and mitochondrial dysfunction in the brain reminiscent of many other neurodegenerative disorders such as Alzheimer's. What is important here is they show that long-term cognitive, memory, and emotive problems can be the result of a short-term environmental insult that causes neuronal hyperactivity. With respect to autism, this suggests there could be many roads to this end which could be genetic or environmental or both.

    (2) They show that negative symptoms track with the level of nrf2 activation. Oddly enough the press release suggested the lab was also looking into resveratrol as a potential solution, even though resveratrol is an nrf2 activator. My reading on this is that nrf2 is being activated in GWI and I would think more nrf2 signaling would not do any good or even make things worse due to an excess oxidative stress response which may deplete cofactors in endogenous antioxidants (B vitamins, etc.). It also might explain why my son has at least a temporary bad reaction to Pomgenex which has two substances that are potent nrf2 activators (Broccoli Sprout Powder and Pomegranate juice). I have been doing this daily the last couple weeks in the hopes of some long-term improvement (even though acute irritability is usually the result), so it is too early to tell, but perhaps this might be a situation where the problem is not a lazy oxidative stress response by the body, but rather the endogenous methods of dealing with oxidative stress are being overwhelmed which may be why NAC has seemed to be especially helpful with SIB over the years (I have done it off and on because PharmaNAC is the only success I have had in getting it down and it is very expensive to do even once a day).

    (3) They show specific hippocampal impairments in neurogenesis and stem cell proliferation due to excess cytokines and oxidative stress. In other studies, this leads to hippocampal atrophy over time and impairments in learning and memory. Older people with Alzheimers disease may not have intellectual disability symptoms until later in the disease because they already have plenty of crystallized intelligence gained throughout their life, while a child with autism may lack the fluid intelligence due partially to hippocampal dysfunction to learn and retain information efficiently, especially information that requires sequential memory (i.e. mixing up the order of things such as the case in speech where saying "John loves Jane" is obviously different than "Jane loves John" but if you don't have the sequential memory for reordering those words, you think both phrases are the same.

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  14. We need to get the major sources of electromagnetic radiation and electromagnetic field pollution out of the environment. Oxidative stress and inflammation is huge and this is the reason that my son is getting occassional seizures and many symptoms. Adding 5G is going to make things worse. There are 23 cell towers within a 2 mile radius of where I live and one within .6 miles. All of the cicadas I once herd are gone in the neighborhood, no more crickets. The avian insect species are virtually gone in the backyard in the last 3 years. I have fruit bearing plants that typically bees, beetles, wasps, and flies love. The new plants I plant are struggling to grow in the entire east facing portion of the house where there is a lot of sun. This used to be a great growing area. The density of insects and birds is gone. The large number of dragon flies I used to see are gone. The wings on the ones I find are not growing fast enough and they cannot take off. Minnesota is home to a large variety of insects but EMF/EMR is hurting there growth. This is trickling over to other life forms and I am seeing more complex chronic conditions in my line of work. We need to work on getting awareness of the devastation of this dirty technology. I watched a bird as it tried to fly from one tree to the next, it looked as if it had been zapped by something I couldn't see. The bird flew and then started spinning down to its death. My son has sores on his legs that are difficult to heal. Normally there are a lot of mosquitos that would explain this; however, the mosquitos are not around in there usual epic numbers. We try to stay in the sunlight anyway so the majority of the species will leave us alone. Our area wants to build a better electronic grid....................My forecast for the area: More health problems.

    I think about atomic health and how to heal at the atomic level with energy and photons but then I think to myself if the environmental problem is never solved than we can throw all of this healing at something and the damage is only going to continue. I suppose I need to find a cave, and try to find a more primitive dwelling.............Our world does not have the intellectual capacity to understand as its driving force is a slave to the dollar. Our country in the United States allows many things before they are really ever studied and I am deeply concerned for our children. I am deeply concerned for our planet.

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    1. Yes, it's tragic. Market driven forces have unleashed environmental violence of the worst kind. And the innocent pay for it...beast and the children. Fifteen years back, we used to drink water straight from the tap. Now every household has a water purifier or is purchasing bottled water...this is Delhi, Indian capital. Somebody is surely making profit here. As India becomes one of the fastest growing economies, I mourn the loss of water, land and air...we have disfigured and destroyed and poisoned our home. My son has not seen a sparrow ever, they are gone even as men celebrate their latest handset purchases, guzzling toxic air. 3G, 4G, 5G....rivers and forests, accept my apology.

      God, what have they done to the rain!

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  15. There are many syndromes and there is something called syndromic surveillance being collected. Industry is funding this. We will eventually see the connections that these syndromes can be connected to that with which we live. We cannot passively ignore and treat all of our symptoms as our body and nature is consistently trying to adapt. The inflammatory response is not going to go away and it serves an innate purpose to protect us. We have to eliminate sources of inflammation from our environment.

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  16. I wonder more about metformin. The effects it has on iron metabolism, and I would like to know more about its role in gut phyla metabolic pathways in terms of metalloproteins? I have noticed that in some individuals it seems so very helpful and in others they are on the toilet most of the day and cannot tolerate it at any dose. It is of great interest in terms of the microbiome effects it has. I wonder if it might even help with the increase in enzymes if the balance shifts in the microbiome???

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