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Showing posts with label Allergies. Show all posts
Showing posts with label Allergies. Show all posts

Tuesday 16 January 2018

How much Histidine? Dermatitis and FLG mutations


Today’s post is not about autism, it is about allergy and atopic dermatitis in particular.
Many people are affected by atopic dermatitis (AD), also known as eczema; it is particularly common in those with autism. Children who develop asthma have often first developed atopic dermatitis (AD).
Atopic Dermatitis is another of those auto-immune conditions and the sooner you stabilize such conditions the better the prognosis.




Skin therapies from a company
spun-off from Manchester University


Histidine
A while back on this blog I was looking at the various amino acids and came across the observation that histidine, a precursor of histamine, appears to be a mast cell stabilizer. Mast cells are the ones that release histamine and IL-6 into your blood. Histamine then does on the trigger yet more IL-6 to be produced.  IL-6 is a particularly troublesome pro-inflammatory cytokine.
At first sight giving a precursor of histamine to people who want less histamine seems a crazy thing to do, but plenty of people report their allergies improving after taking histidine. As we have discovered, feedback loops are very important in human biology and these can be used sometimes to trick the body into doing what you want it to do. Having a higher level of histidine in your blood might make histamine production easier but it might also be telling the body not to bother, or just to delay mast cells from degranulating.  Whatever the mechanism, it does seem to work for many people. 

How Much Histidine?
Most histidine pills are 0.5g and it appears people use about 1g to minimize their allergy. 1g is the dose Monty, aged 14 with ASD, has been using during the pollen allergy season.
My sister recently highlighted a new "high tech" OTC product for skin conditions, Curapella/Pellamex, its main ingredient is histidine and it is a lot of histidine, 4g.




The company that produces the supplement have teamed up with the Universities of Edinburgh and Manchester to make a clinical trial, which is featured below.
They are considering the interaction between histidine and filaggrine (produced by the FLG gene). 

Mutations in the FLG gene are associated with atopic dermatitis and indeed with asthma, hay fever, food allergies, and, rather bizarrely, skin sensitivity to nickel.
In effect it is suggested that histidine makes filaggrine work better and thus atopic dermatitis and some other skin conditions will improve.  



Atopic dermatitis (AD), also known as eczema, is one of the most common chronic skin conditions worldwide, affecting up to 16% of children and 10% of adults. It is incurable and has significant psychosocial and economic impacts on the affected individuals. AD etiology has been linked to deficiencies in the skin barrier protein, filaggrin. In mammalian skin, l-histidine is rapidly incorporated into filaggrin. Subsequent filaggrin proteolysis releases l-histidine as an important natural moisturizing factor (NMF). In vitro studies were conducted to investigate the influence of l-histidine on filaggrin processing and barrier function in human skin-equivalent models. Our further aim was to examine the effects of daily oral l-histidine supplementation on disease severity in adult AD patients. We conducted a randomized, double-blind, placebo-controlled, crossover, nutritional supplementation pilot study to explore the effects of oral l-histidine in adult AD patients (n=24). In vitro studies demonstrated that l-histidine significantly increased both filaggrin formation and skin barrier function (P<0 .01="" respectively="" span="" style="background: yellow; margin: 0px;">Data from the clinical study indicated that once daily oral l-histidine significantly reduced (P<0 .003="" 34="" 39="" 4="" ad="" after="" and="" assessment="" by="" disease="" eczema="" measure="" of="" oriented="" patient="" physician="" scoringad="" self-assessment="" severity="" span="" the="" tool="" treatment="" using="" weeks="">. No improvement was noted with the placebo (P>0.32). The clinical effect of oral l-histidine in AD was similar to that of mid-potency topical corticosteroids and combined with its safety profile suggests that it may be a safe, nonsteroidal approach suitable for long-term use in skin conditions that are associated with filaggrin deficits such as AD. 
In this paper, we suggest that a simpler, nutritional supplementation of l-histidine may have a beneficial potential in AD.

l-histidine is a proteinogenic amino acid that is not synthesized by mammals. In human infants, it is considered “essential” due to low levels of histidine-synthesizing gut microflora and minimal carnosinase activity, which helps in releasing free l-histidine from carnosine.24 Our interest in the use of l-histidine in AD was stimulated by several observations. Firstly, in both infants and adults, a histidine-deficient diet results in an eczematous rash.25 In rodents, 3H-histidine is rapidly (1–2 hours) incorporated into profilaggrin within keratohyalin granules after intraperitoneal or intradermal injection14,26 and within 1–7 days is released as a free NMF amino acid in the upper stratum corneum.14 Furthermore, reduced stratum corneum levels of free NMF amino acids, including histidine and its acidifying metabolite urocanic acid (UCA), are associated with AD disease severity and FLG genotype.27,28

Given this evidence for the dependence of filaggrin processing and NMF formation on suitable levels of l-histidine, we hypothesized that l-histidine would both enhance filaggrin processing in an in vitro, organotypic, human skin model and have beneficial effects as a nutritional supplement in subjects with atopic dermatitis. 

After a 2-week wash-out period in which subjects were asked not to use any medicinal product for their AD, the same measures were repeated and patients were provided with identical sachets containing either 4 g l-histidine (Group A) or 4 g placebo (erythritol); Group B) which was taken once a day, dissolved in a morning fruit drink.  





Conclusion

It looks like 4g of histidine has the same potency as mild topical steroid creams, when treating atopic dermatitis.
The big problem with topical steroids is that you can only use them for a week or two. It you use them for longer, you end up with a bigger problem than the one you were trying to treat.
The 4g a day of histidine is put forward as a safe long term therapy.
Is the mode of action related to mast cells or filaggrin (FLG)? Or perhaps both?
If 1g of histidine does improve your allergies, perhaps you should feel free to try a little more.
You can buy histidine as a bulk powder. Pellamex is quite expensive, particularly if more than one family member is affected, as you would expect to find in a genetic condition.  




Wednesday 4 January 2017

Histidine for Allergy, but as an effective MTOR inhibitor?



Today’s post is likely to be of interest to those dealing with allergy and mast cell activation, but it may have broader implications for those with excess brain mTOR activity.
In the jargon, we are told that:
enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder”.
I have discussed mTOR and mTOR inhibitors previously on this blog.



Amino acids, not just for body builders?


mTOR plays a key role in aging and many human diseases ranging from cancer, diabetes and obesity to autism and Alzheimer’s.

The greatest interest in mTOR seems to be in cancer care.  Many cancer genes and pathways are also involved in autism, so we can benefit from the cancer research.  Another autism gene that is also a cancer gene is PTEN.  PTEN is a tumor suppressor and in the most common male cancer, prostate cancer (PCa), what happens is that PTEN gets turned off and so the cancer continues to grow.  If you upregulate PTEN you slow the cancer growth and if you upregulated this gene in those people at risk of Pca perhaps they would never develop this cancer in the first place?  PTEN is upregulated by statin-type drugs and people already on this type of drug have better PCa prognoses.   The beneficial of effect of statins on PCa is known, but the mechanism being PTEN upregulation does not seem to have been noticed. No surprise there.

Inhibiting mTOR using cancer drugs is very expensive.

Other substances affecting mTOR include amino acids, growth factors, insulin, and oxidative stress.

The amino acid Leucine is an mTOR activator, we don’t need that.  We actually want the opposite effect and, at least in mice, we can get it from some of the other amino acids. 


          Highlights 

·        Amino acids, his, lys and thr, inhibited mTOR pathway in antigen-activated mast cells



·        Amino acids, his, lys and thr inhibited degranulation and cytokine production of mast cells



·        Amino acid diet reversed mTOR activity in the brain and behavioral deficits in allergic and BTBR mice.



Neuroprotective and anti-inflammatory diet reduced behavioral deficits only in allergic mice.

              Abstract

Enhanced mammalian target of rapamycin (mTOR) signaling in the brain has been implicated in the pathogenesis of autism spectrum disorder (ASD). Inhibition of the mTOR pathway improves behavior and neuropathology in mouse models of ASD containing mTOR-associated single gene mutations. The current study demonstrated that the amino acids histidine, lysine, threonine inhibited mTOR signaling and IgE-mediated mast cell activation, while the amino acids leucine, isoleucine, valine had no effect on mTOR signaling in BMMCs. Based on these results, we designed an mTOR-targeting amino acid diet (Active 1 diet) and assessed the effects of dietary interventions with the amino acid diet or a multi-nutrient supplementation diet (Active 2 diet) on autistic-like behavior and mTOR signaling in food allergic mice and in inbred BTBR T + Itpr3tf/J mice. Cow’s milk allergic (CMA) or BTBR male mice were fed a Control, Active 1, or Active 2 diet for 7 consecutive weeks. CMA mice showed reduced social interaction and increased self-grooming behavior. Both diets reversed behavioral impairments and inhibited the mTOR activity in the prefrontal cortex and amygdala of CMA mice. In BTBR mice, only Active 1 diet reduced repetitive self-grooming behavior and attenuated the mTOR activity in the prefrontal and somatosensory cortices. The current results suggest that activated mTOR signaling pathway in the brain may be a convergent pathway in the pathogenesis of ASD bridging genetic background and environmental triggers (food allergy) and that mTOR over-activation could serve as a potential therapeutic target for the treatment of ASD.

  

So in mice a combination of the three amino acids Histidine, Lysine and Threonine reduced brain mTOR activity and improved autism.

I did look at all three of these amino acids and their other effects and I choose Histidine. 
Histidine can be produced in adult humans in very small amounts, but in young children they need to obtain some from other sources, usually dietary.

Histidine is the precursor of histamine.  Histamine has both good and bad effects.

Histidine decarboxylase (HDC) is the enzyme that catalyzes the reaction that produces histamine from histidine with the help of vitamin B6 as follows:



You can treat allergy by inhibiting HDC.

Tritoqualine, is an inhibitor of the enzyme histidine decarboxylase and therefore an atypical antihistamine,

You might think that having extra histidine would result in extra histamine, but this appears not to be the case.  There is a paradoxical reaction where increasing histadine actually seems to reduce the release of histamine from the mast cells that store it.  This may indeed be a case of feedback loops working in our favour.

So it seems that histidine may give two different benefits, it reduces IgE-mediated mast cell activation and it reduces mTOR signalling in the brain.

If the effect on mTOR is sufficient we would then benefit from an increase in autophagy, the cellular garbage disposal service that does not work well in autism.  We might eventually see a benefit from increased synaptic pruning which might be seen in improved cognition.  



Recap on mTOR and Synaptic Pruning

This has been covered in earlier posts.

In autism loss of mTOR-dependent macro-autophagy causes synaptic pruning deficits; this results in too many dendritic spines.









A dendritic spine (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body. The dendrites of a single neuron can contain hundreds to thousands of spines. In addition to spines providing an anatomical substrate for memory storage and synaptic transmission, they may also serve to increase the number of possible contacts between neurons.

A feature of autism is usually too many, but can be too few, dendritic spines.  In an earlier post we saw how the shape of individual spines affects their function.  The shape is constantly changing and can be influenced by external therapy. Wnt signaling affects dendritic spine morphology and so using this pathway you could fine-tune dendritic spine shape.  We did look at PAK1 inhibitors in connection with this.

Synaptic pruning is an ongoing process well into adolescence.

So it may be possible to improve synapse density and structure well after the onset of autism.

It should be noted that using Rapalogs, the usual mTOR inhibiting drugs, would have a negative effect in the minority of autism that feature hypo-active growth signalling.  That would be people born with small heads and small bodies.  So a child affected by the zika virus, might very likely exhibit autism and ID, but likely has too few dendritic spines and would then need more mTOR, rather than less.

Rapalog drugs like Everolimus are very expensive, but as in this recent paper do show effect in some autism. 



The mTOR pathway is a central regulator of mammalian metabolism and physiology, with important roles in the function of tissues including liver, muscle, white and brown adipose tissue, and the brain, and is dysregulated in human diseases, such as diabetes, obesity, depression, and certain cancers.

mTOR Complex 1 (mTORC1) is composed of MTOR, regulatory-associated protein of MTOR (Raptor), mammalian lethal with SEC13 protein 8 (MLST8) and the non-core components PRAS40 and DEPTOR. This complex functions as a nutrient/energy/redox sensor and controls protein synthesis. The activity of mTORC1 is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives (e.g., L-leucine and β-hydroxy β-methylbutyric acid), mechanical stimuli, and oxidative stress

Rapamycin inhibits mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-span extension in animal studies). Rapamycin has a more complex effect on mTORC2.



How do amino acids affect mTOR?

This is not fully understood by anyone, but here is a relevant paper, for those interested.




Mammalian target of rapamycin (mTOR) controls cell growth and metabolism in response to nutrients, energy, and growth factors. Recent findings have placed the lysosome at the core of mTOR complex 1 (mTORC1) regulation by amino acids. Two parallel pathways, Rag GTPase-Ragulator and Vps34-phospholipase D1 (PLD1), regulate mTOR activation on the lysosome. This review describes the recent advances in understanding amino acid-induced mTOR signaling with a particular focus on the role of mTOR in insulin resistance.

We then discuss how mTORC1 activation by amino acids controls insulin signaling, a key aspect of body metabolism, and how deregulation of mTOR signaling can promote metabolic disease. 

Concluding remarks


Recent findings of new mediators and their regulatory mechanisms have broadened our understanding of amino acid-induced mTOR signaling. In addition to the role of the TSC1-TSC2-Rheb hub in transducing upstream signals from growth factors, stressors and energy to mTOR, the lysosomal regulation of mTOR functions as a platform to connect nutrient signals to the Rheb axis. Furthermore, two parallel pathways of amino acid signaling explain the diverse regulation of mTOR signaling. It is yet to be determined which regulators sense amino acids directly and whether the two pathways require separate amino acid sensing mechanisms. The identification of a direct amino acid sensor will shed light on these uncertainties.

A more integrated understanding of mTOR regulation in amino acid signaling will open the door for new therapeutic approaches for metabolic diseases, especially type 2 diabetes. Already, metformin, an antidiabetic drug, inhibits mTOR in an AMP-activated kinase (AMPK)-independent and Rag-dependent manner,64 providing further support for the idea that the regulation of amino acid sensing could be a therapeutic target for diabetes.



How typical is the level of amino acids in autism?



As regards essential amino acid levels, autistic children had significant lower plasma levels of leucine, isoleucine, phenylalanine, methionine and cystine than controls (P < 0.05),while there was no statistical difference in the level of tryptophan, valine, threonine, arginine, lysine and histidine (P > 0.05). In non-essential amino acid levels, phosphoserine was significantly raised in autistic children than in controls (P < 0.05). Autistic children had lower level of hydroxyproline, serine and tyrosine than controls (P < 0.05). On the other hand there was no significant difference in levels of taurin, asparagine, alanine, citrulline, GABA, glycine, glutamic acid, and ornithine (P > 0.05).

There was no significant difference between cases and controls as regards the levels of urea, ammonia, total proteins, albumin and globulins (alpha 1, alpha 2, beta and gamma) (P > 0.05).



  

Conclusion 

For the more common hyperactive pro growth signaling pathway types of autism, histidine should be a good amino acid, whereas for the hypoactive type, that might feature microcephaly, leucine should be a good choice.

Histidine is already used by some people to treat allergy.

Histidine does have numerous other functions and one relates to zinc, so it is suggested that people who supplement histidine add a little zinc. For this reason German histidine supplements thoughtfully all seem to include zinc.

Histidine also has some direct antioxidant effects and has an effect on Superoxide dismutase (SOD).

It is not clear how much histidine would be needed in humans to achieve the mTOR inhibiting effect found in mice.

The RDA for younger teenagers is histidine  850 mg and leucine 2450 mg.  What the therapeutic dose to affect mTOR in humans remains to be seen.

Histidine is also claimed to help ulcers, which is plausible.

For allergy some people are taking 1,500mg of histidine a day.






Tuesday 26 July 2016

Autism, Allergies and Summertime Raging in 2016


  
This time of year many parents in the northern hemisphere are looking up “autism and allergy” on Google and more than 20,000 have ended up at my post from 2013 on this subject.



Not just for Stomach Health


It is clear that many people have noticed that allergy makes autism worse, even if your family doctor might think you are imagining it.

This year, thanks to our reader Alli from Switzerland, there is a new innovation in my therapy for Monty, now aged 13 with ASD.  Now we are firm believers in a specific probiotic bacteria to dampen the immune system (more IL-10, less IL-6 and likely more regulatory T cells) and minimize the development of pollen allergy and all its consequences.

There is a wide range of H1 antihistamines, mast cell stabilizers and inhaled steroids available and many readers of this blog are using a combination of some or all of these to control allergy and mast cell activation.

By using the Bio Gaia probiotic bacteria the magnitude of the allergic response to allergens is substantially reduced, so whatever problems allergy worsens in your specific subtype of autism, these should become much milder.

In our case the allergy will trigger summertime raging and loss of cognitive function.

The use of the calcium channel blocker Verapamil very effectively halts/prevents the raging, but it does not reduce the other effects of the allergy or the loss of cognitive function.

The use of the Bio Gaia probiotic reduces the problem at source; it greatly reduces the allergy itself.  Less allergy equals less summertime raging and equals less loss of cognitive function.

So for anyone filling up on antihistamines, steroids and mast cell stabilizers it could be well worth reading up on the studies on probiotics and allergy, or just make a two day trial with Bio Gaia.

Prior to Bio Gaia, we used Allergodil (Azelastine mast cell stabilizer and antihistamine) nasal spray or the more potent Dymista (Azelastine plus Fluticasone) nasal spray, plus oral H1 antihistamine (Claritin or Xyzal) and sometimes quercetin.  Verapamil was introduced to halt the raging/SIB caused by the allergy, which it does within minutes or can be given preventatively.

Each year the pollen allergy got worse than the previous year, starting five years ago at almost imperceptible and ending up with blood red sides of his nose.  With Bio Gaia there is just a faint pinkness at the side of his nose.

There are additional positive effects of Bio Gaia beyond the allergy reduction, but they do seem to vary from person to person.  In our case there is an increase in hugging and singing.  The research on this bacteria does show it increases the hormone oxytocin in mice.



In some people without obvious allergy, Bio Gaia’s effect on the immune system can also be quite dramatic.  In some people the standard dose is effective, but in others a much higher dose is needed.  The good thing is that the effect is visible very quickly and does seem to be maintained.  The main post on Bio Gaia is here.  

Bio Gaia is based on serious science but is available over the counter.









Thursday 27 August 2015

Cinnamon (Cinnamaldehyde), Mast Cells (Allergy) & Autism










A reader of the previous post on cinnamon left a helpful comment highlighting research that suggests yet another reason why Cinnamon might be an effective treatment for some types of autism.






Abstract
BACKGROUND:
Mast cells (MC) are main effector cells of allergic and other inflammatory reactions; however, only a few anti-MC agents are available for therapy. It has been reported that cinnamon extract (CE) attenuates allergic symptoms by affecting immune cells; however, its influence on MC was not studied so far. Here, we analyzed the effects of CE on human and rodent MC in vitro and in vivo.
METHODS:
Expression of MC-specific proteases was examined in vivo in duodenum of mice following oral administration of CE. Release of mediators and phosphorylation of signaling molecules were analyzed in vitro in human MC isolated from intestinal tissue (hiMC) or RBL-2H3 cells challenged with CE prior to stimulation by FcεRI cross-linking.
RESULTS:
Following oral treatment with CE, expression of the mast cell proteases MCP6 and MC-CPA was significantly decreased in mice. In hiMC, CE also caused a reduced expression of tryptase. Moreover, in hiMC stimulated by IgE cross-linking, the release of β-hexosaminidase was reduced to about 20% by CE. The de novo synthesis of cysteinyl leukotrienes, TNFα, CXCL8, CCL2, CCL3, and CCL4, was almost completely inhibited by CE. The attenuation of mast cell mediators by CE seems to be related to particular signaling pathways, because we found that activation of the MAP kinases ERK, JNK, and p38 as well as of Akt was strongly reduced by CE.
CONCLUSION:
CE decreases expression of mast cell-specific mediators in vitro and in vivo and thus is a new plant-originated candidate for anti-allergic therapy


In a later study by the same authors they identify Cinnamaldehyde as the main mediator of cinnamon extract in mast cell inhibition.



A chemistry note:

Cinnamon contains three major compounds (cinnamaldehyde, cinnamyl acetate and cinnamyl alcohol), which are converted into cinnamic acid by oxidation and hydrolysis, respectively. In the liver, this cinnamic acid is β-oxidized to benzoate that exists as sodium salt (sodium benzoate; NaB) or benzoyl-CoA.

As is often the case with natural substances with medicinal properties, it is unclear which constituent provides the benefit, or whether there is a synergistic benefit between them.

As I suggested in an earlier post, even though Sodium benzoate (NaB) has been shown to be the reason for some of cinnamon’s benefits and is widely available, I propose to use cinnamon itself.

The mast cell benefits of cinnamon come from cinnamaldehyde and may not be produced by the metabolite NaB.
  



Purpose

In terms of their involvement in allergic and inflammatory conditions, mast cells (MC) can be promising targets for medical agents in therapy. Because of their good compliance and effectiveness, phytochemicals are of great interest as new therapeutic tools in form of nutraceuticals. We found recently that cinnamon extract (CE) inhibits mast cell activation. Here, we analysed the effects of a major compound of CE, cinnamaldehyde (CA), on mast cell activation. 

Conclusions

CA decreases release and expression of pro-inflammatory mast cell mediators. This inhibitory action is similar to the effects observed for CE indicating CA as the main active compound in CE leading to its anti-allergic properties.



Conclusion

Today’s post gives a particular reason for people with autism, allergies and mast cell issues to trial cinnamon.

The only thing to be careful of is histamine intolerance.  This does affect several readers of this blog.

The main cause of histamine intolerance is an impaired histamine degradation caused by genetic or acquired impairment of the enzymatic function of DAO or HNMT.

One reader pointed out that the cheap 23andme genetic test includes the genes for histamine intolerance (this service is no longer available in all countries).

The sodium benzoate (NaB) produced by cinnamon is a DAO inhibitor and so will further impair histamine degradation in people with genetic impairment.  

In most people, even if they have allergies, a teaspoon of cinnamon will not affect their ability to degrade histamine.











Tuesday 12 May 2015

Minimizing Summertime Autism Flare-ups in 2015




When I first connected histamine to autism, I did not realize that this might be a common problem.  The most frequently viewed post on this blog is one on histamine and autism; so at least 10,000 people out there have googled “autism and histamine”.

Two years later, the therapy is still evolving and it should be said that, what works best for one person may not help in another person.  The main point is that in some people with autism, they face a summertime regression due to the effect of allergy.  So bad behaviours and aggression increase and good behaviours and indeed cognitive function decrease.  This appears to be the result of histamine and a pro-inflammatory cytokine called IL-6.

For the 2015 pollen season, which started early where we live, this is what we are using:-


Azelastine nasal spray, this is an H1 antihistamine that is also inhibits mast cells from “degranulating” and emptying their load of pro-inflammatory substances.  Once a day.

Quercetin is a cheap flavonoid that has numerous actions including on histamine H1 receptors, mast cells, and inflammation. 125mg two or three times a day.

Verapamil is an L-type calcium channel blocker and also a mast cell stabilizer. 40mg three times a day

Fluticasone propionate 50 µg (micrograms) – see below.  It is a steroid that has recently been shown to have some unexpected effects on mast cells.  


I have found that oral antihistamines were effective for only a couple of hours, but their effect varies widely from person to person.

In theory, Rupatadine should be the most effective anti-histamine, since it is also a potent mast cell stabilizer.  The old first generation antihistamines (that make you drowsy) could in theory be better than the new ones like Claritin, Zyrtec, since they can also cross the blood brain barrier (BBB).

Ketotifen and cromolyn sodium should also be useful, but if the allergy is pollen related, you really need the nasal spray (nasalcrom etc) to get the most effect.  In some countries they sell eye drops and not the nasal spray.  Usually the eye drops are more diluted than the nasal spray.  For example, the Azelastine eye drops contain 50% less Azelastine than the nasal spray, but are otherwise the same.  Where we live they have run out of the nasal spray but not the eye drops, so you could refill the spray with eye drops and double the number of sprays to get the same dose.

Drugs like Claritin and Zyrtec are H1 antihistamines and also partial mast cell stabilizers; they have a positive behavioral effect in some people with ASD, who are apparently allergy free.



New for 2015

I expect that two recent anti-inflammatory therapies, the Tangeretin flavonoid and the Miyairi 588 bacteria/probiotic may have a beneficial, indirect, effect on our usual summertime regression.

A more convention approach is to add fluticasone propionate to reduce the inflammation caused by allergy.  This drug is a steroid and widely used either as an inhaler to control asthma and COPD, or as a nasal spray to treat allergies.

As Flixotide inhaler, Monty, aged 11 with ASD and asthma, has already been taking fluticasone propionate for a few years.  We now use a tiny dose (50 µg), since his autism therapies have greatly reduced any asthma tendencies.

Fluticasone propionate nasal spray (Flixonase, Flonase etc) is widely sold as a treatment for hay fever and rhinitis and was recently combined with Azelastine (see above) as a treatment for moderate to severe allergies in a product call Dymista.

The combination of H1 antihistamine, mast cell stabilizer and anti-inflammatory all in one spray does seem a good idea.  The steroid dose using Dymista is actually lower than the usual dose of steroid when using Fluticasone propionate nasal spray alone.  You want to minimize the amount of steroid absorbed in the blood. When used as a spray/inhaler the amount is tiny, but still should be considered.

Dymista (Azelastine + Fluticasone propionate) does indeed work better than Azelastine alone.  There is no sign of allergy at all (no red eyes, sneezing, itchy nose), with Azelastine you still have an itchy nose.

In our case, the allergy symptoms, even minors ones, do correlate with the change in behaviour and cognitive function; so the target is no allergy symptoms at all.


If anyone has other therapies for summertime flare ups, feel free to share them.






Monday 1 December 2014

Sodium benzoate (Cinnamon) trialed for Schizophrenia (Adult-onset Autism)


Regular readers will have noticed that behavioral diagnosese like autism, ADHD, schizophrenia or even intermittent explosive disorder (IED) do not impress me.  I think that patients deserve a biological diagnosis from a neurologist.

To me, Schizophrenia might as well be called adult-onset autism and ADHD be called autism-lite.

We have already seen an overlap in the genetics/channelopathies of these three conditions.

Schizophrenia affects adults that developed “normally” as children and so they do not have the physical brain damage that has been shown to occur in many cases of autism.  According to Courchesne, the physical abnormalities he finds in autistic brains have occurred before most children even get diagnosed (before 3-5 years of age).  The young brain does remain plastic and this appears to explain why some children make excellent progress.  The various dysfunctions in utero and thereafter have caused some structural abnormalities in the brain.  In schizophrenia, the dysfunctions occur well after the brain has matured; so the result is different.  There are nonetheless very many similarities both in the underlying genetics and also in the observed behaviors.

So I term Schizophrenia, adult-onset autism.  (Many years ago, autism was called child onset Schizophrenia).  Any therapies that show promise in adults with schizophrenia should be trialed in children and adults with autism.

Just as there are many different dysfunctions that can lead to autism, there will be many that lead to schizophrenia.  I believe that there will be a wide overlap between those two groups of dysfunctions.


Back to Sodium Benzoate, Cinnamon and Schizophrenia

In my last post I started to look at Parkinson’s and COPD (severe asthma) and I suggested that the same anti-oxidant gene DJ-1 might also be relevant to autism.

I proposed that sodium benzoate, taken in the form of cinnamon, might be a useful therapy.

Having received a comment that some people with autism do not find sodium benzoate agreeable (it is found in carbonated drinks and is a common food additive), I did some more checking.

Firstly, if you are histamine intolerant, you should avoid cocoa, sodium benzoate and cinnamon.

For anyone unaffected, I found that a trial has already been carried out using Sodium Benzoate in Schizophrenia, with very promising results.



DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer.

INTERVENTIONS Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo.

MAIN OUTCOMES AND MEASURES The primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment.

RESULTS Benzoate produced a 21% improvement in PANSS total score and large effect sizes (range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms–20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health’s Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects.

CONCLUSIONS AND RELEVANCE Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia.


As to be expected, the proposed method of action is nothing to do with DJ-1 and oxidative stress.  They believe it is all about enhancing NMDAR-mediated neurotransmission.

Quite frankly, I do not mind why they think it works, or who is right.

For me what matters is that in adult-onset autism 1 g/day of sodium benzoate produced a 21% improvement in PANSS total score and in other rating scales. 







If you are wondering what is a PANSS score, according to Wikipedia:-




To assess a patient using PANSS, an approximately 45-minute clinical interview is conducted. The patient is rated from 1 to 7 on 30 different symptoms based on the interview as well as reports of family members or primary care hospital workers.


Positive scale

7 Items, (minimum score = 7, maximum score = 49)

·         Delusions
·         Conceptual disorganization
·         Hallucinations
·         Hyperactivity
·         Grandiosity
·         Suspiciousness/persecution
·         Hostility


Negative scale

7 Items, (minimum score = 7, maximum score = 49)

·         Blunted affect
·         Emotional withdrawal
·         Poor rapport
·         Passive/apathetic social withdrawal
·         Difficulty in abstract thinking
·         Lack of spontaneity and flow of conversation
·         Stereotyped thinking


General Psychopathology scale

16 Items, (minimum score = 16, maximum score = 112)

·         Somatic concern
·         Anxiety
·         Guilt feelings
·         Tension
·         Mannerisms and posturing
·         Depression
·         Motor retardation
·         Uncooperativeness
·         Unusual thought content
·         Disorientation
·         Poor attention
·         Lack of judgment and insight
·         Disturbance of volition
·         Poor impulse control
·         Preoccupation
·         Active social avoidance

PANSS Total score minimum = 30, maximum = 210



Note regarding Histamine

Some people have a deficiency of diamine oxidase, this means that their body cannot break down histamine in their food, or produced by their food.  They are histamine intolerant.



There are also mast cell disorders:- Mast Cell Activation Syndrome (MCAS) and Mastocytosis that can affect some people with autism.

This area is not well understood and is subjective to diagnose and therefore treat.  Much will depend on which country you happen to live in.

Some people may have pollen allergies, but be histamine tolerant when it comes to food.  This just means that they produce enough diamine oxidase.

Some people have debilitating problems associated with mast cell disorders combined with histamine intolerance.


Histamine Intolerance

Many people with autism have allergies.  Some people have food intolerance.
In an allergic response, an allergen stimulates the release of antibodies, which attach themselves to mast cells. When histamine is released from the mast cells it may cause one or more of the following symptoms

· Eyes to itch, burn, or become watery
· Nose to itch, sneeze, and produce more mucus
· Skin to itch, develop rashes
· Sinuses to become congested and cause headaches
· Lungs to wheeze or have spasms
· Stomach to experience cramps and diarrhea

The release of histamine can be caused by almost any allergen. Examples include inhalant allergens (ragweed pollen, dust mite, etc.), drugs (penicillin, aspirin), stinging insect venoms, and foods (egg, wheat, milk, fish, etc.).


Histamine in Foods
There are many foods that contain histamine or cause the body to release histamine when eaten. These types of reactions are food intolerances, and are different from food allergy, in that the immune system is not involved in the reaction. The symptoms, however, can be the same as a food allergy.
An enzyme called diamine oxidase should break down any histamine that is absorbed from a histamine-containing food. So when you eat a food which contains histamine it should not affect you. However, some people have a low level of this enzyme. When they eat too many histamine-rich foods they may suffer ‘allergy-like’ symptoms such as headaches, rashes, itching, diarrhea, and vomiting or abdominal pain. This is called histamine intolerance.
Fermented foods may cause allergy symptoms because they are either rich in histamine or because yeast or mold is involved in the fermentation process.
Histamine-Rich Foods (including fermented foods):
· Alcoholic beverages, especially beer and wine.
· Anchovies, Mackerel
· Cheeses, especially aged or fermented cheese, such as parmesan
· Dried fruits such as apricots, dates, prunes, figs and raisins
· Fermented foods, such as pickled or smoked meats, sauerkraut
· Mushrooms, spinach, tomatoes, avocados
· Processed meats - sausage, hot dogs, salami, etc.
· Sardines, Smoked fish - herring, sardines, etc.
· Sour cream, sour milk, buttermilk, yogurt
· Soured breads, such as pumpernickel, coffee cakes and other foods made with large amounts of yeast.
· Vinegar or vinegar-containing foods, such as mayonnaise, salad dressing, ketchup, chili sauce, pickles, pickled beets, relishes, olives.

Histamine-Releasing Foods:
· Alcohol
· Bananas
· Chocolate
· Eggs
· Fish/Shellfish
· Milk
· Papayas
· Pineapple
· Strawberries
· Tomatoes