Palmitoylethanolamide (PEA) vs flavonoids Luteolin, Quercetin and Rutin in Autism, Allergies and Arthritis

You might be wondering the relevance of arthritis to an autism blog. Rheumatoid arthritis is an inflammatory condition in which the body's own immune system starts to attack body tissues.  It is often co-morbid with inflammatory bowel disease (including Crohn's disease and ulcerative colitis).  IBD is comorbid with autism.  The study below shows how many autoimmune diseases, including arthritis are connected with autism. 

Association of Family History of Autoimmune Diseases and Autism Spectrum Disorders

RESULTS: A total of 3325 children were diagnosed with ASDs, of which 1089 had an infantile autism diagnosis. Increased risk of ASDs was observed for children with a maternal history of rheumatoid arthritis and celiac disease. Also, increased risk of infantile autism was observed for children with a family history of type 1 diabetes.

CONCLUSIONS: Associations regarding family history of type 1 diabetes and infantile autism and maternal history of rheumatoid arthritis and ASDs were confirmed from previous studies. A significant association between maternal history of celiac disease and ASDs was observed for the first time. The observed associations between familial autoimmunity and ASDs/infantile autism are probably attributable to a combination of a common genetic background and a possible prenatal antibody exposure or alteration in fetal environment during pregnancy.

Note that in an earlier post on the vagus nerve, we saw how an implanted vagus nerve stimulator could reduce the inflammation in arthritis.  This is being developed as an alternative to the extremely expensive new drugs for arthritis that target IL-6 and TNF.

In earlier posts on Mast Cells we heard all about Dr Theoharides from Tufts University who is big on using naturally occurring flavonoids to stabilize mast cells and so treat all kinds of allergic reactions as in mastocytosis and in some types of autism.  See below for a reminder of the roll mast cells play in allergies:-

 

Source: Wikipedia

 

Luteolin is Theoharides’ favourite flavonoid because it is the most the most lipophilic and therefore more likely to enter the brain.  Mast cells are all over the body, including the brain.  In autism, he clearly is focused on the mast cells in the brain, but perhaps the mast cells elsewhere are equally problematic.  Indeed, perhaps the mast cells outside the brain are far more important, just because there are far more of them and the inflammatory mediators released by them will travel throughout the entire body.

 

The other two flavonoids know to effect mast cells and inflammation are Rutin and Quercetin. 

Arthritis Luteolin and Palmitoylethanolamide

I was quite surprised to find that research had been carried out on the anti-inflammatory effect of both Luteolin and Palmitoylethanolamide (PEA).  PEA is the substance I have been researching recently, it is not a flavonoid, but it is naturally occurring within the body and has some very interesting properties.

One of the inflammatory markers that is raised in autism is called IL-6.  The research was on arthritis in mice, but it did measure the effect of Luteolin and PEA on IL-6.  The result was interesting:-

 

PEA had the greater effect, but in combination with Luteolin the result improved further. 

Palmitoylethanolamide and luteolin ameliorate development of arthritis caused by injection of collagentype II in mice

This gives yet more reason to look into PEA for autism, but not to forget Luteolin.

The problem with Luteolin and Theoharides’ formulation called Neuroprotek is that it is really expensive in the suggested dosage.

 

What about Quercetin?

Quercetin is relatively cheap.

Unfortunately there is no direct comparison of Luteolin vs Quercetin in arthritis, but there is plenty of research showing that Quercetin is highly beneficial in arthritis. 

Therapeutic and preventive properties of quercetin in experimental arthritis correlate with decreased macrophage inflammatory mediators 

Abstract

Pentahydroxyflavone dihydrate, quercetin (QU) is one of common flavonols biosynthesized by plants and has been suggested to modulate inflammatory responses in various models. In the present study, we investigated in vivo effects of oral or intra-cutaneous QU in chronic rat adjuvant-induced arthritis (AA). Growth delay and arthritic scores were evaluated daily after AA induction in Lewis rats. Oral administration of QU (5 x 160 mg/kg) to arthritic rats resulted in a clear decrease of clinical signs compared to untreated controls. Intra-cutaneous injections of lower doses (5 x 60 mg/kg) of QU gave similar anti-arthritic effects, while 5 x 30 mg/kg concentrations were inefficient in this respect. Finally, injection of relatively low QU doses (5 x 30 mg/kg) prior to AA induction significantly reduced arthritis signs. As QU was suggested to inhibit macrophage-derived cytokines and nitric oxide (NO), we then analyzed macrophage response ex vivo. Anti-arthritic effects of QU correlated with significant decrease of inflammatory mediators produced by peritoneal macrophages, ex vivo and in vitro. These data indicate that QU is a potential anti-inflammatory therapeutic and preventive agent targeting the inflammatory response of macrophages. 

Here is a great paper summarizing the many and varied benefits of quercetin:-

QUERCETIN: A VERSATILE FLAVONOID

An interesting point with all flavonoids is their bioavailability.  This means what proportion that you eat is actually absorbed.

Quercetin is present in apples, but the largest amount is in the peel and is highest in red apples.   Quercetin is found is lesser amounts in red wine, but it appears the bioavailability is much higher because of the alcohol.  So grape juice would not help much. 


Applications of Quercetin

Asthma

Quercetin is an effective bronchodilator and helps reduce the release of histamine and other allergic or inflammatory chemicals in the body.

Quercetin has demonstrated significant anti-inflammatory activity because of direct inhibition of several initial processes of inflammation.

Cancer

Laboratory studies have investigated Quercetin's potential for use in anti-cancer applications. The American Cancer Society says while quercetin "has been promoted as being effective against a wide variety of diseases, including cancer," and "some early lab results appear promising, as of yet there is no reliable clinical evidence that quercetin can prevent or treat cancer in humans."

Eczema

Serum IgE levels are highly elevated in eczema patients, and virtually all eczema patients are positive for allergy testing. Excessive histamine release can be minimized by the use of antioxidants. Quercetin has been shown to be effective in reducing IgE levels in rodent models.

Inflammation

Several laboratory studies show quercetin may have anti-inflammatory properties, and it is being investigated for a wide range of potential health benefits.

Quercetin has been reported to be of use in alleviating symptoms of pollinosis. An enzymatically modified derivative was found to alleviate ocular but not nasal symptoms of pollinosis.

Studies done in test tubes have shown quercetin may prevent immune cells from releasing histamines which might influence symptoms of allergies.

A study with rats showed that quercetin effectively reduced immediate-release niacin (vitamin B₃) flush, in part by means of reducing prostaglandin D2 production. A pilot clinical study of four humans gave preliminary data supporting this.

Fibromyalgia

Quercetin may be effective in the treatment of fibromyalgia because of its potential anti-inflammatory or mast cell inhibitory properties shown in laboratory studies

Monoamine-oxidase inhibitor

Possibly an active component of heather, quercetin was suspected from a bioassay test on crude extracts to selectively inhibit monoamine oxidase, possibly indicating pharmacological properties.

Prostatitis

Quercetin has been found to provide significant symptomatic improvement in most men with chronic prostatitis, a condition also known as male chronic pelvic pain syndrome.

Luteolin

Luteolin is known to stabilize mast cells.  It has been studied in several preliminary in vitro scientific investigations. Proposed activities include antioxidant activity (i.e. scavenging of free radicals), promotion of carbohydrate metabolism, and immune system modulation. Other in vitro studies suggest luteolin has anti-inflammatory activity, and that it acts as a monoamine transporter activator, a phosphodiesterase inhibitor, and an interleukin 6 inhibitor. In vivo studies show luteolin affects xylazine/ketamine-induced anesthesia in mice. In vitro and in vivo experiments also suggest luteolin may inhibit the development of skin cancer.

In autism the ability to stabilize mast cells and inhibit IL-6 is very useful.

 

Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1

Luteolin, a flavonoid found in high concentrations in celery and green pepper, has been shown to reduce production of proinflammatory mediators in LPS-stimulated macrophages, fibroblasts, and intestinal epithelial cells. Because excessive production of proinflammatory cytokines by activated brain microglia can cause behavioral pathology and neurodegeneration, we sought to determine whether luteolin also regulates microglial cell production of a prototypic inflammatory cytokine, IL-6. Pretreatment of primary murine microlgia and BV-2 microglial cells with luteolin inhibited LPS-stimulated IL-6 production at both the mRNA and protein levels. To determine how luteolin inhibited IL-6 production in microglia, EMSAs were performed to establish the effects of luteolin on LPS-induced binding of transcription factors to the NF-κB and activator protein-1 (AP-1) sites on the IL-6 promoter. Whereas luteolin had no effect on the LPS-induced increase in NF-κB DNA binding activity, it markedly reduced AP-1 transcription factor binding activity. Consistent with this finding, luteolin did not inhibit LPS-induced degradation of IκB-α but inhibited JNK phosphorylation. To determine whether luteolin might have similar effects in vivo, mice were provided drinking water supplemented with luteolin for 21 days and then they were injected i.p. with LPS. Luteolin consumption reduced LPS-induced IL-6 in plasma 4 h after injection. Furthermore, luteolin decreased the induction of IL-6 mRNA by LPS in hippocampus but not in the cortex or cerebellum. Taken together, these data suggest luteolin inhibits LPS-induced IL-6 production in the brain by inhibiting the JNK signaling pathway and activation of AP-1 in microglia. Thus, luteolin may be useful for mitigating neuroinflammation.

Health effects of Rutin

While a body of evidence for the effects of rutin and quercetin is available in mice, rats, hamsters, and rabbits, as well as in vitro studies, no clinical studies directly demonstrate significant, positive effects of rutin as dietary supplement in humans.

• Rutin inhibits platelet aggregation, as well as decreases capillary permeability, making the blood thinner and improving circulation.^]
• Rutin shows anti-inflammatory activity in some animal and in vitro models^]
• Rutin inhibits aldose reductase activity.
• Recent studies show rutin could help prevent blood clots, so could be used to treat patients at risk of heart attacks and strokes.
• Some evidence also shows rutin can be used to treat hemorrhoids, varicosis, and microangiopathy.
• Rutin increases thyroid iodide uptake in rats without raising serum T3 or T4.
• Rutin is also an antioxidant, compared to quercetin, acacetin, morin, hispidulin, hesperidin, and naringin, it was found to be the strongest. However, in other trials, the effects of rutin were lower or negligible compared to those of quercetin.

 

Vox Populi (from Amazon.com reviews)

Rutin   

Few comments

-    “This works wonders for hemorrhoids”

 

Quercetin

Hundreds of positive comments for: Nasal allergy, eczema, sinusitis, prostatitis, joint pain etc.

“Lifesaver for allergies”

“This really helps and works like Sudafed” 

Luteolin / Neuroprotek (main ingredient is Luteolin)

Few comments mainly:  mastocytosis, allergies, eczema, autism

Works for some people with autism and not for others:

“My son with autism stopped his aggressive behaviour in a day”

“Works for my fibromyalgia”

 

Conclusion

I do have a couple of jars of Neuroprotek, which I was going to try on Monty, aged 10 with ASD, when the pollen season returns in the summer.  Using it all year round would not be cheap and might have little effect.  I find Quercetin very interesting and worthy of investigation; but PEA remains my current favourite.

It does come down to the question of which mast cells de-granulating cause the problem in autism.  In some people it could be the ones in their digestive tract and in others the ones in their eyes and nose.  The ones in the brain may or may not be relevant; these are the ones Theoharides seems to focus on.

PEA, Quercetin and Luteolin seem to have many benefits unrelated to mast cells.  Since they cannot be patented, there is no incentive for Big Pharma to invest in developing their potential.  So even if they did had some remarkable property, like in cancer therapy, we would likely never find out.

If I was a mouse with arthritis, I would add PEA and Quercetin (or Luteolin) to my weekly shop.  Anyone who is a big user of H1 antihistamines should find Quercetin helpful.

Is a Subtype of Autism an Allergy of the Brain?

 

 

I am actually in the middle of writing up my ideas about autism and the various human growth factors, but I just came across a paper worthy of its own post.  It is by one of those researchers already on my Dean's List, Dr Theoharis Theoharides from Tuft's University.

Is a Subtype of Autism an Allergy of the Brain?

You may recall that Theoharides works in the very small world of the mast cell.  These cells play a key role in allergies.  They contain histamine, serotonin and various other inflammatory agents.

The allergy causes the mast cells to "degranulate" and all the contents is released into the blood supply.  This then starts a chain reaction of events all over the body.

I was just reading about Nerve Growth Factor (NGF) which appears to behave strangely in autism.  It turns out that mast cells synthesise, store and release NGF.

NGF is very important for the brain, but it can also be highly neuro-inflammatory.  In autism NGF levels are elevated, just like Serotonin levels usually are.

What is the connection between NGF, Serotonin and Autism?  The degranulation of the mast cell.

Well, Theoharides knows everything about mast cell stabilizers.  These are agents that stop the mast cells emptying their contents into the blood stream.

But perhaps he has actually missed a connection.  In my forthcoming post on Human Growth Factors, we will find out about palmitoylethanolamide (PEA), a natural substance found in body that counters the inflammatory effect of NGF.  According to the Nobel Laureate who discovered TNF, PEA itself has mast cell stabilzing properties.

And one other strange thing, in people with autism and ADHD, they have low levels of PEA.

Put all the pieces together and then reconsider:-

        Is a subtype of autism an allergy of the brain?

I think the answer is of course yes; but more than that, I think it may well affect all subtypes of autism, just not all the time.

In some people they may have this "allergy" and nothing else.  In other people there are other issues like ion channel dysfunctions, but when their autism suddenly flares up, think over-activated immune system in Peter-speak or allergy of the brain in Theoharis-speak.

I think we are in effect speaking the same language.



 

 

Autism Flare-ups - News on Allergy Drugs

I wrote earlier posts about the role of histamine in summertime autism flare-ups.  I ended up using a combination of a regular antihistamine like Claritin with Ketotifen, which though also an antihistamine, is a partial mast cell stabilizer.
 

I recently found a very useful table which shows different regimens that can be used for just this problem:-

 

The table is from a paper, again by Dr Theoharides, called:
 Autism: an emerging ‘neuroimmune disorder’ in search of therapy

Rupatadine is a safe and cheap antihistamine mainly sold in Europe.  The science appears to show that it is more effective at stabilizing the mast cells involved in allergies than Ketotifen.

The problem I found with Ketotifen is that it has very little immediate effect, unlike Claritin, so I ended up using both.  By the looks of things, Rupatadine may indeed do the job of both.

The table also mentions Periactin, which is an old first generation antihistamine.  It has a secondary antiserotonergic properties.  It was trialed in Iran for autism, apparently with some success.

Cyproheptadine in the treatment of autistic disorder: a double-blindplacebo-controlled trial.

 

Conclusion

Not all antihistamines are the same and some have very interesting secondary effects.  It looks like science has given up on investigating this further, which is a pity; but you don't have to.

 

Autism flare ups and comorbidities

Anyone familiar with autism will know that it seems to go in waves of good and not so good.  Generally this gets accepted as just the way it has to be.

I chanced upon an unusual paper recently, it was all about comorbidities in autism.  As you may know, comorbidities are other diseases that seem to frequently occur alongside autism.  The main point of the paper and the charity behind it, is that comorbidities should be diagnosed and treated, rather than ignored, just because the person has ASD.

The paper was produced by Treating Autism, a UK charity that follows a biomedical approach similar to the American DAN organisation.  They have a link to a very comprehensive summary of what DAN actually recommends. The DAN paper is by a Dr Jepson.

The idea of treating the comorbidities as they crop up, seems entirely logical to me; but it seems to miss the bigger issue of what the comorbidity might help tell us about the autism itself.

Their list of comorbidities to keep a look at for:-

·         Allergic disorders in ASD: effects of allergies on behaviour, cognition and anxiety. Food and inhalant allergies, allergic rhinitis.

·         Autoimmunity in ASD. 

·         Autonomic nervous system dysfunction (dysautonomia) in ASD

·         Seizure disorders in ASD

Allergic rhinitis was of course the one that caught my eye.  This is the medical name for the itchy red eyes and runny nose caused by summertime pollen and pollution.  This reinforced by own observation that histamine can have a major negative impact on behaviour in ASD.  This was presented in my recent posts on histamine and antihistamine drugs.

Also of note to me was the observation that atopic dermatitis (itchy skin) and asthma are comorbidities.  Asthma was one of the comorbidities I choose to investigate myself.  An interesting observation I came across was that atopic dermatitis is actually a good predictor of developing asthma and, in fact, that by effectively treating it with a particular drug (ketotifen), you can actually halt the progression to asthma.  There is a study investigating exactly this issue; one half of the trial were itchy toddlers with a placebo and the other itchy toddlers had ketotifen.  A year later the group with ketotifen had a far lower percentage that had developed asthma than the placebo group.  I call that interesting but how many family doctors, let alone parents, are aware of that?

 Prevention of asthma by ketotifen in infants with atopic dermatitis

Also, another interesting paper all about childhood allergies is called The Allergic March.

Conclusion

Autism flare ups seem to be common and a little investigation may well lead to a better understanding of your child’s type of autism.  By recording data on bad behaviours, as in an ABA programme, or my preference, by just be keeping a watchful eye, you may well identify the cause and then find a remedy.  It might be a wobbly tooth, or it might be something more subtle like histamine.

I also believe that a detailed understanding of the comorbidities will ultimately lead to some effective therapies for autism itself.  Since it is clear that different people have different types of autism, knowing what triggers your child's flare ups may well help define what type of autism he/she has and therefore what therapies may or may not prove effective.

Histamine, allergies and reducing challenging “autistic-like” behaviours

Having recently discovered that an anti-histamine drug like Claritin can markedly reduce autistic behaviours, I have been looking into exactly why this might be and to see if there could be any other related interventions.  Here are the results and they pull together all sorts of related comorbidities and in the end I seem to have found a better solution for managing summertime autism flare-ups.

Allergies have long been linked to aggressive behaviours

It seems to be well known among allergists, that children with allergies may exhibit challenging behaviours.  It goes beyond the simple fact that the child with an allergy will be irritable and therefore behave badly; the allergy itself is affecting the behaviour.  Allergies tend to worsen behaviour and the science can explain exactly why this happens.   This applied to pollen type allergies, food allergies and even asthma.

In the case of asthma, I found several studies, one is called:  Prevalence of Behavior Problems in US Children With Asthma

The study concluded with:

Clinicians caring for children with asthma and their families should be aware of the relationship between asthma and emotional and/or behavioural problems and anticipate that a substantial number of their patients may have mental health services needs.

One alternative health website, gives a list of symptoms they believe histamine allergies produce in kids with ASD.

Some different types of responses to histamine seen in ASD children: If histamines become too high, you can see hyperactivity, compulsive behaviors, depression, abnormal fears, intense mood swings, runny nose, itchy eyes, sneezing, perfectionism, strong wills, explosive anger, anxiety, hair pulling, lack of focus, scripting (repeating commercials or television programs, etc.), high libido, giggling (which can be a sign of yeasty behaviors), aggression, change in bowel movements, a craving for salt, frequent urination and rashes. Those who have seasonal allergies tend to see a worsening of these symptoms during spring time.

 What I recently noticed in Monty, aged 10 with ASD, were some of these behavioural problems, but  with only the slightest outward sign of an allergy.

Food allergies causing autism-like behaviours

I was surprised to find one allergy site listing the behavioural effects of food allergies, it reads like a long list of autistic behaviours.  This made me wonder if many of the milder cases of autism and the so-called autism epidemic may just be unresolved food allergies.  Many of the DAN interventions are about “healing the gut”, so maybe they are really more about treating food allergies.  Many cases of classic autism appear to have no problem with their digestive system at all.

Here is a list of behaviours from one site on food allergies:

 • Poor coordination

• Trouble communicating

• Self-destructive behavior

• Staring

• Difficulty in group games or sports

• Obsessions

• Nonsense talk

• Inability to read tones of voice and/or body language

The best studied/documented allergies

Asthma is the best researched allergic condition that I found, followed by food allergies and the rare condition of mastocystitis; this condition is rare but sufferers write extensively about it on the internet.  They also report on the effect of different drug combinations in managing their conditions.   Mastocystitis is also a comorbidity of autism that has been researched by Theoharides, who proposes his NeuroProtek supplement.

The result is that there has been a great deal of research and many established drug therapies exist.  The link between allergies and behaviour was investigated in the 1980s, but there has not been much written since, which is a pity.

Mastocystitis

The Mastocystitis Society of Canada have a good website.  It defines Mastocytosis as a myeloproliferative neoplastic (mpn) stem cell disorder, caused by an over-abundance of good immune system cells called mast cells and the release of mast cell mediators.

What that really means is that when the mast cells encounter an allergen they overreact and release too much histamine and also inflammatory messenger, such as cytokines.  These chemical disperse throughout the body.  The histamine activates the four types of histamine receptors around the body.  The pro inflammatory cytokines react in a different way, but promote an excessive inflammatory response.

To grossly simply the condition, mastocystitis is an extreme form of allergic response.

Mastocystitis is a comorbidity of autism and the mast cell response has been proposed to be a key part of autism.  It is interesting to look at how mastocystitis is treated.  Click the link here.

Note the use of both H1 and H2 histamine antagonists, many asthma drugs including the steroid Prednisone, and the mast cell stabilizer Ketotifen.

Histamine & Histamine Antagonists

 Histamine is a chemical in your body with three distinct functions:-

1.       Histamine triggers the inflammatory response

2.       Regulates physiological function in the gut

3.       Acts as a neurotransmitter

Most histamine in the body is generated in granules in mast cells or in white blood cells called basophils. Mast cells are especially numerous at sites of potential injury — the nose, mouth, and feet, internal body surfaces, and blood vessels.

Histamine functions in coordination in 4 types of receptors (H1, H2, H3 and H4).  In the central nervous system H1 and H3 receptors.  H1 is involved in allergies and asthma.  H2 is mainly involved invasodilation and gastric acid secretion.  H3 controls neurotransmitter release (histamine, acetylcholine, norepinephrine, serotonin).  H4 Plays a role in chemotaxis.

Histamine antagonists are drugs that inhibit the action of histamine by blocking specific receptors in specific parts of the body.  The most common drugs are H1 antagonists that block the H1 receptor in summertime allergies.  H2 antagonists reduce gastric acid secretion to heal peptic ulcers.

Histamine is the link between allergies and behavioural change

Histamine in the brain has been shown to directly influence behaviour (see later in this post for links).  There is also plenty of anecdotal evidence from allergists, as shown earlier in this post.

In addition histamine has been shown to weaken the blood brain barrier.   This would then let into the brain pro-inflammatory agents that might then cause a spike in neuroinflammation and oxidative stress.  This in turn leads to more challenging behaviours.   

The disruption to the BBB can be best reduced by the use of H2 antagonist. H1 antagonists have a much smaller effect.  See this study, which concludes:

 It is concluded that histamine causes an increase in blood-brain barrier permeability which is mediated via endothelial H2 receptors,

Ketotifen

Ketotifen is an H1 histamine antagonist.  It is a 40 year old antihistamine drug that is available over the counter in Europe.  Not only can it be used to treat  allergies (it is the active ingredient in many eye drops) and help control asthma, but it has some additional benefits.  It acts as a mast cell stabilizer, reducing the amount of histamine released by the mast cells when they encounter allergens.  It is the only  H1 histamine antagonist that does this.  In  addition it also blocks H1 receptors like the other widely used H1 histamine antagonists.
It is also used by body builders.  They are using another asthma drug called Clenbuterol.  This drug has the side effect of reducing your body mass index (BMI), so it makes you more muscular if you take enough of it for long enough.  Such use of Clenbuterol has side effects, the body builders are using Ketotifen to reduce these and allow them to use Clenbuterol for longer.  The misuse of Clenbuterol  affected beta-adrenergic receptor functions, for those who are curious.  Ketotifen blocks this from happening.

Celebrities, like a certain very well-known footballer’s wife, take Clenbuterol to stay thin.  Maybe they also take Ketotifen?

Ketotifen is extremely cheap and widely available in Europe and Canada.  In the US it is much more difficult to get hold of and so seems to have great rarity value.

In the US, some DAN doctors give Ketotifen to autistic children as a therapy for Gastrointestinal problems.  The well-known DAN doctor, with an audio lecture on this subject, states that Ketotifen is “mainly active in the gut”.  He obviously has not read the research, since the opposite is actually true.  Based on my limited research, it appears that some of these kids may just have autistic-like symptoms causes by the excess histamine in their brain. In other words they may just have a case of food intolerance / Irritable bowel syndrome rather than autism.  That would certainly be a relief to the parents concerned.

Other H1 Antagonists

You will know these drugs by their brand names :  Claritin, Zyrtec, Benadryl, Allegra, Phenergan etc.  There are several types of these drugs.  The early examples passed into the brain and so made people drowsy.  The second generation are the current big sellers, based on their non-drowsy effect.  When you dig deeper, you will see that they are all slightly different, and some work better than others in different people.  They also vary in which part of the body they have the most affect.

The older types are off patent and sold cheaply as generic over the counter drugs.

Mast cell stabilizers and irritable bowel syndrome

It has been long known that certain drugs reduce the allergic reaction in food intolerance.  Remarkably the same drugs are today also used to treat asthma.  The expensive drug I was prescribed as child called Intal (Cromoglicic acid) for food intolerance, is today called a mast cell stabilizer and  used in asthma therapy.

Mast cell stabilizers prevent the release of inflammatory chemicals like histamine from mast cells.

Another insight courtesy of the Mastocystitis Society of Canada:-

“Mast Cell Stabilizers - Ketotifen is preferred as most effective for entire body, Cromolyn mainly targets gastrointestinal system”

So it looks like the DAN doctors have chosen the wrong treatment for their GI problems, they should be using Intal not Ketotifen.

Modern second generation anti-histamines do not enter the CNS

First generation H1 antagonist crossed the blood brain barrier and had a sedative effect, making sufferers drowsy.  As a result there was a big search made of drugs that could relieve allergy symptoms but not make sufferers drowsy.  These second generation drugs are the current big sellers, although the first generation drugs are still widely available.

These modern drugs should therefore have less impact on histamine driven challenging behaviours than the old ones.

Most anti-histamines block the receptor rather reducing the amount of histamine

The popular H1 antagonist like Claritin do not reduce the amount of histamine produced in the body, they rather block the receptors used to detect it.  The amount of histamine flowing through your body remains the same.  That histamine weakens the blood brain barrier, allowing in things that might be better kept out.
It turns out that the H2 antagonists can reduce this degradation of the BBB, but H1 antagonists like Claritin have only a marginal effect.  This is all based on research in rats.

Sufferers of mastocystitis take copious amounts of H1 antagonists and H2 antagonists plus a whole host of other drugs.  H2 antagonists are old drugs like Tagamet, that were designed to reduce acidity in your stomach for treating ulcers and GERD.  It appears that also have unforeseen effects in your brain and elsewhere.

Histamine in the Brain

For those scientists among you, the areas to read up on are mast cells and how histamine functions in the brain.  Many of the papers on histamine in the brain are not available without payment.  Here is a short paper that is available.

The histaminergic system in brain: neurophysiology

Other good ones, not available free include:

The physiology of brainhistamine

and from way back in 1988:- 
Behavioral effects of histamine and its antagonists: a review

Research studies in to the use of H1 and H2 antagonist in autism

I was pleased to find that I was not the first to look into the use of histamine drugs in autism.  I did find two studies, and both were positive.  It is strange that in the 12 years since these studies were carried out, the research effort has not been followed up.

From my recently acquired insight, the H1 antagonist improved behaviour by blocking some of the unwanted response to histamine in the brain and the H2 antagonist help restore the blood brain barrier and keep out those unwanted pro-inflammatory agents like cytokines and perhaps even some histamine.

Niaprazine in the Treatment of Autistic Disorder  (H1 antagonist)

Abstract

Niaprazine is a histamine H₁-receptor antagonist with marked sedative properties. It has been employed in subjects with behavior and sleep disorders. No data concerning the use of niaprazine in subjects with autistic disorder are reported in the literature. The authors performed an open study to assess niaprazine efficacy in a sample of 25 subjects with autistic disorder and associated behavior and sleep disorders. Niaprazine was administered at 1 mg/kg/day for 60 days. A positive effect was found in 52% of patients, particularly on hyperkinesia, unstable attention, resistance to change and frustration, mild anxiety signs, heteroaggressiveness, and sleep disorders. Statistical comparison between responders and nonresponders showed no influence on niaprazine effect by age over or under 12 years, presence of neurologic signs, epilepsy, or abnormalities seen on brain imaging. Niaprazine was more efficacious in subjects with a mild or moderate degree of mental retardation. No side effects were observed. Because of its sedative effects and good tolerability, niaprazine can be used as a first-choice drug to improve behavior and sleep disorders in patients with autistic disorder. (J Child Neurol 1999;14:547-550).

 Famotidine treatment of children with autistic spectrum disorders: pilot research using single subject research design.  H2 receptor antagonists

Abstract

Using single subject research design, we performed pilot research to evaluate the safety and efficacy of famotidine for the treatment of children with autistic spectrum disorders. We studied 9 Caucasian boys, 3.8-8.1 years old, with a DSM-IV diagnosis of a pervasive developmental disorder, living with their families, receiving no chronic medications, and without significant gastrointestinal symptoms. The dose of oral famotidine was 2 mg/kg/day (given in two divided doses); the maximum total daily dose was 100 mg. Using single-subject research analysis and medication given in a randomized, double-blind, placebo-controlled, cross-over design, 4 of 9 children randomized (44%) had evidence of behavioral improvement. Primary efficacy was based on data kept by primary caregivers, including a daily diary; daily visual analogue scales of affection, reciting, or aspects of social interaction; Aberrant Behavior Checklists (ABC, Aman); and Clinical Global Improvement scales. Children with marked stereotypy (meaningless, repetitive behaviors) did not respond. Our subjects did not have prominent gastrointestinal symptoms and endoscopy was not part of our protocol; thus, we cannot exclude the possibility that our subjects improved due to the effective treatment of asymptomatic esophagitis. The use of famotidine for the treatment of children with autistic spectrum disorders warrants further investigation.

Conclusion

Several important conclusions can be drawn based on a few hours of research on Google Scholar.

·         Your child may be subject to an allergic response that is outwardly hardly visible

·         The allergic response may be visible first as challenging autistic-like behaviour, rather than sneezing, runny nose, red eyes or wheezing

·         H1 antagonists can supress both the autistic-like behaviours and the typical allergic reactions

·         People do not all react the same way to H1 antagonist drugs.  A little experimentation is in order.  A drug that should work 24 hours can be effective for only 4 hours.

·         To avoid excessive use and possible side effects, allergists often combine different H1 antagonists, even though the information from the drug firm warns not to do this.

·         In some people the old H1 antagonists, that make you drowsy, work better than the new 2^nd and 3^rd generation drugs.

·         One old H1 antagonist called Ketotifen, seems to work wonders for some people.  It is both a mast cell stabilizer and a histamine receptor blocker.

I have ended up with a combination of Ketotifen and Claritin.  Claritin has an effect on behaviour within 20 minutes, Ketotifen had no apparent impact in the short term whatsoever.   You cannot keep giving Claritin every 4 hours.  It is supposed to be 10ml per day.

The day after taking Ketotifen things did change, and without having to overuse the Claritin.  The allergy is still mildly visible, but the challenging behaviours have gone.

I wish I had known about this last summer.  When Monty was aged 9, he went completely berserk on an aircraft and so as to restrain him, I was almost sitting on top of him, holding arms, legs and head; the flight attendant was asking if he would like a glass of water.  This year I will be well prepared with my Ketotifen/Claritin combo and anticipate no such problems.



Related Post:-

More on anti-histamines in Autism and introducing H4