Summertime Raging in Autism – H1 Anti-histamine Effect on Histamine Levels and IL-6

Last summer, I wrote a lot about autism getting much worse in that time of the year and how I found that common “24 hour” anti-histamine drugs seemed to have a magical effect; but one that lasted only 2-3 hours. There were only visible signs of a mild allergy, which could indeed easily be overlooked.

I did later receive a message from a reader who noticed his child’s ASD behaviours were greatly improved by Zrtec and his doctor agreed to prescribe this H1 antihistamine all year round.

Recently, I stumbled upon a blog, rich with many comments of parents of kids with severer types of autism.  Here I noted some parents referring to “summertime raging”, and I thought to myself, I know what they mean.  Fortunately, I found out how to make it go away.

Ant-histamine drugs

The two most common antihistamine drugs are Claritin (Loratadine), its active derivative Aerius (Desloratadine) and Zrtec (Ceterizine) and its active derivative Xyzal (levocetirizine).

The main action of an antihistamine is not actually to reduce the amount of histamine in your blood, rather it is to block the effect of histamine on the H1 receptors.

An H2 antihistamine blocks H2 receptors that are mainly in your intestines, and is used to reduce the amount of acid in the stomach.

This led me on a quest for substances that actually stop the increase in histamine, rather than just blocking some effects.  The only thing that does this is something that can stop so-called mast cells from degranulating and spilling their load of histamine, serotonin, nerve growth factor and cytokines, including IL-6, into the blood; from where, all except serotonin, are free to travel to the brain, across the blood brain barrier (BBB).  Serotonin cannot cross the BBB.

According to the mast cell specialist Theoharides, conventional drugs are not genuine mast cell stabilizers.  There are some partial ones, like Ketotifen, Cromalin, Rupatadine and Azelastine, but Theoharides thinks naturally occurring flavonoids like Luteolin and Quercetin work best.

Last summer in this blog I looked at newly discovered histamine receptors types H3 and H4 which are known to be present in the brain.

So how is it that Claritin and Zrtec can reduce autistic behaviours ?

I did note that both the above drugs did reduce summertime raging and also the Theoharides' research that showed they probably should not, since they are not mast cell stabilizers. 

Since my blog reader also found Zrtec helpful, so much so he gives it to his kid year round and it now seems summertime raging is not an unusual phenomenon in autism, I did some more checking.

In spite of what Theoharides tells us, it turns out that both Claritin and Zrtec do indeed reduce the amount of histamine in the blood.

Also, it turns out that not only is the pro-inflammatory cytokine IL-6 released from mast cells but it is also released from another type of cell, called the endothelial cell.

The endothelium is the thin layer of cells that lines the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. The cells that form the endothelium are called endothelial cells. Endothelial cells in direct contact with blood are called vascular endothelial cells, whereas those in direct contact with lymph are known as lymphatic endothelial cells.

And what prompts endothelial cells to release IL-6? Histamine does.

Indeed we have studies showing how Claritin (loratadine) and  Zrtec (Ceterizine) reduce histamine and IL-6; it is the IL-6 from the endothelial cells.

Inhibitory activity of loratadine and descarboxyethoxyloratadine on histamine-induced activation of endothelial cells.

"CONCLUSION:

These results demonstrate that both L and DCL are active to reduce the histamine-induced activation of EC. Interestingly, DCL seems to be effective at lesser concentrations especially to inhibit cytokine secretion."

The above study would suggest that Aerius (DCL) should be more effective than Claritin (L) its predecessor.

Human Mast Cells(HMC-1 5C6) Enhance Interleukin-6 Production by Quiescent and Lipopolysaccharide-Stimulated Human Coronary Artery Endothelial Cells

"Histamine is a major constituent of the mast cell. The effect of histamine on endothelial cells is primarily mediated through H1R

Collectively, our results suggest that mast cell-derived histamine and proteases play an important role in vascular inflammation and calcification in addition to their well-recognized participation in allergic diseases."

This study, and others like it, show how mast cell degranulation contributes to heart disease.  This would suggest that mast cell stabilizers have a much wider role in human health than is realized.  Another example of how a red apple a day (with the skin) may indeed help keep the doctor away and a glass of red wine will do the same.  Both are rich sources of the mast stabilizer Quercetin.  The alcohol increases the bio-availability.

Cetirizinea histamine H1 receptor antagonist improves viral myocarditis

"Conclusion

These results suggest that cetirizine exerts its beneficial effects on viral myocarditis by suppressing expression of pro-inflammatory cytokines, genes related to cardiac remodeling in the hearts of mice."

So how do Claritin and Zrtec reduce summertime/year round raging in autism?  Well it could be histamine or it could be IL-6, we cannot know for sure.  The science tells us that the brain has many H3 and H4 receptors, so they are possibly to be implicated.  Or, it may just be IL-6;  histamine’s involvement could be just provoking the endothelial cells to release more IL-6.

Conclusion

Claritin/Zrtec/Xyzal are relatively cheap, in theory they are long lasting drugs.  In Monty, aged 10 with ASD, they all work for summertime time raging, but not for long.  Adults should take one per 24 hours.  Monty would need one every 3 hours.

The, supposedly better, mast cell stabilizers like Ketotifen and Rupatadine take a few days before they have any effect at all.  Azelastin is available as a nasal spray and is supposed to be effective quickly as an allergy treatment.

My preferred mast cell stabilizing, IL-6 inhibiting, strategy is to combine PEA (palmitoylethanolamide) which is already naturally in your body, with the flavonoid quercetin, which is found in the skin of red apples and red grapes.  In theory, according to the research, this is both a potent combination and should be free of harmful side effects.

Very frequent doses of Claritin/Zrtec/Xyzal are not going to be good.

Links

Blog with 1000s of parent comments, some are very insightful

  

Theoharides on mast cells

On this blog:-

http://epiphanyasd.blogspot.com/2014/02/is-subtype-of-autism-allergy-of-brain.html

http://epiphanyasd.blogspot.com/2014/03/palmitoylethanolamide-pea-vs-flavonoids.html

http://epiphanyasd.blogspot.com/2013/07/histamine-allergies-and-reducing.html

http://epiphanyasd.blogspot.com/2013/11/seasonal-autistic-mastocytosis.html

More on anti-histamines in Autism and introducing H4

In my previous posts on histamine, you would have read that I found that Claritin appeared to reduce autistic behaviours.  Once I had got to the bottom of what was going on, I found out that histamine has a long record of stimulating challenging behaviour in all children.  It also became clear that typical anti-histamines (H1 antagonists) are all slightly different and one may be effective in one person and ineffective in another.  Each one tends to have additional secondary effects.

It now appears that the secondary effect of certain H1 antagonists may actually be more important than the primary intended effect of reducing itchy eyes and runny noses.

There are three generations of H1 drugs.  The fastest working and most potent is still the first generation, the second generation are non-drowsy derivatives of the first generation.  The third generation are the active metabolite of the second generation.  As you will see in today’s central paper, the third generation probably does not warrant the tittle.  For many users they may be just expensive versions of the second generation drug.

The excellent paper  New anti histamines: a critical view is from Brazil, but it has an English version.  It is highly readable.  It tells of the specific secondary effects of certain second generation  H1 antagonists.   (She omits to mention the secondary effects of the first generation. Some people say Ketotifen is 1^st generation and other people say 2^nd generation, anyway it appears not to be sold in Brazil).  I suggest you read the paper, if you have a child with an ASD. The key section is this:

Antiallergic/anti-inflammatory effects

Originally, studies of the relative potencies of H1 antihistamines were based on the capacity of different compounds to competitively inhibit the H1 receptor binding of histamine, i.e. on their blocking effect on the receptor.⁸ Nevertheless, it has already been known for some time that, in addition to acting on H1 receptors, many H1 antihistamines, at appropriate doses, are capable of inhibiting not only the release of histamine by mast cells,^9,10 but also mast cell activation itself.¹¹ Some of them can even regulate the expression and/or release of cytokines, chemokines, adhesion molecules and inflammatory mediators.^5,8

Therefore, the antiallergic properties of H1 antihistamines are generally a reflection of their capacity to affect mast cell and basophil activity, inhibiting the release of preformed mediators such as histamine, tryptase, leukotrienes and others.⁸ Several second-generation H1 antihistamines have demonstrated antiallergic properties, irrespective of their interaction with the H1 receptor.^5,8

Chronic allergic inflammation resulting from the late-phase reaction, exhibits components that are similar to other forms of inflammation, including chemotaxis of inflammatory cells followed by activation and proliferation, with subsequent production and release of many chemical mediators. Among cells involved in allergic inflammation are: antigen-presenting cells (for example, macrophages), mast cells, basophils, T lymphocytes, epithelial/endothelial cells and eosinophils - major effectors of chronic inflammation. Cytokines, chemokines, inflammatory mediators and adhesion molecules also contribute to this process which ultimately leads to dysfunction of the affected organ.⁸

Many second-generation H1 antihistamines (particularly cetirizine) are capable of inhibiting the influx of eosinophils to the site of allergen challenge in sensitized individuals.^5,8 Studies have demonstrated that some of them can also alter adhesion molecules expression on epithelium and eosinophils, and reduce in vitro survival of eosinophils. Finally, some second-generation H1 antihistamines are capable, in vitro and in vivo, of altering the production of inflammatory cytokines (for example, TNF-a, IL-1b and IL-6) and the Th1/Th2 balance regulation cytokines (for example, IL-4 and IL-13).^5,8

Therefore, it is well established that, in addition to their effects on H1 receptors, many second-generation H1 antihistamines also manifest antiallergic and anti-inflammatory properties which differ depending upon their molecules and the experiments used for their evaluation.⁵

 

From my own experience, I have already replaced Claritine (Loratadine) with Cetirizine to see if it will remain active for longer.  Rather than working for 24 hours, Claritine is working for about 5 hours.

I thought Cetirizine might remain active for longer, but the main difference seems to be in how it works, rather than for how long it works.  With Cetirizine autistic behaviour has pretty much returned to where it was at the start of summer, before the allergy season.  With Claritine things improved greatly, but not all the way back to "normal".

Reading the paper and one of its references -

Compared pharmacological characteristics in humans of racemic cetirizine and levocetirizine, two histamine H1-receptorantagonists

makes me think that the expensive new  version of Cetirizine, called Levocetirizine, might be even better.  It happens to be available locally, but it is seven times as expensive.

The Brazilian paper does rather contradict some of what Dr Theoharides says about stabilizing mast cells.  You can choose who you think has got it right.  The good thing is that both Dr Inês Cristina Camelo-Nunes and Dr Theoharides seem very serious, objective people, which cannot be said about all the people offering their advice on the internet.

In fact, I found an interesting paper on the anti-inflammatory effects of the new version of Claritin, called Aerius/Clarinex (Desloratadine).

Antihistaminic, Anti-Inflammatory, and Antiallergic  Properties of the Nonsedating Second-Generation Antihistamine Desloratadine: A Review ofthe Evidence

It really seems to be the case of trying several antihistamines and selecting the one that works best for you.

 

The H4 Histamine Receptor and Inflammation

You may recall that there is a fourth histamine receptor, naturally called H4.

It was only recently discovered, as you might guess from the short entry in Wikipedia.  It seems that the H4 receptor plays a substantial role in the inflammatory response.  It is seen as playing a key role in conditions ranging from arthritis to asthma.

Here is a full text paper for those interested in the science:-

The role of histamine H4 receptor in immune and inflammatory disorders

 Here is a graphic from that paper:-

I wonder if that H4 is a ticking bomb in autism as well ?

Those more peaceful people among you will be less aware of what C4 is, and hence the sticks of H4 dynamite.