Intermittent Explosive Disorder (IED) + Autism

An altogether different kind of IED, although you may not always feel so.

Many people think that childhood psychiatric disorders, including autism, are grossly over-diagnosed in the US.

This did spring to mind when I came across a reference to “intermittent explosive disorder” and autism.

Before we get into that, I received an interesting graphical presentation of ADHD in the US, from a company called Healthline; they want me to give a link on my post on Clonidine.  It shows many things including how ADHD diagnosis varies wildly by State, just as the CDC’s autism data does.  The difference is remarkable. I don’t think anybody really believes that ADHD is 3 times more prevalent in Kentucky than in Nevada.  It just shows how inconsistent the diagnosis is; perhaps you could correlate the diagnosis with the medical school attended by the doctor/psychiatrist?

Back to Intermittent Explosive Disorder

Intermittent explosive disorder (IED) is a behavioral disorder characterized by explosive outbursts of anger, often to the point of rage, that are disproportionate to the situation at hand.

  

This is pretty tame stuff to many carers of anyone with autism.  So I thought it odd that anyone bothered to diagnose autism + IED.

The question is usually where the IED is directed, to the carer or to self (Self Injurious Behavior).

So IED is a normal part of autism, but it can be treated, without recourse to the drugs psychiatrists use.  They often cause further problems.

I was curious to find out what the research says about IED in other people.  Rather surprisingly, or maybe not, the mechanism turns out to be the same.

IED in Autism

Regular readers will recall the posts all about inflammatory agents (cytokine IL-6 and histamine) that turned out to trigger the summertime raging in Monty, aged 11 with ASD.

Using Verapamil to stabilize the mast cells and so lower the level of histamine and IL-6, I made the raging and aggression go away.  It really does work.

IED in Everyone Else

Elevated plasma inflammatory markers in individuals with intermittent explosive disorder and correlation with aggression in humans.

press release

"The researchers measured the inflammatory markers CRP (C Reactive Protein) and IL-6 levels in 197 physically healthy volunteer subjects. Sixty-nine of those subjects had been diagnosed with IED, 61 had been diagnosed with psychiatric disorders not involving aggression, and 67 had no psychiatric disorder.

Both CRP and IL-6 levels were higher, on average, in subjects with IED, compared to either psychiatric or normal controls. Average CRP levels, for example, were twice as high for those with IED as for normal healthy volunteers. Both markers were particularly elevated in subjects who had the most extensive histories of aggressive behaviors. Each marker independently correlated with aggression, the authors note, suggesting that "both have unique relations with aggression."

Overall, the findings reported in this new paper suggest that "medications that reduce inflammation may also drive down aggression," Coccaro said. Anti-inflammatories such as Celebrex, or even aspirin, might make a difference for those with IED. Since available treatments bring less than 50 percent of patients into remission, the authors wrote, "additional strategies for the examination and intervention of human impulsive aggression are needed."

Pass the NAC, please

Not surprisingly people with IED also tend to suffer from oxidative stress.

Elevated Plasma Oxidative Stress Markers in Individuals with Intermittent Explosive Disorder and Correlation with Aggression in Humans

Background

Animal and clinical studies suggest a link between inflammation and oxidative stress. Because oxidative stress is an inherent part of inflammation, and inflammation is associated with behavioral aggression in lower mammals and humans, we hypothesized that markers of oxidative stress would be related to aggression in human subjects. In this case-control study, markers of oxidative stress and aggression were assessed in human subjects with histories of recurrent, problematic, impulsive aggressive behavior and in nonaggressive comparator subjects.

Conclusions

These data suggest a positive relationship between plasma markers of oxidative stress and aggression in human subjects. This finding adds to the complex picture of the central neuromodulatory role of aggression in human subjects.

I had one reader tell me that the most noticeable effect of the antioxidant NAC on her son with autism, was that he stopped biting her.  One less IED to defuse in her house.

ABA is also a potent tool to understand the underlying cause of aggression and SIB; but if you suffer from neuro-inflammation and oxidative stress, even ABA can do with a little extra help.

How to avoid Autism (and also treat TBI)

It appears that in classic autism, most of the damage is done before birth, but a gradual second decline does often seem to occur between 24 and 54 months, even in a child who you would not think of as suffering from regressive autism.

When people think back about their child with regressive autism, they often recall examples of odd behaviours occurring long before the big regression occurred.

So my "extrapolation" from this, is that there are actually two waves of neurological damage in these two common types of autism. It is just that in one case there is a tidal wave before birth and a smaller change as a toddler.  In regressive autism, the first wave usually passes unnoticed, and the main, unmistakable damage occurs in the second wave.

Perhaps we can avoid this first wave of damage done before birth, in both classic early onset autism and regressive autism.

In an earlier post, I made my case for why girls do not get mild autism and why mothers, who are alpha-females, are more prone to have kids with ASD.

Why Girls don’t get Mild Autism and Why Alpha Females may have Kids with Autism.

This was based on reading that the female hormone progesterone is extremely neuro-protective and that oxidative stress, now seen as a cause of autism, has many causes and is extremely damaging to the brain.  A good example of progesterone use, is its experimental use immediately after a traumatic brain injury.  All I did was extend this to autism.  Now it appears I am not the only one.

Here is a paper I spotted in a corner on Paul Whiteley’s ASD blog.

Low maternal progesterone may contribute to both obstetrical complications and autism

Abstract

Studies show increased autism risk among children born to mothers experiencing obstetrical complications. Although this is usually interpreted as suggesting that the obstetrical complications could be causing autism, it is possible that a single factor could be responsible for both complications and autism. We hypothesized that low levels of the hormone progesterone is responsible since it is supplied to the fetus maternally and does not only support pregnancy but also promotes brain development. Following a review of the literature, we report findings from a survey of mothers of autistic children (n=86) compared to mothers of typically-developing children (n=88) regarding obstetrical histories, including five obstetrical risk factors indicative of low progesterone Using this analysis, the ASD group had significantly more risk factors than controls (1.21 ± 0.09 vs. 0.76 ± 0.08, p< .0001), suggesting low progesterone. Thus, results suggest that low progesterone may be responsible for both obstetrical complications and brain changes associated with autism and that progesterone levels should be routinely monitored in at-risk pregnancies. Our hypothesis also suggests that ensuring adequate levels of progesterone may decrease the likelihood of autism.

The authors’ hypothesis suggests that ensuring adequate levels of progesterone may decrease the likelihood of autism.  Well, I for one, find this interesting.

In another earlier post, I referred to my advice to Ted, the nom de guerre of my very neuro-typical elder son, on how to avoid autism in the next generation.  I think I can now extend that advice further:-

People like Ted, with a close relative with ASD, could do some of the following:-

·        Find a partner who is calm beta-type female

·        Ensure she avoids emotional stress and shocks during pregnancy (particularly early on)

·       Take maternity leave straight after pregnancy is noticed, rather than mainly after birth; or, best of all, have the partner quit work as soon as pregnancy is noted

·        Ensure high levels of neuro-protective agents throughout pregnancy

·        Progesterone

·        Glutathione GSH (i.e. take NAC)

 

You might be expecting me to have statins on my list, since they are also very neuro-protective, but I do not;  even though:-

Johns Hopkins – a new use for statins

Statins in traumatic brain injury

During pregnancy, statins are detrimental to human placental development.  So although people in high speed skiing accidents, who suffer traumatic brain injuries, would have a clear benefit, for a woman with a 10% chance of having a child with ASD, the risks would outweigh the possible benefit.  Most likely, the primary, cholesterol lowering effect of the statin, is doing the damage, since the baby’s brain does need cholesterol. 

Statin warning for pregnant women

Progesterone would also be a potential therapy for people with ASD.  It might though not be wise for boys around puberty.  There are reports of people with ADHD finding progesterone helpful.
 

Should I happen to have a TBI (traumatic brain injury), please put in my IV drip progesterone, atorvastatin/lovastatin and N-acetylcysteine.


P.S.  During pregnancy, ensuring the mother is not hypothyroid and does take folic acid will also shift the odds away from an outcome with ASD.

 

 

Autism, a Dynamic Encephalopathy, Indeed

 

With a title like that, not many people will stumble upon this post with Google.

So, for the hard-core of readers, today I am going to develop an idea of Martha Herbert, the pediatric neuroscientist from Harvard, who writes a lot about autism.

Incidentally, most researchers do not like publicity, and particularly those looking at autism.  Martha, herself makes some side remarks as to why this is; as I suggested in earlier posts it dates back 10+ years to a certain Dr Wakefield.

“A further barrier to considering the body’s impact on the brain was the reaction to the work of Wakefield, who argued not only that there was a link  between  autism  and  vaccines  but  also  that  this  link was mediated through the gastrointestinal system. For the better part of a decade any attempt to discuss gastrointestinal or immune issues with autism was construed as a support of Wakefield’s vaccine hypothesis, and it was difficult to discuss, let alone get funding for, clinical or research observations about these problems.  One way around the essentially taboo character of somatic problems in autism was to treat them as coincidental symptoms. For example, one could  talk about gut problems provided one made  it clear that they did not cause the autism in the brain. Improvement after treatment of gut problems, which is often observed, would then be explained as a consequence of reduction of pain and discomfort, but not of any direct impact on core brain mechanisms generating autistic behaviors.”

Another fearless autism researcher, not shy to voice his opinions by blog and tweet, is Paul Whiteley, in Sunderland.   Paul is very much a believer in the role the gut/diet in autism, he and Paul Shattock are the driving force behind the gluten and casein free diet as a therapy for autism.  Given what Martha writes above, and the association between Shattock and Wakefield, is it surprising that the GCF diet remains on the fringes?  I know some parents who wholly endorse it.

Here is a link to one of Martha’s recent works, for Herbert fans:-

From Static Genetic Brain Defect to Dynamic Gene- Environment- Modulated Pathophysiology

Dynamic Encephalopathy

It was Martha who called autism a dynamic Encephalopathy.  Encephalopathy just means a brain disease.

What she means is that over time autism changes, day to day and year to year.  Just as during fever, autism symptoms may wane, other environmental provocations may cause flare ups.  With age come hormonal changes that will inevitably change the central hormonal homeostasis, I hope for the better, as generally is the case.

Other than being a fancy word, Encephalopathy, is probably a much better word than autism.  There are many types of Encephalopathy and there are multiple causes, it refers to a syndrome of global brain dysfunction; this syndrome can have many different organic and inorganic causes.  As with autism the hallmark of encephalopathy is an altered mental state.

 
Forget Autism think Encephalopathy

If you have not already opened up Wikipedia, I suggest you do.

http://en.wikipedia.org/wiki/Encephalopathy

From my desk research and primary research, I know that one factor behind this encephalophy is chronic inflammation, otherwise known as neuroinflammation.

At this point, we should look at what neuroscience can tell us about neuroinflammation

The Dana Foundation is a private philanthropic organization committed to advancing brain research.  Founded in 1950 and with $230+ million in assets I think they should be a good source.  Here  is an excellent paper, that is written for non-scientists. 

 Consequences of the Inflamed Brain

Among the many interesting insights are these:- 

 “Until recently the CNS and peripheral immune sys­tem were thought to operate independently.”

“However, new research has led to important advances in our understanding of how immune-related events in the periphery can influence CNS processes, thereby altering cognition, mood, and behavior, and these advances are suggesting that inflammation may have important long term implica­tions for the brain.”

 “Inflammation in the body can lead to inflammation in the brain”

“The same cytokines that participate in produc­ing the inflammatory response in the body also initiate the communication process to the CNS. They accumu­late in the bloodstream and thereby travel to the brain”

“They cross into the brain in regions where the barrier is weak, and they bind to receptors on the insides of the cerebral vascular blood vessels, thereby inducing the production of soluble mediators within the epithelial cells that can cross into the brain.”

“In addition, there are neural as well as blood-borne communication routes. For example, there are cytokine receptors on nerves, such as the vagus, that innervate peripheral immune organs, and these nerves communicate to the brain and are activated during infection.”

“During a normal infection, neuroinflammation and the resulting adaptive sickness behaviors persist only for several days. However, if these responses become exaggerated or prolonged, the outcomes may well become estab­lished, leading to cognitive impairment instead of brief memory disruption,”

 “… physiology can become pathology when a set of processes designed to be rela­tively brief becomes prolonged.”

“However, peripheral inflammation is highly complex and involves many immune cells and their products. Existing anti-inflammatory drugs often target only one of these. For example, non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, inhibit only a hor­mone, prostaglandins, leaving other actors in inflam­mation (cytokines, chemokines, etc.) untouched.”

“A second way that central neuroinflammation could be prolonged is less obvious. The CNS may come to over-respond to the same signal from the peripheral immune system. As noted above, microglia and the cytokines they produce when activated are at the core of the neuroinflammatory response that pro­duces sickness behaviors. If microglia were to become “sensitized,” which means they respond in exagger­ated or prolonged fashion, then sickness behaviors would become intensified and prolonged—pathology instead of physiology.”

“Most encouragingly, studies in numerous animal models show that the development and expression of chronic pain can be blocked with drugs that inhibit either microglial activation within the spinal cord, or the inflammatory cytokines that microglia produce.”

“In addition, microglia also can become sensi­tized without a prolonged peripheral inflammation. For example, aging appears to sensitize microglia so that microglia, particularly in the hippocampus, respond in exaggerated fashion to input. Thus, neuroinflammation produced by surgery, peripheral infection, and the like, is greatly exaggerated in aged subjects. Correspond­ingly, aging also augments the chances of depressive behaviors, cognitive impairments, and pain produced by peripheral inflammatory events. Encouragingly, however, some human studies show that inhibition of microglia and cytokines in the brain blunts such patho­logical outcomes.”

“Blockade of inflammation in the periphery and microglial activation/cytokine action in the CNS, may well become important therapies for a range of disorders not often thought of as mediated by these factors.”

Conclusion

There is nothing new to me in the Dana paper; this in itself is rather a shock.  If you have followed my blog from the start, you should also not be surprised; but I have never seen quite so much scientific good sense written in just four pages.  It tells me a lot and reassures me that I am on the right track with my cytokine blocking therapies, mast cell stabilization and somewhat far fetched, vagus nerve stimmulation ideas.

There are other science-based "inflammation control" therapies and I will be writing about them later.

P.S.  Why no Dean’s List for Martha?

Regular readers of my blog may have noticed that a small number of the several hundred researchers, whose papers are discussed here, are given a pat on the back and moved to the Dean’s List.  Why not Martha?

There is a good reason.  For many years Martha keeps going on about the “Fever Effect” in autism.  This is the strange phenomenon where autistic behaviours abate during fever, i.e. sickness associated with high temperature.  I myself witness this every time Monty, aged 10 with ASD, has a high temperature.  I think that conclusively solving this, might indeed tell us something profound about this wide phenotype of autism.

I think with the resources of Harvard, she should be able to figure this out.  Her TRANSCEND Program gives her a pool of research subjects.

Peter has just one mouse model of autism and, at the age of 10, he is getting a big to be called a mouse.

So Martha, put aside the MRIs and the calcium channelopathies, if you figure it out before me, you get on the Dean’s List.

If I can prove the underlying reason, I will put myself on the Dean’s List.

 

Cytokine Theory of Disease & the Vagus Nerve

If you are a regular reader of this blog you will know that the key to controlling autism is reducing oxidative stress and neuroinflammation.  One of the key drivers of the on-going neuroinflammation are signalling molecules called cytokines; if you can limit the release of harmful cytokines you can reduce neuroinflammation.  This appears to be easier said than done.  I learnt that some statins limit the release of pro-inflammatory cytokines and neuroscientists in the US are researching their use, but not yet in autism.  I did some home research and found a positive effect within 24 hours.

It turns out there is an entire field of neuroscience relating to cytokines as a mediator of disease and this is all channelled through the Vagus nerve.  There is an eminent  neuroscientist, Kevin Tracey, who dominates this field; he is credited with discovering that vagus nerve stimulation inhibits inflammation by suppressing pro-inflammatory cytokine production.   Tracey is also an inventor, he is seeking to apply the science and has an interesting start-up company.  So I have found a kindred spirit and if you read his papers, you will find that often missing element, a sense of humour.

Tracy has even written a book, which explains his discoveries.

Fatal Sequence: The Killer Within

For those scientists among you, a very readable paper is:- 

Physiology and immunology of the cholinergic  Anti-inflammatory pathway

For those in a hurry, here is summary

The cytokine theory of disease is a concept that cytokines produced by the immune system can cause the signs, symptoms, and damaging aftereffects of disease.

One example is the case of TNF, a cytokine implicated as a necessary and sufficient mediator of lethal septic shock. Administration of TNF to healthy humans reproduces the metabolic, immunological, and pathological manifestations of the disease and the gene knockout or pharmacological blockade of TNF activity prevents the development of lethal septic shock. Other pathophysiological activities ascribed to TNF are the capacity to cause fever and localized inflammation. Clinical successes in the 1990s using drugs that specifically inhibit TNF for patients with inflammatory bowel disease or rheumatoid arthritis directly implicated a pathogenic role of this cytokine in other diseases and validated in humans the fundamental premise of the cytokine theory of disease.

 

 

The cholinergic anti-inflammatory pathway

Tracey reasoned that, since the CNS coordinates major physiological responses via innervated circuits, it might also use neural input to control a potentially deadly cytokine response. In classical physiological systems, the sensory projections of the autonomic nervous system provide input to brain networks about essential bodily functions. These elicit a coordinated neural output from the CNS to maintain homeostasis for parameters as varied as heart rate, blood pressure, digestion, body temperature, organ perfusion, and blood glucose levels. Accordingly, it seemed possible to posit the existence of a comparable mechanism to control cytokine release that could, at least in theory, function as an extremely fast, reflex-like anti-inflammatory pathway controlled by brain networks.  Stimulation of vagus nerve signals was shown to significantly inhibit TNF release in animals receiving lethal amounts of endotoxin. Subsequent work established that vagus nerve signaling inhibits cytokine activities and improves disease endpoints in experimental models of sepsis, schemia/reperfusion, hemorrhagic shock, myocardial ischemia, ileus, experimental arthritis, and pancreatitis. The cellular molecular mechanism for inhibition of cytokine synthesis is attributable to acetylcholine (ACh), the major vagus nerve neurotransmitter. Macrophages and other cytokine-producing cells express acetylcholine receptors (AChRs), which transduce an intracellular signal that inhibits cytokine synthesis. The best characterized of these cholinergic receptors that suppress cytokines is the α7 subunit of the nicotinic AChR (α7 nAChR).

 

 

It takes nerve to restrain cytokines: anatomy of an innervated cytokine system

Recent studies of the physiology, functional anatomy, and cellular molecular mechanisms of the cholinergic anti-inflammatory pathway indicate that the principal components for cytokine suppression by the vagus nerve converge in the spleen. Endotoxin localizes to macrophages primarily in the spleen and liver, thereby activating an immediate early cytokine response. The spleen is the major source of both hepatic and systemic TNF during endotoxemia; it releases newly synthesized TNF into the splenic vein, which drains into the liver, and from there, TNF crosses into the systemic circulation.

 Vagus nerve stimulation, or administration of α7 nAChR agonists, inhibits not only TNF but also IL-1, IL-6, IL-8, and high mobility group box 1 (HMGB1)

 

Preclinical efficacy of experimental therapeutics

Preclinical studies are in progress to determine whether it may be possible to develop therapeutics based upon either devices that stimulate vagus nerve activity or drugs that activate the cholinergic anti-inflammatory pathway to suppress cytokine damage. A significant number of studies indicate that the cholinergic anti-inflammatory pathway is a robust regulator of cytokine-mediated damage in local and systemic experimental disease.

The role of exercise

Exercise reduces levels of TNF and other cytokines, confers protection against cardiovascular disease and type 2 diabetes, increases vagus nerve activity, and confers protection against the development of atherosclerosis. It is possible that the mechanism of these exercise effects is at least in part attributable to exercise-induced increases in cholinergic anti-inflammatory pathway activity. Obesity, on the other hand, is characterized by diminished vagus nerve output and elevated cytokine levels, which have been implicated in mediating insulin resistance and atherosclerosis. Since weight loss and exercise are each associated with increasing vagus nerve activity, one can consider whether enhanced activity in the cholinergic anti-inflammatory pathway might decrease cytokine production and reduce the damage and metabolic derangements mediated by chronic, low-grade systemic inflammation that is characteristic of the metabolic syndrome

His conclusion:-

“It is bemusing to think that one of the fundamental premises of the ancient Greeks was that dietary manipulation controlled humoral balances. This concept is now, at least in principle, supported by new evidence of a direct link between dietary composition and the regulation of cytokines by the cholinergic anti-inflammatory pathway. Modern clinical studies have advocated supplementing diet with fish oil, soy oil, olive oil, and other fats to significantly increase vagus nerve activity, reduce inflammatory markers, and improve disease severity in inflammatory bowel disease, rheumatoid arthritis, and cardiovascular disease. These clinical anti-inflammatory responses may be linked to the fat-induced stimulation of the cholinergic anti-inflammatory pathway, as is the case in rats. And now it appears that a major source of systemic TNF during lethal challenges is the spleen, the source of Galen’s black bile. One can’t help but wonder: How did the ancient Greeks know?”

 

Anti-inflammatory activities of vagus nerve stimulation

The discovery by Tracey that vagus nerve stimulation inhibits inflammation by suppressing pro-inflammatory cytokine production has led to significant interest in the potential to use this approach for treating inflammatory diseases ranging from arthritis to colitis, ischemia, myocardial infarction, and congestive heart failure. Action potentials transmitted in the vagus nerve activate the efferent arm of the Inflammatory Reflex, the neural circuit that converges on the spleen to inhibit the production of TNF and other pro-inflammatory cytokines by macrophages there. This efferent arc is also known as the Cholinergic anti-inflammatory pathway Because this strategy targets the release of TNF and other pro-inflammatory cytokines, it may be possible to use vagus nerve stimulation instead of anti-inflammatory antibodies (e.g., Remicade or Enbrel) to treat inflammation. SetPoint Medical, Inc. is an early-stage medical device company, set up by Tracey, developing an implantable  neurostimulation platform for the treatment of inflammatory diseases.

Remicade and Enbrel are ultra-expensive drugs, costing about $20,000 per year.  Not surprisingly, some US autism doctors are wondering what they would do in autism.

My Conclusion

I was wondering if Kevin Tracey might be related to Jeff Tracy, in which case, can Brains please make Monty, aged 10 with ASD,  a vagus nerve stimulation device, preferably with a built-in nuclear power pack.  (I refer to a cult British TV series from the 1960s called Thunderbirds, a favourite of both Monty and his big brother, Ted.)  

 

 

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.