PolyPill Updated with Agmatine

After several months of testing Agmatine, including stopping and then re-starting, it is time to add it to my PolyPill.

The idea to trial Agmatine came from our reader Tyler. It ticks all the boxes, it really does have a benefit; that benefit continues for at least several months. When you stop taking it, the benefit stops and when you restart you see the same benefit return. It is safe, inexpensive and widely available if you live anywhere outside the EU. Since it is relatively recent to the market as a supplement, it can no longer be sold in the EU until someone applies for it to be approved; long established supplements bypass this recent legislation.

There were earlier posts evaluating why it might help some types of autism and now there even is one study on an animal model of autism. 

Hypoperfusion in Autism Revisited 

Nitric Oxide (NO), Arginase and Endothelial Dysfunction in Autism 

Agmatine - a Magic Bullet inClinical Neuroscience? 

Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism.  

I think the positive effect very likely comes from the vasodilatory effect produced by the increased eNOS, there is also increased BDNF.  This I believe is why it also effective in two models of dementia. Agmatine is also an NMDAR antagonist, like Memantine and this is the mode of action proposed by autism researchers in the animal model above.  My opinion is that at this "bodybuilder's" dose the mode of action is not NMDAR antagonism.

Effects of agmatine on cognitive functions during vascular dementia in biological aging through eNOS and BDNF expression 

Nitric oxide mediates agmatine-induced improvements in memory 

Agmatine improves cognitive dysfunction and prevents cell death in a streptozotocin-induced Alzheimer rat model. 

The effect of Agmatine?

The energetic bunny on the left is the one taking 0.7g a day of Agmatine.

In the case of Monty, aged 14 with ASD, Agmatine gives him boundless energy, which in his case is beneficial.

I think the effect will manifest itself slightly differently in different people. In animal models it improves cognitive function.  

If you have autism + ADHD, then it might not be helpful. When I tried it on myself it made me feel slightly nauseous. In Monty's big brother it made him feel "different", but not better or worse and certainly not more energetic.

Other People’s PolyPills

Other readers of this blog have developed their own science-based “Polypill” therapies, for their specific type of autism. What works for my son may not help your child, but other  things discussed in this blog just might help.

High doses of the immuno-modulating Biogaia Gastrus probiotic bacteria clearly help some people greatly; but others get a negative reaction.

Immunomodulation by antibiotic is used successfully by some, but has some drawbacks. 

PAK1 inhibition ticks the science boxes and if you can obtain a potent PAK1 inhibitor it helps some people.

Butyric acid (from sodium butyrate, Miyairi 588 bacteria, more fiber or even rancid butter) is an HDAC inhibitor and is also required for gut wall integrity and likely BBB integrity. It is widely used in animal feed and some humans respond well to it, but the effect is dose dependent. HDAC inhibition can work epigenetically to change the expression of hundreds of "autism" genes, as highlighted in recent research using a potent cancer drug HDAC inhibitor.

Numerous individual amino acids (glutamine, taurine, methionine, aspartic acid etc) seem to help in some people. These tend to be OTC bulk powders like Agmatine.

In a sub-group of people with autism it is clear that digestive issues, unusual gut bacteria or food sensitivity is a major problem that is treatable relatively easily.

People with regressive autism may have (had) mitochondrial disease and this has a very specific therapy to protect from further regression and to allow for remyelination and mitochondrial biogenesis in the short term and hope for neurogenesis in the long term.

The Autism PolyPill 5 years on from December 2012

2^nd WOW!

Still autistic, but less so, and no longer cognitively challenged.

It is exactly five years since Monty, now aged 14 started his Polypill therapy. At first it was just bumetanide, but shortly thereafter NAC and atorvastatin were added, more followed later.  All without any side effects.

I received Monty’s end of term school report just before Christmas and it bears little resemblance to what he received back in 2012. Now it does not look like the report of someone who is cognitively challenged. Almost all the grades are As; these are his best ever results and unlike 5 years ago, these are the same tests as taken by his NT peers, not an easy version. 

At the beginning of this first year in high school, there was a view that Monty should not be there, that he would fail to cope and later have to leave; he has proved otherwise.  None of this was malicious; it was just that the head of the high school used to teach in the junior school and has known Monty since he was four years old. Back then, and until he was nine years old, he was seriously challenged, academically. The post-Polypill Monty came as a big surprise, he is still autistic, but now academically functional.  He is now never disruptive and behaves like an attentive model student, just one that does not talk much.

Monty’s assistant recently asked me why, since some doctors do read this blog and apply it, don’t more doctors now treat their kids with autism? She mentioned a top local neurosurgeon who has twins with severe autism; why isn’t he treating his own kids? If you can do it, why can’t he? My answer was that a neurosurgeon is not a neuroscientist.   His job is quite primitive; he drills holes in people’s skulls and pokes around for visible defects in the brain. Treating autism is about tweaking tiny things like ion channels that you cannot even see. Being a neurosurgeon does not really help much, unless you read the neuroscience literature, which he likely does not.  

Wow Moments

I do like “Wow moments”. They do not come very often, the last one was four years ago when I first saw a little yellow pill (Verapamil) make an extended episode of self-injury, melt away in front of my eyes. That was like winning the Lottery and this therapy continues to have the same effect.

A “Wow moment” occurred in late December when I opened the end of term report, of Monty’s NT big brother, who attends the same school.  Monty’s grades are better. Yes, Monty is in year 7 and big brother is in year 13, his final year of school. You should not compare one sibling with another sibling, but nobody would have dreamt that a boy with classic autism would ever outshine his intelligent NT brother academically, under any circumstances. I think that deserves a “Wow”. Even big brother was impressed by little brother.

Nowadays an autism diagnosis usually is not associated with MR/ID; it is much more likely to be better described as a variant of Asperger’s. If you have Asperger’s there is no reason you should not aim for College/University. Unfortunately that is not Monty’s case, he has strictly defined autism (SDA), meaning more severe biological dysfunctions and his school reports from 5 years ago reflected that. He could not function academically; school was more for “socialization”.  People with SDA usually do not make it past the basics of school academically.  Where we live, autism = SDA and severe autism means something extremely challenging, so I find it very strange to read comments on the internet written by people claiming to have severe autism themselves.

One medical researcher recently asked me how effective is sodium benzoate (NaB) proving as a cognitive enhancer. All I could say was the current level of academic performance is shocking everyone. We had teachers thinking the assistants were boosting his test performance, so we all agreed to be super careful not to give help during tests. So now they are 100% his work, before I think it was 90% his work with some “hinting”.  I cannot say with certainty whether NaB helps or not. I stopped for a week over Christmas, and I concluded that there may well be a difference.

The extreme case of “hinting” is so-called facilitated communication, when the assistant ends up doing 90% of the work. The result is an illusion of what you would like to think the child is capable of, rather than reality. We do not need any of that.

There are also prompting methods like RPM, but at the end of the day what matters is what the child can eventually achieve entirely unaided. It does not matter if they type their work, or handwrite it.

Is the OAT3 inhibitor helping? For the last few weeks I have used coffee flavanols to boost the pharmacodynamics of bumetanide (by delaying its excretion). 

There are still plenty of ideas I have not yet implemented (RORα, PDE4 etc.) but the current PolyPill has delivered results far beyond my expectations. I do not think it is realistic to go from strictly defined autism (SDA) to entirely NT. The target I mentioned long ago was to go from SDA to something like Asperger’s. Monty is never going to be quite like his older brother, but after 5 years he now evidently has a typical level of IQ, and most importantly he can apply it at school and in daily life.

This Christmas Monty made his way through the self-scanning passport control at the airport and when randomly selected for the whole body scanning machine, he coped without incident.  Air travel is now a highlight of a trip and the more turbulence the better.

Now to the next five years.

The open question is whether Monty can obtain formal educational qualifications. In the English system there are externally assessed exams at age 16 (year 11) and at age 18 (year 13). Monty’s class group are two years his junior, so he will be 18 at the year 11 assessment. Years ago our piano teacher, who only teaches people with special needs, was pretty blunt about the fact that none of her kids leave school with formal qualifications, except sometimes in music. 

The situation varies greatly depending on where you live.  In the US things are very different and if you have an IEP (Individualized Education Program) and attend high school, you automatically seem to “graduate” high school with some kind of diploma. Many people with an IEP in the US do not have severe learning disabilities and they graduate with the standard diploma.

Monty has never had an IEP because he does not go to a school that offers them. In effect he has had a very customized education program for more than a decade, just it was run from home.

Time to update the Autism Polypill?

It has been a long time since I added anything new to my autism Polypill. This is the combination of therapies that consistently, and materially reduce the symptoms of autism in Monty, now aged 13 with ASD.

As regular readers will be aware, due to the heterogeneous nature of autism, what works wonders for one person with autism may be totally ineffective, or even make matters worse, in another person with a different type of autism.

However, once you have found one therapy that is effective you have an opportunity to identify the underlying biological dysfunction that you have stumbled upon, without the need for any fancy genetic or metabolic testing.  Then you can look for other therapies for that dysfunction and other people who fall into that sub-group of autism and see what else works for them.

I am surprised how many people do respond to some of the therapies I am highlighting in this blog. 

Time to update?

I had been expecting to add the Biogaia Protectis probiotic bacteria to the Polypill.  It does indeed work in Monty and in other readers, but prolonged use does have a problem, at least in some people.  The behavioral effects fade and, in our case, it switches from suppressing allergy to promoting allergy.

The person who originally told us about Biogaia for autism uses the more potent Biogaia Gastrus, which contains the Protectis bacteria and a second one.  She uses a high dosage and uses it three weeks on and one week off.

Like some other readers found, Monty had an immediate negative reaction to the second bacteria in Biogaia Gastrus.  We are users of Biogaia Protectis, but not every day.

A long time ago I proposed the flavonoid Tangeritin/Sytrinol as a safe PPAR gamma agonist that is also a P2Y2 receptor antagonist. Research studies have shown that the flavonoids Tangeritin and kaempferol are antagonists at P2Y2 receptors and may be of interest as potential anti-inflammatory drugs.  Robert Naviaux, from the University of California at San Diego, believes that antipurinergic therapy is a key potential strategy to treat autism and also chronic fatigue syndrome and fibromyalgia.

The broccoli sprout powder already in the Polypill is a rich source of kaempferol.

Tangeritin/Sytrinol has been shown to have sufficient bioavailability to reduce the level of cholesterol in people with high cholesterol.   

KBr

The most likely contender to enter the Polypill for everyday use is potassium bromide (KBr), it does seem to tick all the boxes. 

·        It works

·        It continues to work after longer term use

·        Mode of action is understood

·        Safety record is very well understood

·        Effective at a low dosage

·        Not expensive, about 30 cents a day.  Much less if you use bulk KBr.

KBr should be effective in people who respond to bumetanide, since they both reduce intra-cellular chloride levels, but by different mechanisms.

In people who stop responding to bumetanide, I think KBr might be a good choice.  In responders to bumetanide, increasing inflammation due to an unrelated condition, may further reduce the expression of the KCC2 transporter that lets chloride exit neurons. So the inflammation increases the level of intracellular chloride and wipes out the benefit that was being produced by the bumetanide.  The effect of the KBr will be to reduce chloride again, this time by substitution with the relatively inert bromide.

It is also possible that some people with severe autism do not respond to bumetanide because their chloride level is so high that bumetanide is not sufficiently potent.  In those people the additive effect of KBr might just tip the balance.

In some countries bumetanide tablets include potassium chloride (KCl) to compensate for potassium lost in diuresis.  The cleverer thing in autism would be to add KBr, since you benefit from the K⁺ and the Br^-.

Due to the very long half-life, you need to take a low dosage of KBr for 4 to 6 weeks until you reach the peak level of Br^- in your body.  Only then can you judge whether you are a responder or not. 

What I am considering the autism dose (8mg/Kg) is far lower than the dose used for intractable pediatric epilepsy (30-50mg/Kg), specifically to avoid the known side effects.  The main side effect at high doses is bromo-acne. Children with intractable epilepsy opt for some facial spots over seizures.

Quite possibly a higher KBr dosage would be even more effective in autism, but then you will for sure be dealing with bromo-acne.

Summertime Add-ons

One conclusion from the gene studies is that often in autism and schizophrenia there are variances in the genes linked to the immune system. So the immune–related therapies that help Monty a great deal during spring and summer may indeed be applicable to a substantial sub-group of autism. For others they are likely to be ineffective.

I am hopeful of yet another step forward this summer using the amino acid L-histidine.  Histidine is very closely related to histamine and you might think that would be the last thing that could help in those prone to allergy-driven autism flare-ups.  However in an earlier post we saw that there is a paradoxical effect when raising the level of histidine, inhibits the release of histamine from mast cells.  We also saw that histidine has an inhibitory effect on mTOR, one of the suggested common core autism pathways that was highlighted yet again in the gene studies.

L-histidine, is an essential amino acid that is not synthesized in humans.  You have to eat it.

Longitude, Latitude & Epilepsy in Autism

It is not always easy to decide which subjects to study, never mind if you have autism.

For Monty, aged 12 with autism, it has been me choosing what he studies.  At the beginning it was rather overwhelming for his 1:1 assistant, because there was so much to learn and never enough time.  It takes years to learn very simple things that typical kids just pick up naturally.

One big change after three and half years of Polypill use, is that Monty follows the standard academic curriculum, albeit for kids two years his junior.

An excellent but not very user friendly curriculum/skill list is in a book called ABLLS (assessment of basic language and learning skills).  It is both a curriculum and an assessment tool.  It covers all the very basic skills that kids need as a foundation for future learning.

We were working from this list of simple skills for four years, until the age of eight.  These are skills most kids effortlessly pick up in the first three or four years of life.

After you have mastered those simple skills what do you teach next to someone with classic autism?

I did my research and concluded the generally accepted answer is “not much”.

One phrase I still recall was a mother writing “our kids don’t need to learn longitude and latitude”, because this is going to go way over their heads.

It seems that for kids entirely non-verbal at three, about 10% have some maturational dysfunction that self-corrects by six, leaving just minor tics or perhaps mild "quirky" autism. Most of the remaining 90% end up "graduating" high school with an academic level of a four to seven year old.  A small number do better.  

A few years after ABLLS and Monty has mastered X,Y coordinates, even using negative numbers and identifying objects using Northwest, Southeast etc.

Regular readers will be aware that Monty’s recent academic development did not happen spontaneously, nor through ABA, it came from pharmacotherapy (drugs) and is reversible (hopefully not entirely).

Burden of proof

In spite of all this change it would be hard to prove what has caused it. Fortunately I do not need to.

Monty is still autistic, just less so and is now educable. That is a really big deal to me, but not to others. 

If you could convert 100% of kids with autism into outgoing, talkative, social, intelligent, typical kids then people would take note.  No therapy will ever deliver this. Just to confuse the issue, 10% will indeed "recover" without any intervention at all, which then is used to justify all kinds of interventions that those people used.

Have I measured Monty’s IQ?  No I have not.  A lady from California asked me why not, because over there they have excellent autism services, even assisted employment and sheltered housing but it is rationed based on things including IQ. 

One doctor reader of this blog suggested that some of the drug interventions in this blog will also reduce the development of seizures and therefore reduce the rate of premature death in autism; “surely we should tell people about this”.  I had a sense of déjà vu.

It is clear that in treating the excitatory/inhibitory imbalance that underlies much autism and also treating other channelopathies, you should also be avoiding some of the neuronal hyper-excitability that is epilepsy.

So treating autism should reduce death from seizures that reduce life expectancy in severe autism to just 40 years old.

This is all true and a year or so back I did suggest this to the Bumetanide researchers.  There was little interest and some skepticism. 

In fact there is a great deal of epilepsy research and some does indeed overlap with autism research.  One key area is Cation Chloride Cotransporters (CCCs), where the same type of immature neurons found in autism are found in epilepsy. Another is elevated BDNF (brain-derived neurotropic factor); in epilepsy, seizures trigger an increase in BDNF which then reduces expression of KCC2 which then shifts neurons further towards immature (high intra-cellular chloride) worsening the excitatory/inhibitory imbalance and making the next seizure more likely.  A clever idea we can borrow from the under-utilized epilepsy research is to consider blocking BDNF, or trkB, as a means of increasing KCC2 expression.  This could be a useful adjunct therapy to bumetanide, which blocks NKCC1. We want less NKCC1 but more KCC2, to give lower levels of chloride inside the cells and then neurons can fire when they are supposed to.

It takes decades for research findings, like those in the above paragraph, to be translated across into therapies.

If you, or particularly a researcher, make a statement that is controversial and not backed by a big stack of evidence (based on human trials, not mouse trials) nobody is going to believe you.  Worse still, the next time you make a claim, they will be even less likely to believe you.

So better under-promise but over deliver.  Start finally treating some autism and then watch in the next thirty years that epilepsy incidence falls and along with it SUDEP (Sudden Unexpected Death in Epilepsy).  Then you can say “I told you so, it was those Cation Chloride Cotransporter after all ”.

In spite of all the “evidence” that some autism is treatable, cognitive dysfunction is reversible, the world has not taken any notice.  Where is the undisputed concrete proof?  I just have to think “longitude and latitude”, that’s my proof.

So in reality while avoiding epilepsy should be a big deal for the parents, it is not for anyone else.  The current wisdom is keep your fingers crossed and hope that you are not in the one third that will develop epilepsy around puberty.  In some people this triggers an epigenetic change, opening the way to many future seizures.  For those who are interested:-

          Epigenetics and Epilepsy

If you follow 100 kids with autism on bumetanide for 10 years and found 5 developed seizures that would not be regarded as proof.

Based on my reading of the literature, you would expect 30+% of people with classic autism to develop epilepsy.  So if they had just 5 cases, I would see that as vindication, but it would not be seen as conclusive proof by others, just another paper to file and forget.

So the idea of prophylactic drug treatment to avoid the onset of epilepsy in autism is unlikely to catch on and is easy to rubbish.

Just like prophylactic use of drugs to avoid dementia, avoid type 2 diabetes or avoid the nasty side effects of type 1 diabetes, they will not enter the mainstream.

Conclusion

Setting low standards and targets will guarantee poor outcomes.  Aim to learn longitude and latitude, but it might be easier with a daily dose of bumetanide.

Some epilepsy is avoidable, some may not be, but if treating autism can also reduce the chance of epilepsy and SUDEP do you really need to wait for absolute evidence?

It is currently a matter of geography and google competence who is going to access effective pharmacotherapy.  For a change it is the poorer countries who have the advantage, since they have less rigid control over access to prescription medication.

I was just reading that the excellent New England Center for Children (NECC) charges up to $300,000 a year to educate kids with autism.  It is a great school and we employed a former teacher from there a few years ago, to help with our home program.  With something like 0.3% of all kids having serious autism, there needs to be a less expensive solution available to all.  

Spending $300,000 at NECC will almost definitely have a positive impact on one severely autistic child for one year.  Alternatively, for the same money, you could treat 480 kids with strict definition autism with my Polypill for one year.  It looks like around a half would respond very well.  Ideally you would spend $300,620 and have both the NECC and the Polypill; this is pretty much what was my target, but without leaving home.

 

Autism PolyPill vs Personalized Medicine and the KD/MAD diet

The idea behind personalized medicine is the realization that humans are all slightly different and that some of the diseases they suffer, like autism, are also all slightly different.  In order to treat them optimally, you would need to use drugs and dosages customized to each person.

Here below are three slides used to illustrate Personalized Medicine in cancer care.  Instead of treating “cancer”, four sub-types are identified and then treated using four different drugs.  Each person only receiving the effective drug.

Source: http://scitechconnect.elsevier.com/personalized-cancer-medicine-will-time-now/

Autism is not cancer, but understanding cancer gives you a much better concept of what can underlie a highly complex disease like autism.  You need to consider multiple hits as in cancer, which is very similar to Russian Roulette.

The thing that does not seem to exist in cancer is the "double tap", when in a minority of cases, a moderate case sudden changes to a severe case.  This is caused by a new factor coming into play, or an existing factor that had been dormant. In cancer, metastasis is a progression of the existing condition, not something unrelated.  

In the above case there were just for four types of cancer and all you have to so is to find the molecular biomarker for each one.  Then you treat each person with the appropriate drug and avoid side effects from the wrong drugs.

Autism is much more complex because it has "layers" and these may change over time. You have to treat the outer layer first.  This explains why some effective autism treatments appear to "stop working".  Something else has started to work and now forms the outer layer.  This could be related to mast cells, mitochondrial dysfunction or probably a whole host of other factors.

The autism equivalent graphic above, would have people in multiple colours as if dressed.  Just as people change the colour of their clothes, some of the colours of each figure might vary over time and this is what really complicates things.

People with oxidative stress might be represented by having blue socks, reductive stress red socks and "no" stress black socks. There would be lots of blue socks and very few of red or black socks.

NAC for those with blue socks.

PolyPill

So my idea of a PolyPill arose from the idea that when a non-verbal three year old with some odd behaviors goes to his doctor, he might not come home empty handed, and not with those wholly inappropriate psychiatric drugs.  The PolyPill might contain some ingredients that were not necessary, but it would show that a single pill could produce marked improvements in the majority of cases.  All without any complicated and expensive genetic or metabolic testing.

Since I only treat one person, my PolyPill is really a perfect example of personalized medicine.  As time passes, it becomes even more tailor-made.

Monty’s big brother did recently ask why don’t you actually make the PolyPill?  Good question. I did look into this in some detail and even gave a presentation to the European drug regulator (EMA).  There are enormous barriers, few of which relate to developing the drug itself.

If I was James Simons (of the Simons Foundation) that is exactly what I would do, make a PolyPill that could help hundreds of thousands of people.  But unless I receive a call from them, I’ll be sticking with a personalized medicine called Monty’s PolyPill.

The huge advantage of Personalized Medicine is that it minimizes the number of drugs and quasi-drugs that you give.  Let's not pretend that nutraceuticals and OTC supplements are not drugs. This is a concern raised on this blog, just how many ingredients can you (safely) have?  

It certainly can be a bother dispensing them.  Your typical multivitamin contains 14+ ingredients, who would give their child 14 pills at breakfast?  Almost nobody.  But a single little multivitamin pill is just fine. Do they even need all 14?  Unlikely.



So, how many drugs can a PolyPill have?

That was Agnieszka's point in a recent comment.  Things do interact and this does include supplements as well as drugs.  It can be time consuming preparing all these ingredients, not to mention having to swallow them.

This is why someone took Dr Kelley's mitochondrial therapy and packaged it up and sell it as a single product, Mitospectra.




DAN! and Diets over Time

Another vaguely related issue is what happens to autism therapies over time.

It is clear that while allergies may moderate over time and hormonal changes have secondary effects, the core dysfunctions in autism are likely to be permanent.  You can treat them, but you probably cannot cure them.  None of my therapies seem to be disease changing.

So what happens to the thousands of kids, mainly in the US, who follow DAN therapies and diets?  This was raised recently on a popular autism blog and the conclusion was that, after a few years, the great majority of people give up.

This is rather sad.  It shows that the majority of those therapies had no significant effect on the majority of people that tried them, otherwise they would not have given up.

An example being the blog author, with one of those children who had a "second tap", that shifted him to the very severe kind of autism.  This became a new "outer layer", in Peter-speak.  What if that second tap was due to mitochondrial dysfunction (as appears to be relatively common)?  If that was the case, it is not surprising that the gluten free diet did not help, nor  HBOT etc.  Surprisingly, there actually is a diet that might have helped.  No, not the GAPS diet, but the Ketogenic Diet (KD); more a medical therapy than a diet, so well worth reading about.

I was surprised how much evidence there is that indicates that the Ketogenic Diet (and hence likely also the Modified Atkins Diet, MAD) MIGHT  help those with mitochondrial disease. There is no reason to think unrelated diets would do any good whatsoever.

In some cases the Ketogenic Diet can have disease changing effects, meaning you do not need to stay on it for life.  Many people transfer to the MAD.

So if you have a case of severe autism, resulting from a second tap, or a late regression, and nothing covered in this blog seems to help, test for mitochondrial disease.  

If Dr Kelley's therapies reverse the decline, but progress is painfully slow thereafter, it could be worth trying the KD or MAD.

Verapamil, Autism, Summertime Allergy, Asthma and Eczema

As the symptoms get stronger, so does the therapy, 

going up in steps from May to July/August and then down to October

Today’s post is a practical one.  There is an interesting scientific one in preparation all about applying the emerging science of gene silencers and enhancers. 

I discovered in previous years that the summertime raging exhibited by Monty, now aged 12 with ASD, could be prevented using a small dose of the L-type calcium channel blocker, Verapamil.  Verapamil is also a mast cell stabilizer and blocks potassium channels linked to some inflammatory response.

This summer the story has repeated itself.  As the amount of airborne allergens increases from spring to summer the same seemingly mild allergy symptoms return.  So in late spring there was some sneezing and by mid-summer some eczema (atopic dermatitis) behind the knees and finally a very mild amount of asthma (slight wheezing); all of which were easily treated.

This apparently mild allergy triggers a flare-up in autism that is anything but mild.  To treat that the “silver bullet”, so to speak, is Verapamil.  It has a short half-life and so after 3-4 hours, depending on the initial dose, the effect is lost.  So in the peak of the allergy season, 20 mg every 4 hours provides near guaranteed protection.  Skipping a dose, like first one in the morning, will almost guarantee a mood change to agitation and then extreme anger.  That mood reverses within a few minutes of treatment again with Verapamil.

In late spring and early summer the use of allergy treatments (Azelastine, plus quercetin) and verapamil twice a day keeps things all under control.  But once the first faint signs of asthma reappear, due to the growing allergy effect, the only way to maintain normalcy is to make more frequent use of small doses of verapamil.  Using more antioxidants (NAC) does not have any effect; the verapamil addresses a summertime need.

In a previous post I did mention that I tried verapamil on a winter-time flare-up, just to see.  It had no effect whatsoever.  That problem was traced back to losing milk teeth and was solved with some ibuprofen, which was later replaced with Sytrinol/Tangeretin, the PPAR gamma agonist.  

Some children with autism are treated long term with Ibuprofen, or other NSAIDs, on a daily basis.  I have no doubt that it can be effective in specific cases, but the known side effects made me look for a safe alternative, which turned out to be Sytrinol.  Sytrinol has exactly the same effect as Ibuprofen, for this kind of flare-up, with no apparent side effect. Sytrinol is not a painkiller.

Since the roots of the final four milk teeth take several months to melt away and all the time levels of the inflammatory cytokine IL-6 are raised, there will be recurring behavioral flare-ups in those with the kind of over-activated immune system common in autism.  It seems plausible that the PPAR gamma agonist is down regulating  the activated microglia and thus blunting the immune over-reaction.  Anyway it works, for whatever reason.

The mast cells, degranulating due to allergens, release histamine and IL-6, the histamine causes further subsequent release of IL-6. Verapamil blocks this process.  The IL-6 released by the body to signal teeth to dissolve clearly is not reduced by Verapamil. 

The amount of inflammatory cytokines (IL-6 etc) produced by allergy is logically over a different order of magnitude to that used to signal milk teeth to dissolve.  The effect of Sytrinol is perhaps too mild to sufficiently dampen the response to the IL-6.   Maybe it helps somewhat, but I really cannot say one way or the other.

There seems to be a good case for Sytrinol year round and then Verapamil as required.  When I next update my Polypill formulation, Sytrinol will be included.

I think Verapamil likely has beneficial pleiotropic effects and so, in those who well tolerate it, it might be useful year round.  A small number of people do experience side effects.

     

End of School Year

As another school year comes to an end it was time for Monty, aged 11 with ASD,’s end of year grades and the parent teacher meeting.  Monty attends a small mainstream international school with his own assistant.

This year is particularly interesting because we have the same class teacher, Miss B, this year that we had three years ago (prior to starting to develop Monty’s autism Polypill).  So if anyone can judge the impact, it should be her.

In the English system Year 4, is where you find 8-9 year old typical kids and equates to 3^rd grade in the US system.  Monty just finished Year 4.

After completing Year 3 first time round with Miss B three years ago, with a traumatic several months of aggression and cognitive and behavioral regression, we put Monty to start Year 2 again.  At the end of the first term in Year 2 (second time around) he started Bumetanide.

Year 1

Year 2

Year 3            Miss B

Year 2            (repeated)

Year 3            (repeated)

Year 4            Miss B again (current year now ending)

Year 5            Next school year starting Sep 2015

First time around with Miss B, Monty could not really follow any instruction from her and he was entirely dependent on his 1:1 assistant.  

At home, in the afternoons and holidays, he had learned to speak, read and write using ABA.  At school he was assessed on simple tasks like being able to change into his indoor shoes independently, or with prompting.  Academic assessment was all customized for him; no attempt was made to use the same assessments as his classmates.  Assessment was extremely basic, like adding one to a single figure number.

Some children are diagnosed very young with autism and by five years old things have changed so much that they have lost their diagnosis.  Monty is not one of those.  He was diagnosed at three and a half and continued to get more autistic.  Using PECS and ABA he gained basic speech.  With 40 hours a week of 1:1 assistance he learned to read and write, but we did not even try and teach numeracy.

We were following the standard trajectory of classic autism; no learning followed by (very) slow learning.

This distorted learning trajectory is one reason why I feel that Asperger's should remain entirely separate from classic autism; calling them both "autism" does justice to neither.  In Asperger's there is no language delay and no impaired cognitive function, resulting in quite different people, with very different issues.  I am beginning to feel that when you treat classic autism, as far as you can, the result will be something not dissimilar to Asperger's. What happens if you treat Asperger's?

After initiating pharmacological therapy, we now have had nearly three years of skill acquisition at a rate similar to a typical child, of average IQ.

So Monty finished Years 2, 3 and 4, had the same assessment as the NT classmates and is not at the bottom of the class of 12 kids, in any subject.  Monty is certainly not a “straight-As” student, like his big brother is; he is now more of a C student with some Bs.  But as I told his teacher Miss B, the great achievement is that we are even discussing the results of standard assessments at all.

Pleiotropic effects?

Sometimes drugs seem to have broader beneficial effects than intended, these get called pleiotropic effects.

It looks very likely that one or more elements in Monty’s Polypill have some pleiotropic effects, or some synergistic effects.  

There is a study showing the effect of ten months of Bumetanide treatment.

Improving emotional face perception in autism with diuretic bumetanide: A proof-of-concept behavioral and functional brain imaging pilot study

My feeling after 30 months of Bumetanide treatment is that it provides a critical step-change in cognitive function.  Following this one-time gain, things seemed to progress faster cognitively only when other elements were added.

The following papers on pleiotropic effects of drugs in the PolyPill do not refer to autism, but are interesting.eiotropic Effects

PLof

Pleiotropic effects of calcium channel blockers

PLEIOTROPIC EFFECTS OF STATINS

N-acetyl-cysteine pleiotropic effects

  

Future progress

As I told the teacher,Miss B, a good plan seems to be to just keep following the regular kids and keep going until the end of year assessment might put Monty at the bottom of the class.  Should that happen, we can just repeat that year again.

This is not the advice you will likely find anywhere else regarding educating a boy with classic autism in a mainstream classroom.  Indeed it is pretty clear that in mainstream schools “inclusion” just means a class within a class; so the child with autism and his assistant are doing one activity, while the class teacher and the other kids do something entirely different.