Updated Conceptual Map of Behavioural Homeostasis in Autism

Ten months ago I decided to invent my own, admittedly subjective, autism scale to map the progress of Monty, aged 10 with ASD; a lot has changed since then, so I decided to update it.

For background to the scale, read the earlier post.

Conceptual Map of Behavioural Homeostasis in Autism

 

 

 

The chart above is an update of the original; I added the bright yellow line to reflect events since April 2013 and a future prediction.  I decided that predicting more than three years is pointless.

The orange line shows that autism was very present from birth, with a second wave hitting causing more symptoms and then a nice shallow decline.  Aged 8 and half, emotional stress causes a huge regression and he enters into the world of SIB and aggression.  The situation is gradually recovered using exclusively an ABA approach.  The new homeostasis is at a higher plateau.  I expect some epigenetic change occurred.

At 17 December 2013, we switch to the red line; this is the point when he started taking Bumetanide (BU), courtesy of Ben-Ari and Lemmonier, and then we see a sharp step change in improvement.  This was followed shortly thereafter by another step down, following the start of NAC.  This takes us to April 2013.  Now we switch to the yellow line.

In April 2013, 10 months ago, I started to look for further help in the form of "agent X".  I gave myself a year to find it, but it came much faster; statin therapy had arrived.

Come summer, everything goes sharply into reverse, with a big spike in the yellow line back up into the danger zone.  The spike seems to have been caused by over-activation of the immune system caused by pollen, of all things.  Using mast cell stabilizers the situation was fully recovered.  There was no net loss (no epigenetic damage).

Then in January, the experimental Polypill takes shape and we see another sharp drop in the autism rating on the yellow line.

Now we are on the verge of “nerd cloud”, which separates kids with serious autism from the regular kids below it.  The top end of the cloud might be called high functioning autism and the lower part Asperger’s.  When I was a child this cloud existed, but people were just called odd or weird; in the US they were already called nerds.  In 1950 the word nerd was created by Dr Seuss, in his book, If I Ran the Zoo.

It is of course a pejorative term, but nowadays there are some very successful and wealthy nerds, so maybe it should not be.

Time will tell whether we can continue to descend through the nerd cloud.  What is going to happen in a few months when the pollen returns?  Will the Polypill be mightier than the re-activated immune system?  Perhaps mast cell stabilizers should be in the Polypill?

 
It is clear that more work is going to be needed and, perhaps, in addition to an Autism Polypill, there is a need for an Autism Toolkit.  The Toolkit is what you need when the Polypill stops working, and perhaps, before it can start working in some people.

 

Melatonin for Kids with Autism, and indeed their Parents

I have long heard about kids with autism having sleeping problems; these range from difficulty falling asleep, waking frequently during the night and waking up very early in the morning.  The same problems apparently occur in ADHD.

I think some of the sleep related problems are behavioral in nature; some children with ASD live actually with less structure than typical kids.  Some kids with ASD do not get much physical exercise to tire them out by bed time.  

Having said all that, there does seem to be something else going on.

Long ago people found out that Melatonin, a hormone available cheaply without prescription in many countries, had a very positive effect on sleeping patterns.

What is also interesting, is the other properties of Melatonin and the other types of people who can benefit from it.  This does take us some way from our core theme of autism, towards treating cancer and other illnesses of older age.  I expect most my readers are parents of a child with ASD, well this time science has some news for you too.

What is Melatonin?

Melatonin is a hormone secreted by the Pineal Gland in the brain. It helps regulate other hormones and maintains the body's internal clock. The circadian rhythm is an internal 24-hour clock, that plays a critical role in when we fall asleep and when we wake up. When it is dark, your body produces more melatonin; when it is light, the production of melatonin drops. Being exposed to bright lights in the evening or too little light during the day can disrupt the body’s normal melatonin cycles.

Melatonin helps control the timing and release of female reproductive hormones. Some researchers also believe that melatonin levels may be related to aging.

Young children have the highest levels of night time melatonin. Researchers believe these levels drop as we age. Some people think lower levels of melatonin may explain why some older adults have sleep problems.

Melatonin has powerful antioxidant effects. Research suggests that it may help strengthen the immune system.

Melatonin is derived from serotonin. Serotonin levels in autism are often high in the blood, but can be low in the brain.  Serotonin cannot cross the blood brain barrier.  The Pineal Gland is inside the brain, but outside the blood brain barrier.

 

Dose Response

One clever study tried to establish the dose at which Melatonin had an effect on sleep.  It is interesting that they found the dosage was not correlated to weight.  The vast majority of drugs are dosed on how big you are, and often trials assume this to be the case.

Melatonin for Sleep in Childrenwith Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes

Dose-response

All 24 children who completed study procedures obtained a satisfactory response (as defined above) to melatonin at doses between 1 mg and 6 mg. Seven children obtained a satisfactory response at 1 mg, 14 at 3 mg, and only 3 required 6 mg. The child’s age or weight was not associated with melatonin dose response. The mean age/weight (standard deviation) of children responding to 1 mg was 5.9 (1.9) years/26.4 (11.1) kg; and to 3 or 6 mg was 5.9 (2.3) years/25.4 (11.2) kg.

In effect you are treating a hormone deficiency, like any other.  Just as a small person may need more thyroid hormone than a very big person; the same appears to be true with Melatonin.

Much of the “specialist advice” from "doctors" on the web looks incorrect on this subject:-

Melatonin. This naturally occurring peptide released by the brain in response to the setting of the sun has some function in setting the circadian clock. It is available without prescription at most pharmacies and health food stores. Typically the dosage sizes sold are too large. Almost all of the published research on Melatonin is on doses of 1 mg or less, but the doses available on the shelves are either 3 or 6 mg. Nothing is gained by using doses greater than one milligram. Melatonin may not be effective the first night, so several nights' use may be necessary for effectiveness.

(this was advice for people with ADHD, which I regard as part of ASD)

 

Abnormal Melatonin Synthesis in ASD and in Parents

A surprising amount of work has been done looking at abnormalities in melatonin synthesis in both kids with ASD and their parents.  Hence the title of this post.

The low level of melatonin synthesis is acquired from one or more parent, who will probably also have a sleep disorder.  Not only that, but low melatonin is also linked to increased risk to some serious health conditions, more on that later. 

Abnormal Melatonin Synthesis in ASD

"In autism spectrum disorders (ASD), low melatonin levels have been reported by three independent groups,^13–15 but the underlying cause of this deficit and its relationship to susceptibility to ASD was unknown

the serotonin level was significantly higher in individuals with ASD (P=2×10⁻¹¹) and their parents (P=10⁻⁸) than in controls

 Our results confirm that low plasma melatonin concentration (half the mean of the control values) is a frequent trait in ASD patients, as observed in 65% of the patients tested, a proportion very similar (63%) to that previously reported by Tordjman et al.¹⁵ We show for the first time that abnormal melatonin levels are also present in the unaffected parents of ASD patients, suggesting a genetic origin. Indeed, the melatonin deficit observed in the patients was associated with low ASMT activity, suggesting that variations in the ASMT gene could be the cause of this deficit."

Effect of Hormone Supplementation on the Pineal Gland

If you start interfering with human hormones, you need to be aware of the possible consequences.  For example, a relatively common autism therapy in the US is to give thyroid hormones T4 and T3 to children who are not clinically hypothyroid.  Some parents report great improvements, but some comment that over time they have to increase the dosage.  This is because the feedback loops that control the thyroid gland are telling it to gradually shut down.  Over time, such a child might become entirely dependent on the T4/T3 tablets.

So, if you have a pineal gland that does not produce enough melatonin, what happens to it when you take supplements?  I do not think anyone can tell you with certainty.

There have been long term trials over a few years in sleep disorders.  When supplementation stops the sleep disorder returns.  Nothing bad was reported.

Natural release of melatonin is controlled by exposure to light and dark.  To what extent does this change when supplements are added?

To what extent to supplements interfere with other less well understood melatonin mechanisms?  

On balance, common sense would tell you to leave a fully functioning pineal gland well alone; but if you have an autistic child with a challenging sleep disorder, this would be suggest that the pineal gland needs some external help.  In an ideal world, your doctor would test the pineal gland function and check Melatonin levels were age appropriate.

Melatonin and Behaviours

Research in ADHD suggests that while Melatonin improves sleep disorders it does not improve behaviour.

Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. 

Abstract

OBJECTIVE:

To investigate the effect of melatonin treatment on sleep, behavior, cognition, and quality of life in children with attention-deficit/hyperactivity disorder (ADHD) and chronic sleep onset insomnia.

METHOD:

A total of 105 medication-free children, ages 6 to 12 years, with rigorously diagnosed ADHD and chronic sleep onset insomnia participated in a randomized, double-blind, placebo-controlled trial using 3 or 6 mg melatonin (depending on body weight), or placebo for 4 weeks. Primary outcome parameters were actigraphy-derived sleep onset, total time asleep, and salivary dim light melatonin onset.

RESULTS:

Sleep onset advanced by 26.9 +/- 47.8 minutes with melatonin and delayed by 10.5 +/- 37.4 minutes with placebo (p < .0001). There was an advance in dim light melatonin onset of 44.4 +/- 67.9 minutes in melatonin and a delay of 12.8 +/- 60.0 minutes in placebo (p < .0001). Total time asleep increased with melatonin (19.8 +/- 61.9 minutes) as compared to placebo (-13.6 +/- 50.6 minutes; p = .01). There was no significant effect on behavior, cognition, and quality of life, and significant adverse events did not occur.

CONCLUSION:

Melatonin advanced circadian rhythms of sleep-wake and endogenous melatonin and enhanced total time asleep in children with ADHD and chronic sleep onset insomnia; however, no effect was found on problem behavior, cognitive performance, or quality of life.

 

The studies in autism indicate a different story; behaviours do improve.  After a good night’s sleep, most people’s behaviour improves; it would be odd if it did not.

I think this is another case of ADHD disorders being of a different magnitude to disorders further along the autistic spectrum.  

For the impact in autism, it best to read the studies; here is an excerpt from Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes:-

“The behavioral outcome measures that showed change with melatonin (e.g., attention-deficit hyperactivity, withdrawn, affective problems, stereotyped behaviors, compulsive behaviors) resemble that of prior work. The literature emphasizes that the behavioral construct of hyperactivity is affected by sleep disturbance—this had been documented in ASD populations (Goldman et al 2009; Mayes and Calhoun 2009) as well as typically developing children treated for obstructive sleep apnea (Chervin et al 2006). Other behavioral parameters which have been associated with poor sleep in children with ASD include repetitive behavior, including compulsive behavior, and oppositional and aggressive behavior, anxiety, depression, and mood variability (Malow et al 2006; Goldman et al, 2009; Mayes and Calhoun 2009). In an intervention study of parent education, hyperactivity and restricted behaviors showed improvements with treatment (Reed 2009).”

Strangely, when it came to parental stress, they found less impact:-

“Parenting stress, as measured by the Difficult Child Subscale, improved with treatment. We did not find improvement in the PSI parent-related domains (Parental Distress or Parent-Child Dysfunctional Interaction) suggesting that parental stress in autism is multifactorial and may not be addressed with a single intervention.”

 

Why is Melatonin so good for the CNS (Central Nervous System)?

It appears that Melatonin does some very useful things

·        It is an antioxidant/free radical scavenger

·        It stimulates the production of the body’s other key antioxidants

·        It inhibits the production of pro-oxidative enzymes

·        Protects nuclear and mitochondrial DNA

Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system.

Abstract

This review briefly summarizes the multiple actions by which melatonin reduces the damaging effects of free radicals and reactive oxygen and nitrogen species. It is well documented that melatonin protects macromolecules from oxidative damage in all subcellular compartments. This is consistent with the protection by melatonin of lipids and proteins, as well as both nuclear and mitochondrial DNA. Melatonin achieves this widespread protection by means of its ubiquitous actions as a direct free radical scavenger and an indirect antioxidant. Thus, melatonin directly scavenges a variety of free radicals and reactive species including the hydroxyl radical, hydrogen peroxide, singlet oxygen, nitric oxide, peroxynitrite anion, and peroxynitrous acid. Furthermore, melatonin stimulates a number of antioxidative enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. Additionally, melatonin experimentally enhances intracellular glutathione (another important antioxidant) levels by stimulating the rate-limiting enzyme in its synthesis, gamma-glutamylcysteine synthase. Melatonin also inhibits the proxidative enzymes nitric oxide synthase and lipoxygenase. Finally, there is evidence that melatonin stabilizes cellular membranes, thereby probably helping them resist oxidative damage. Most recently, melatonin has been shown to increase the efficiency of the electron transport chain and, as a consequence, to reduce election leakage and the generation of free radicals. These multiple actions make melatonin a potentially useful agent in the treatment of neurological disorders that have oxidative damage as part of their etiological basis.

 

Why is Melatonin good for the Immune System?

It is known that Melatonin interacts with the immune system, but the mechanism is not fully understood yet.  As you see below, Melatonin is not just produced in the Brain, it is also sythesized by the immune system. 

A review of the multiple actions of melatonin on the immune system

Abstract

This review summarizes the numerous observations published in recent years which have shown that one of the most significant of melatonin's pleiotropic effects is the regulation of the immune system. The overview summarizes the immune effects of pinealectomy and the association between rhythmic melatonin production and adjustments in the immune system as markers of melatonin's immunomodulatory actions. The effects of both in vivo and in vitromelatonin administration on non-specific, humoral, and cellular immune responses as well as on cellular proliferation and immune mediator production are presented. One of the main features that distinguishes melatonin from the classical hormones is its synthesis by a number of non-endocrine extrapineal organs, including the immune system. Herein, we summarize the presence of immune system-synthesized melatonin, its direct immunomodulatory effects on cytokine production, and its masking effects on exogenous melatonin action. The mechanisms of action of melatonin in the immune system are also discussed, focusing attention on the presence of membrane and nuclear receptors and the characterization of several physiological roles mediated by some receptor analogs in immune cells. The review focuses on melatonin's actions in several immune pathologies including infection, inflammation, and autoimmunity together with the relation between melatonin, immunity, and cancer.

 

Anti-aging Treatment

There are all sorts of products and therapies put forward to an eager public to combat the aging process; melatonin is one of these products.   I think, in this case, they may very well have got is right.  Yet again, a drug for older people seems to be effective for kids with ASD. 

In anti-aging, one well known practitioner, Dr Pierpaoli, recommends:-

30-39 years of age             1.5mg at bedtime

40-49 years of age             1.5mg to 3mg at bedtime

50-74 years of age             3mg at bedtime

Above 75 years                   3mg to 6mg at bedtime

 

Other use of Melatonin, related to subjects covered in this blog

Melatonin appears to help in Alzheimer’s by interfering with Amyloid beta, which was covered in an earlier post.

Amyloids, APP, ADAM17 and Autism

Melatonin appears to reduce symptoms in irritable bowel symptom.

Melatonin has been used to treat cluster headaches.

Information for Parents

We have seen earlier in this post that parents of a child with ASD also tend to have a low level of Melatonin.  If you read the layperson’s guide from the University of Maryland, you will see that a low Melatonin level in women is linked to increased risk of breast cancer and in men an increased risk of prostate cancer. 

“Studies show that men with prostate cancer have lower melatonin levels than men without the disease. In test tube studies, melatonin blocks the growth of prostate cancer cells.”

“Laboratory experiments have found that low levels of melatonin stimulate the growth of certain types of breast cancer cells, while adding melatonin to these cells slows their growth”

Since Melatonin is a powerful antioxidant, this may just mean that breast cancer and prostate cancer are linked to oxidative stress and so Melatonin is being used up; but it might also mean that Melatonin is somehow protective.

I read a long time ago that NAC improves outcomes in breast cancer and I expect it does on other types of cancer.

I already take NAC daily, I should probably take some Melatonin as well.  And you?

Conclusion

Melatonin would seem a good candidate for a drug that can make small positive improvements in autism.  Based on an earlier post, it is under consideration for the yellow side of the Polypill.

 

Note that Melatonin has to be given just before bed time.

Note that Melatonin interacts with some drugs used in autism and ADHD.

 

 

Increasing Good Behaviors and Reducing Bad Behaviors in Autism

This blog is all about clever chemicals that can make life better for people with autism, but for several years I have also been learning all about behavioral therapy to achieve the same goal.  So I thought I should look for any lessons that I might apply from my earlier endeavours.  

Two of the best books in my ABA collection, based on feedback from all of our Assistants/Therapists/Friends are the oldest, and indeed the lightest.  They are more than 30 years old, as you might imagine from the front cover, which is a big turn off for many parents.

They are great books, that tell you what you actually want to know: how to get rid of horrible behaviours and how to encourage nice ones.

Dr Foxx is still going strong and won the 2013 Award for Distinguished Professional Contributions to Applied Research from the American Psychological Association. Foxx is a professor of psychology at Pennsylvania State Harrisburg and an adjunct professor of pediatrics at the Pennsylvania State University College of Medicine.

The thing I always found odd was why Dr. Foxx wrote two separate books, surely it is all the same subject matter.  He had his reasons.

Here is my parallel with my quest to develop a smart combination of safe drugs to help in autism. 

So far, most of what I have been doing is focused on decreasing the bad behaviors, so the blue part of the pill; the remaining work is find to ways to promote the good behaviors, the yellow part of the pill.

This might actually be more relevant that you realize.  While it is clear that bad behaviors in autism vary widely in both type and extent, desirable good behaviors should have much more in common.  We know that many individual drugs on the "blue side" are effective only in a minority of people, but perhaps there will be much more commonality on the "yellow side".  I expect this to be the case.

So my Polypill is taking colour, as well as shape.

Another good piece of news is that I found a precedent for orphan drug designation in classic autism.  It appears that in 1998 the FDA awarded orphan drug status to Naltrexone to treat childhood autism with SIB.  In the US, orphan drug status is only possible for rare diseases affecting less than 200,000 people.  There are other cases of orphan drugs in autism, but they are for rare genetic variants. Currently the FDA website for orphan drugs does not list Autism for Naltrexone.

Also, an interesting Australian drug NNZ-2566,  mentioned in a previous post, has recently been given orphan drug status in the US, this time based on Fragile X designation.  The drug is an analogue of IGF-1 and looks interesting to me.

If you want to see what orphan drug designation in the EU means, here is what Novartis received for its new Fragile X treatment, Mavoglurant.

Orphan drug status reduces the cost of approving a drug.  But how rare is classic autism, these days?

 

PolyPill for Autism - Part 2

In an earlier post I referred to polypills for autism. 

Polypill for Autism

These are one-size-fits-all pills that contain multiple drugs.  In theory they should be cheap and make it more likely that patients takes their medications.  It has been shown that the more pills you are on, the less likely it is you are to take them all.

The most popular application is heart disease, where the combination of a handful of drugs would extend many people's lives by several years.

In the UK such a pill has been launched and is, remarkably, available on-line.  It contains drugs that each have existing licences; but this polypill, as a combination, has not yet been licensed. 

Here is an except from PharmaTimes:-

The pill's four component medicines - the cholesterol buster simvastatin and blood pressure lowerers bendroflumethiazide, losartan and amlodipine - have each been licensed for individual use in the UK for many years, but the combination has not been cleared by any regulatory processes. 

This is because to obtain official approval through normal channels for the polypill as a preventative medicine is extremely complicated and "would take years and years", a spokesman for the programme told PharmaTimes UK News.

"You need randomised trials that demonstrate efficacy and safety for each component and in combination. It’s so difficult that for practical purposes it’s impossible,” Polypill patent owner Professor Sir Nicholas Wald, from the Wolfson Institute of Preventive Medicine at Queen Mary University of London, told the Financial Times.

However, the spokesperson confirmed to PharmaTimes that regulatory approval for the single pill is still being sought, "but we wanted to provide people with access to it in the meantime", he said. 

It is perfectly legal to sell the polypill because doctors are allowed to prescribe unlicensed drugs "off-label" where appropriate.

The unusual thing is that you get your consultation with a doctor on-line and for free.  Given how parents with kids with ASD struggle to access prescription medications for "off label" use, I found this interesting.
 
Here is the site:-

https://www.polypill.com/   

So when I finish my investigation into autism, in a few months time, maybe I will after all create the Peter Autism PollyPill, which will be a combination  of licensed drugs for "off label" application. 





 

Polypill for Autism

A polypill is a pill that contains multiple pharmaceutical ingredients.  The idea is that for common conditions, like cardiovascular (heart) disease, a very cheap one-size-fits-all pill would actually bring great health benefits.  Many people in rich countries do not bother to take multiple pills and in poor countries most people cannot afford them, or cannot afford to visit the doctor more than once.

In the case of heart disease, it was shown that such a pill would cost about 10 cents and would be highly effective and extend people's live by several years.  Perhaps the Penny Pill might be another name for it.

 Polypill helps people stick to heart disease prevention regimens

Polypill for Autism

The main problem with autism is that 90+% of doctors are not even trying to treat it and are unaware of even the limited knowledge that does exist, to diagnose and treat sub-types (eg Landau-Kleffner syndrome).

So it would be clever to develop a one-size-fits-all pill and even if one or two of the ingredients were ineffective in a particular patient, overall there would be a big benefit.  I was then thinking what I would put in the Peter Polypill.

The Theoharides Polypill(s)

I was pleasantly surprised to find that somebody else has had the same idea and has gone so far as to patent it.  Dr Theoharides, from Tufts University in the US, has filed patents on several such polypills.  I have read much of his autism and mast cell research and was beginning to wonder why, after 25 years in the field, he has only brought to market an OTC supplement (Neuroprotek).

Just take a look at what he would put in his autism polypill:-

Methods of treating autism spectrum disorders and compositions for same

and more recently a very similar one:-

ANTI-INFLAMMATORY COMPOSITIONS FOR TREATING BRAIN INFLAMMATION

If you are a doctor or science graduate, you will probably read the full patent information, but if not, here is a summary:-

SUMMARY OF THE INVENTION

(Methods of treating autism spectrum disorders and compositions for same)

[0007] It has been discovered that measurement of certain serum markers capable of making brain blood vessels leaky can identify patients with ASDs. It has also been discovered that certain compositions can inhibit leakage of brain vessels that would otherwise allow entry of noxious molecules in the brain. The compositions disclosed herein have been found to improve the conditions associated with ASDs through inhibition of blood vessel leakage, as determined by behavioral improvement and as noted in the examples disclosed herein. Together, these data support that modulation, and, in particular, inhibition, of brain blood vessel leakage is a valuable intervention point for the treatment of ASDs. This discovery has been exploited to develop the present application, which includes methods and compositions for treating ASDs in a subject, as well as methods for screening for an ASD in a subject suspected of having an ASD.

[0008] One aspect of the application is directed to a method of treating an ASD in a subject. In this method, a composition comprising of one or more flavonoids, alone or in combination with, a serotonin blocker, a histamine- 1 receptor antagonist, a histamine-3 receptor agonist, an antipsychotic agent, a heavy metal chelator, a neurotensin blocker, olive kernel extract and a physiologically acceptable carrier, is administered to a subject in need thereof, wherein the composition modulates the leakage of brain blood vessels.

SUMMARY OF THE INVENTION

(ANTI-INFLAMMATORY COMPOSITIONS FOR TREATING BRAIN INFLAMMATION )

The invention comprises compositions for human use containing one or more of a flavonoid compound, a non-bovine heavily sulfated proteoglycan, an unrefined olive kernel extract, a sulfated hexosamine, S-adenosylmethionine (“SAM”), histamine-1 receptor antagonists, histamine-3 receptor agonists, antagonists of the actions of CRH, folic acid, a straight chain polyunsaturated fatty acid, a phospholipid, a polyamine, an interferon and glutiramer acetate, together with appropriate excipients and carriers, said compositions having improved absorption from the gastrointestinal tract, skin surface, and nasal and pulmonary surfaces, and anti-inflammatory effects synergistic with each other and synergistic with available conventional clinical treatment modalities.

It has been discovered that various combinations of a sulfated proteoglycan, unrefined olive kernel extract, a flavone (a.k.a. flavonoid compound), a sulfated D-hexoseamine, a phospholipid, a long chain unsaturated fatty acid, a CRH antagonist, a histamine-1 receptor antagonist, a histamine-3 receptor agonist, glutiramer acetate, an interferon, and a polyamine have synergistic anti-inflammatory effects when used as a dietary supplement, a topical product or an aerosol for nasal or pulmonary administration, without or with a conventional clinical treatment for inflammatory diseases. Within the present context, such inflammatory diseases result from the activation, degranulation and consequent secretion of inflammatory biochemicals from mast cells, and the resultant inflammatory diseases include the group consisting of: allergic inflammation, arthritis (to include osteoarthritis and rheumatoid arthritis), fibromyalgia, chronic fatigue syndrome, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome, migraines, atherosclerosis, coronary inflammation, ischemia, chronic prostatitis, eczema, multiple sclerosis, psoriasis, sun burn, periodontal disease of the gums, superficial vasodilator flush syndromes, hormonally-dependent cancers, and endometriosis. The olive kernel extract alone may be used to improve the transmembrane transport of difficultly-absorbable biomolecules in the intestine, skin and pulmonary alveoli.

The patent goes into great detail of exactly which drugs might be included, and in the second patent even the dosages.

Histamine H1 and H3 Agonists

I wrote extensively in this blog about histamine and autism.  Theoharides proposes to use an H1 agonist and an H3 agonist.  The problem is that H3 agonists are still experimental and unlicensed; however his choice of possible H1 agonists is very interesting and something that can be applied today.

Azatadine is an antihistamine and serotonin blocker

Azelastine is a second generation antihistamine and mast cell stabilizer available as nose spray or eye drops.  Seems to be the most effective for hay fever.  OTC in UK

Cyproheptadine or Periactin is a first generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties.    OTC in UK

A clinical trial exists in autism of this drug.

Hydroxyzine another first generation antihistamine. Due to its antagonistic effects on several receptor systems in the brain, hydroxyzine is claimed to have strong anti-anxiety and mild antiobsessive as well as antipsychotic properties

Merelastine is another first generation antihistamine

Rupatadine is a second generation antihistamine and PAF antagonist used to treat allergies.  It has mast cell stabilizing properties.

Antipsychotic and Chelator

I was surprised to see these drugs mentioned, the heavy metal chelator is meso-2,3-dimercaptosuccinic acid (DMSA) and  the antipsychotic agent is risperidone.

The evidence for chelation actually looks a bit shaky.  In fact two antioxidants proposed for use in autism, NAC (N-acetyl cysteine)  and ALA (lipoic acid) are highly likely to remove any heavy metal nasties anyway.

Mitigating Methyl mercury Exposure: Study Confirms Potential of NAC as Antidote and Biomarker

I will be sticking with NAC and certainly not using antipsychotics, since they are known to have major side effects.

Neurotensin blocker

Neurotensin (NT) is another neurotransmitter.  Neurotensin has been implicated in the modulation of dopamine signaling, and produces a spectrum of pharmacological effects resembling those of antipsychotic drugs, leading to the suggestion that neurotensin may be an endogenous neuroleptic.

Children with autism have elevated levels of NT and the level seems to correlate with the severity of their autism.

Neurotensinis increased in serum of young children with autistic disorder

Targeting Neurotensin as a Potential Novel Approach for the Treatment of Autism

Neurotensin blockers have existed in research for some time, but there is no licensed drug.

Serotonin blocker

The serotonin blocker is azatadine or cyproheptadine.  Both of these are actually H1 histamine antagonists.  Cyproheptadine, also known as Periactin is available OTC in some countries, including the UK.

SAMe, folic acid

Supplementation of the compositions described above with the methylation reagent S-adenosylmethionine (“SAM”) adds antioxidant, anti-inflammatory and cytoprotective properties, particularly in inflammatory joint and cardiovascular diseases. Addition of SAM also accelerates metabolism of homocysteine, which amino acid has been implicated in coronary disease, to cysteine, which is harmless. Folic acid may be added to certain of the present formulations for similar reasons.

In fact NAC + B12 is an alternative way to reduce homocysteine levels, as already mentioned in an earlier post.

The Peter Polypill

I found Dr Theoharides patents very interesting and it is encouraging to see that someone is actually doing to some research, reading other peoples research and trying to bring products to the market.  

Of Theoharides’ ingredients, the ones I would also include in the Peter Polypill are the H1 agonists (including the serotonin blocker).

The Neurotensin blocker and H3 agonist look interesting, but it will be many years before they are licensed as drugs.

The hypothetical Peter Polypill is currently as follows:-

A twice daily effervescent tablet containing:-

Atorvastatin, with co-enzyme Q10 added to counter the secondary effect of the statin

Bumetanide, with Ca, K, and Mg added to counter the losses due to diuresis

NAC plus a small amount of acetyl-L carnitine

Rupatadine, as H1 agonist and mast cell stabilizer

Taltirelin hydrate, the TRH analog

Vitamins D, B6, B9 and B12 + selenium

Then I would give Dr Theoharides oil-based flavonoid supplement to help stabilize mast cells and maybe, before bed I would add Periactin, the sedating H1 anti histamine and serotonin blocker.  For summertime allergies, it looks like the nasal spray containing Azelastine should be the best.