Thursday, 19 September 2013

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 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:-

and more recently a very similar one:-

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


(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.



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.

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.

1 comment:

  1. Ideally, we shall chase after:

    Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486 ….. Bridget M. Dolana, …. Susumu Tonegawa

    Finally, a single administration of FRAX486 is sufficient to rescue all of these phenotypes in adult Fmr1 KO mice, demonstrating the potential for rapid, postdiagnostic therapy in adults with FXS.


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