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Showing posts with label TRH. Show all posts
Showing posts with label TRH. Show all posts

Monday, 11 November 2013

Creatine, the Sub-types of Autism is Affects, and the Missing $26 million



Poly Genetic Theory of Autism

Autism appears to be the result of the expression of multiple abnormal genes acting in concert, likely initiated by some external factor(s).  This would explain why there are so many variants of autism and why there can seem to be autistic-like traits in close relatives.
 

 

Gene-based Autism Research
Several candidate genes have been identified, such as those linked to fragile X syndrome, tuberous sclerosis etc.  Researchers then follow the science from the target gene to identify a possible therapy.  At this point the researchers then seem to lose their scientific logic; they then try and apply their new therapy to all kinds of autism, i.e. the ones without the “faulty gene”.

This really goes back to our current limited understanding of the brain, medicine is more art than science, and we should perhaps suspend logic and accept this trial and error approach as valid.  At least call it trial and error.

Creatine
Creatine is an organic acid produced naturally in the body.  It helps to supply energy to all cells in the body. This is achieved by increasing the formation of adenosine triphosphate (ATP).

Creatine is not an essential nutrient, as it is manufactured in the human body from L-arginine, glycine and L-methionine.
Its main use as a supplement/drug is among people wanting to develop their muscles, like athletes and bodybuilders.  Taking the standard dose of 5-10 mg has the same effect as eating a very high protein diet.  In people with muscle wasting diseases, Creatine is also used.  What I found interesting was the research showing an effect in depression.  There are marked similarities between conditions like depression and ASD.
We will return later in the post to another reason that Creatine may be relevant to autism; it appears to be something the research community did not notice.  Now back to those professional researchers:-
 
Creatine Deficiency
Science has identified three types of Creatine deficiency and all three lead to mental retardation and/or autism.  Two types are very rare, but are treatable; the third type is far more common, affecting about a million people worldwide, and is currently untreatable in humans.  In mice, this third type has been “cured”, but the money is not yet available to develop and test a human version of the therapy.
 
 
1.      AGAT 
AGAT (L-Arginine:glycine amidinotransferase) is an enzyme.  This enzyme is needed for the body to produce Creatine.  AGAT deficiency will cause Creatine deficiency  and lead to mental retardation and autism.
For those regularly following my blog, please note the following: It has been suggested that AGAT activity in tissues is regulated in a number of ways including induction by growth hormone (GH) and thyroxine (T4).

The actual genetic mutation associated with AGAT involves a tryptophan codon being converted to a stop codon at residue 149.
You may recall in my post on serotonin, we learnt about its precursor tryptophan and how it appears to be degraded in the autistic brain.


2.     GAMT
GAMT (Guanidinoacetate N-methyltransferase) is another enzyme required to produce Creatine.  As with AGAT deficiency, if you are deficient in GAMT, autism and mental retardation will follow.

Treatment
If diagnosed, defects of Creatine biosynthesis are treated with Creatine supplements and, in GAMT deficiency, with ornithine and dietary restriction of arginine through limitation of protein intake.
 
3.     X-linked Creatine deficiency
The final type of Creatine deficiency is much more common, but is much more difficult to treat.  The defect is the Creatine transporter that should allow the Creatine into brain cells, where it plays a critical role in the brain’s energy needs.  No matter how much Creatine you give to people with this disorder, they cannot use it, because their Creatine transporters (CRTs) are defective.

Fortunately, thanks to Dr Joseph Clark, Professor of Neurology at the University of Cincinnati, there is light at the end of the tunnel.  Dr Clark has been researching the Creatine metabolism for some years.  Very unusually, he has been sharing his experiences with us, via his blog.
To cut a long story short, the good doctor has figured out that by using an analog (a modified version) of Creatine called cyclocreatine he could normalize the function of mice with  X-linked Creatine deficiency.  All he now has to do, is to make it work in humans, fully test it and get it FDA approved.  The problem is there is no more money.  In his blog post he tells us that all he needs is:-
$26 million and three more years

Here is the official report from the University:- 
 
Peter’s thoughts on Creatine
I started looking at Creatine because it appears to stimulate IGF-1 (insulin-like growth factor 1).  This is not a fact well-known to endocrinologists, but it is very well known to athletes and body builders.  They take Creatine orally and it stimulates muscle growth.  Research has even measured the change in IGF-1 in muscle tissue resulting from Creatine supplementation.

In a recent post I pointed out that IGF-1 is itself being used in autism trials, as is a novel Australian analog of IGF-1 [1-3] called NNZ-2566.  The big advantage of NNZ-2566 is that it is taken orally.

The release of IGF-1 is stimulated by growth hormone GH.  Secretion of growth hormone (GH) in the pituitary is regulated by the hypothalamus, which release the peptides Growth hormone-releasing hormone (GHRH) and Growth hormone-inhibiting hormone (GHIH) into the blood surrounding the pituitary. GH release in the pituitary is primarily determined by the balance of these two peptides, which in turn is affected by many physiological stimulators (e.g., exercise, nutrition, sleep) and inhibitors (e.g., free fatty acids) of GH secretion.
Stimulators of growth hormone (GH) secretion include:
  • peptide hormones
    • GHRH  through binding to the growth hormone-releasing hormone receptor
    • ghrelin through binding to growth hormone secretagogue receptors
  • sex hormones
    • increased androgen secretion during puberty (in males from testis and in females from adrenal cortex)
    • estrogen
  • clonidine and L-DOPA by stimulating GHRH release

·         α4β2 nicotinic agonists, including nicotine, which also act synergistically with clonidine 
      (Interestingly clonidine is a drug used for ADHD, or autism-lite, as I call it)

Factors that are known to cause variation in the levels of (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake. The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals. These are chemicals found in both household and industrial products that are known to interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of normal cell metabolism. 
Based on my earlier primary research, I am pretty sure that in the sub-type of autism I am dealing with, there is a deficiency of either GH or TRH, in the brain.  As I result, I am interested in mention of these hormones.


 SHANK3 deficiency
(also known as 22q13 Deletion Syndrome or Phelan-McDermid Syndrome)

IGF-1 is being trialled at Mount Sinai Hospital in New York in autistic children with SHANK3 deficiency.  In true “art” rather than “science” approach, the plan is then to trial IGF-1 on children without SHANK3 deficiency.

Here is a good explanation.
If you live in the Big Apple:-

Where Can I Get Testing?


The Icahn School of Medicine at Mount Sinai offers genetic testing for Phelan-McDermid Syndrome/22q13 Deletion Syndrome and for SHANK3 mutations. A blood sample is needed to conduct the test. For more information about testing, visit The Seaver Autism Center, call (212) 241-0961  

It appears that SHANK3 deficiency accounts for about 1% of autism cases.
If, as is hoped, IGF-1 turns out to be a useful therapy in SHANK3 deficient children, it will be tried on all ASD kids.  If it works, then what was the relevance of SHANK3 in the first place?   It seems pretty odd to me.  I think most likely our current understanding of genetics is so basic, as to be flawed.

I am working via observation, rather than genetics; I know what circumstances produce near neurotypical behaviour, I just need to understand what is going on biologically.  This is how I ended up with TRH and/or GH.


Conclusion
Well if the Mount Sinai study is successful, as it probably will be, we should find Dr Clark in Cincinnati and give him $26 million.  Then we put creatine and cyclocreatine in a pill and give it to ALL people with ASD, since 99% will never get their sub-type diagnosed. 

Either the creatine, the cyclocreatine or the extra IGF-1 will do some good, depending on the sub-type – something for everyone. And no needles.

 

Sunday, 22 September 2013

Central Hypothyroidism or Low Brain D2 Levels in Autism



I am returning to an old theme of mine, which is my hypothesis that the thyroid releasing hormone (TRH) may be of therapeutic value in autism.  I have been reading up on what some endocrinologists are doing the US and also looking a bit deeper into the underlying biology of the related hormones and thinking about my research sample of one, Monty aged 10 with ASD.   My original hypothesis was argued in an earlier post.


The Peter Hypothesis of TRH-induced Behavioural Homeostatis in Autism


Since none of the TRH researchers care to reply to my emails, I decided to refine and document my hypothesis further and then plan to go and see a child endocrinologist for myself.  In most countries, the doctor does the talking and the patient does the listening, so I know that I need something unusual; I called it “an open minded endocrinologist”.

Peter’s TRH & Central Hypothyroidism Theory

Research has documented which parts of the autistic brain are often damaged.  The Purkinje cell layer and the cerebellum in general has been a focus of my blog; but the hypothalamus, which is very close by, is also known to be different in autistic people.   It has been shown that diminished grey matter exists in a region of the hypothalamus, which synthesizes the behaviorally relevant hormones oxytocin and arginine vasopressin.  My pet hormone “TRH” is also produced in the hypothalamus.  The pituitary gland is a protrusion off the bottom of the hypothalamus at the base of the brain. The pituitary gland is functionally connected to the hypothalamus via a small tube called the pituitary stalk. The pituitary gland secretes nine hormones that regulate homeostatis; one of these is TSH (thyroid stimulating hormone). 

In summary, TRH from the damaged hypothalamus travels down to the pituitary gland where it triggers the release of TSH.  TSH travels a bit further to the thyroid gland where two important hormones, T3 and T4, are produced.

When the levels of T3 and T4 are low a condition called hypothyroidism exists.  T4 is a so-called pro hormone of T3.

I have already noted that when Monty was a young toddler he was tall for his age, about the 90th percentile; aged 10 his is now about the 25% percentile.  When I started this blog, I saw in the old autism literature there are lots of studies about head circumference in autism.  In summary they found that in autism the head (and by inference the brain) grows very fast in the first couple of years and then by 3 or 4 years of age the brain has prematurely reached adult size.  The brain grew faster than normal and certain parts developed abnormally.  I did not see any research into abnormal development in height.  It would be very easy to study this, since in most countries a child’s height is regularly recorded.

When I recently checked to see what are the effects of hypothyroidism in typical children, I found interesting reading:-

Effects of Hypothyroidism During Infancy. Transient hypothyroidism is common among premature infants. Although temporary, severe cases can cause difficulties in neurologic and mental development.
Infants born with permanent congenital (inborn) hypothyroidism need to receive treatment as soon as possible after birth to prevent mental retardation, stunted growth, and other aspects of abnormal development (a syndrome referred to as cretinism). Untreated infants can lose up to three to five IQ points per month during the first year. An early start of lifelong treatment avoids or minimizes this damage. Even with early treatment, however, mild problems in memory, attention, and mental processing may persist into adolescence and adulthood.

Effects of Childhood-Onset Hypothyroidism. If hypothyroidism develops in children older than 2 years, mental retardation is not a danger, but physical growth may be slowed and new teeth delayed. If treatment is delayed, adult growth could be affected. Even with treatment, some children with severe hypothyroidism may have attention problems and hyperactivity.

Hypothyroidism is usually caused by a failure of the thyroid gland.  TRH is being released to the pituitary, which the produces TSH.  The problem is in the thyroid.  The cure is usually to give T4 in tablet form.  The body is usually able to produce T3 from the T4.

Role of D2 and D3 & Oxidative Stress

Both T3 and T4, are produced in the thyroid gland. The ratio of T3 to T4 released into the blood is 1:20.  Both T3 and T4 then reach the individual body organs, where the prohormone T4 is converted to the biologically active hormone T3. The organ/tissue levels of T3 are regulated locally primarily by the activity of two different selenoenzymes, deiodinases type 2 (D2) and type 3 (D3), although deiodinase type 1 is also involved. In the CNS, approximately 70-80% of T3 originates from intracerebral T4 to T3 conversion, while the plasma contribution amounts to 20-30 %  and D2 is responsible for most of the T3 supply within the brain.

The major source of the biologically active hormone T3 in the brain is the local intra-brain conversion of T4 to T3, while a small fraction comes from circulating T3.

As evidence derived from in vitro studies suggests, in response to oxidative stress D3 increases while D2 decreases (Lamirand et al., 2008; Freitas et al., 2010).  As we know in the autistic brain we have a lot of oxidative stress.

Furthermore, in ASD, the lower intra-brain T3 levels occur in the
Absence of a systemic T3 deficiency (Davis et al., 2008), most likely due to the increased activity of D3.

 
Central Hypothyroidism

There is a supposedly rare condition called Central Hypothyroidism, which occurs when the pituitary gland does not produce enough TSH in response to TRH.  In the research jargon they call it “a blunted response”.  Note that blood levels of TSH, T3 and T4 can be normal in cases of central hypothyroidism.

Research has long ago shown that in autistic children often have a blunted response of TSH to TRH.  Interestingly in many psychiatric conditions, like depression, research also shows a blunted response.


 


In the US, psychiatrist have longed prescribed the hormone T3 for depression.  I cannot find much in the way of explanation by psychiatrists of this, other than that some endochronologists do not seem to approve.

In theory if you are low on T3 and T4, the therapy is to give just T4. But as we learned above, if D2 and D3 are misbehaving T3 will not be produced as required.

In the “rare” cases of central hypothyroidism the researchers report being able to correct T4 quite easily but not T3.  So their bodies are not converting enough T4 into T3, because D2 and D3 levels are out of balance.


So the Peter theory has to evolve

In autism there is very likely to be central hypothyroidism, a deficiency of D2 in the brain causes low T3 and I conjecture that there is also a reduced level of TRH being produced in the hypothalamus.  Both the hypothalamus and the pituitary gland are under-responsive.  As a result many hormones are going to be reduced including TRH, TSH, oxytocin, arginine vasopressin and others.

Because TRH also has secondary, only recently understood, behavioral effects, the central hypothyrodism symptoms fits nicely with my earlier TRH theory.

In the US some “holistic” doctors specialized in autism have long been claiming that the majority of kids with ASD are hypothyroid.  They claim that the modern T3 and T4 blood tests are “inaccurate” and that the old TRH stimulation test is more “accurate”.  They then end up prescribing supplementary T3 and T4.  This always looked odd to me; in fact it is yet another case of getting the right answer, but for the wrong reason.

The perfect solution might have been just to give TRH.  You cannot do this because the half-life of TRH is just a few minutes and it needs to be delivered into a vein.   A nasal TRH spray is being developed with funding from the US military.  TRH has mood changing properties and the military has a big problem with suicide.

My idea of using a TRH analog, such as Taltirelin Hydrate, is practical since it has a long half-life and can be taken orally.  It is licensed as a drug, but only in Japan.  It also has a reduced effect on TSH, so you get the benefit of the behavioural properties of TRH rather than just producing more TSH.  This avoids the patient then going hyperthyroid.


A word from the Harvard Medical School

After interest in the 1970s researching autism and the thyroid, not much has been written for decades.  Recently a paper was published by researchers at the Harvard Medical School showing how oxidative stress in the brain, if present, would disrupt thyroid hormone homeostatis.  It has been a long time coming, but it looks like their thinking is spot on.

 
According to this hypothesis, brain region-specific oxidative stress in autism may be associated with increased D3 and decreased D2 activity resulting in a region-specific T3 deficiency in the brain. Future human studies utilizing the CSF of living ASD individuals or postmortem brain tissue of ASD donors will support its validity. Such findings would have several significant implications. They may result in methods of early ASD diagnosis; detection of high brain D3 levels in postmortem human brains may suggest the benefits of measuring the levels of its product (rT3) in the CSF of living patients to assess the risks, monitor the disease progression and efficacy of ongoing treatment. Furthermore, several tissue-specific and TH receptor (TR)-specific thyromimetics have been developed as potential treatment for atherosclerosis, obesity and Type 2 diabetes and might be able to correct local brain TH deficiency without systemic thyrotoxicity (Baxter and Webb, 2009) and may thus be considered as potential therapeutic agents. Finally, confirmation that autism may be associated with increased D3 and decreased D2 activity resulting in a region specific T3 deficiency in the brain could lead to or reinforce dietary treatments, because D2 activity can be modulated not only by selenium but also by xenobiotic compounds (da-Silva
et al., 2007). In conclusion, TH abnormalities in autism warrant a second look.

This paper from Harvard is encouraging and not only concludes that thyroid abnormalities in autism warrant a second look, but suggests ways to raise the level of D2 and correct local brain hypothyroidism

The xenobioyic compound they refer to is the flavonoid kaempferol.

The flavonoid kaempferol looks interesting and there is also much written about its anti-diabetic effects.  This would be a way to raise the amount of D2 and consequently T3 in the brain.  This might be more effective that just supplementing T3.

By the way, just look at all the other things claimed of this flavonoid:-

Numerous preclinical studies have shown kaempferol and some glycosides of kaempferol have a wide range of pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, anticancer, cardioprotective, neuroprotective, antidiabetic, antiosteoporotic, estrogenic/antiestrogenic, anxiolytic, analgesic, and antiallergic activities.
Kaempferol consumption is also correlated with a reduced lung cancer incidence.
Kaempferol may be a potent prophylactic against NOX-mediated neurodegeneration

If you like natural cures, you will like this paper.  Take a look at page 28.  

As with other flavonoids, there is low bioavailability – they are absorbed by the body in tiny quantities.  And they are VERY expensive.


 
Conclusion


I wish the Harvard Medical School would follow up fast on its own research, so I do not have to rely on the internet writings of “holistic” doctors.  As the Harvard paper concluded “TH abnormalities in autism warrant a second look”.

Oral T3 clearly does enter the brain in marked quantities, otherwise I suppose US psychiatrists would not keep using it with their depressed patients.  Research shows that most T3 in the brain originates from T4 converted there by D2.  This implies to me that an alternative therapy would be to give something like kaempferol to raise the level of D2.  The problem, as with other useful flavonoids, like Quercetin and Rutin, is low bioavailability – they are absorbed by the body in tiny quantities.  Kaempferol appears to have the basis of being a wonder drug, but let's wait 20 years to see.

In the meantime, I will review all this with my sought for “open minded endochronologist”.  All I can measure is TSH, T3 and T4 in the blood, I cannot even guess at T3 or D2 in the brain.  The old TRH stimulation test involves lots of needles and that is something I have to try and avoid.  Autistic kids don’t sit still for needles. 


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:-


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.

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.