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Showing posts with label nicotine. Show all posts
Showing posts with label nicotine. 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.

 

Monday 21 October 2013

Piracetam for Autism, Comrades





Piracetam was first synthesized in 1964 by a Romanian scientist called Corneliu Giurgea, who was highly unusual.  He was educated in then communist Romania, followed by research in Russia and then at the University of Rochester in the US, before ending up in Belgium, eventually as the Head of Research at drug firm UCB and being a Professor at a Belgian university.  How this was possible under the strict form of communism followed in Romania,  I do not really understand.

Anyway, Giurgea was clearly very resourceful and he decided to invent a new class of drugs, to be called Nootropic.
He stated that Nootropic drugs should have the following characteristics:
1.     They should enhance learning and memory.
2.     They should enhance the resistance of learned behaviors/memories to conditions which tend to disrupt them (e.g. electroconvulsive shock, hypoxia).
3.     They should protect the brain against various physical or chemical injuries.
4.     They should increase the efficacy of the tonic cortical/subcortical control mechanisms.
5.     They should lack the usual pharmacology of other psychotropic drugs (e.g. sedation, motor stimulation) and possess very few side effects and extremely low toxicity.

Piracetam was soon followed by other drugs developed by competitors.
This class of drug seems never to have been licensed in the US, but was used widely in the Soviet Union, Eastern Europe and some western European countries.
As seems all too common in medicine, nobody knows for sure how Piracetam works.  There are many proposed mechanisms and I was attracted by one of them.

Autism in Ukraine
The internet does give the impression of giving you all the answers.  Often it gives you far too much information, much of it of dubious quality.  In reality, you are only seeing what is written in English, and although it is the international language of science and medicine, you will never see the majority of Russian, Japanese and Chinese knowledge/research.  Medical practice varies widely between Western medicine and the others.
In Japan for example, the MMR vaccination has been banned since 1993 and Prozac, the anti-depressant prescribed in huge quantities in the US, is a banned substance.  
So it was not a surprise to find only passing references to apparently widespread use of Piracetam for autism in the Ukraine, going back for decades.  I have no doubt if you could access the Russian research you would find studies on this.

Side Effects
There is no shortage of drugs prescribed in the US for autism, such as Ritalin, Prozac and Risperidone.  I have no doubt that they have some very good qualities; however they all have very real side effects, some of which are permanent.  Giurgea was very wise to only consider drugs with very few side effects and low toxicity.

In the 50 years since he synthesized Piracetam, one thing everyone seems to agree on, is that either it has no side effects, or it has very minor side effects.

Does Piracetam work?
In the 1970s there were numerous studies on Piracetam in a wide range of neurological conditions.  Today Piracetam is extensively used “off label” as a treatment for many of those conditions.  Does Piracetam work in autism?

I guess the doctors in the Ukraine must think it works.  Dr Akhondzadeh, a researcher into autism, ADHD, and other mental health conditions in Iran, found it to be effective.  Kelly Dorfman of the Development Delay Resources in Pittsburgh thinks it is effective for learning disabilities and dyspraxia, but less so for autism.
Olga Bogdashina, President of the Autism Society of Ukraine, notes that piracetam is widely used as an autism treatment in the Ukraine. Having conducted her own small-scale study, she found that piracetam improved the attention spans and mental capabilities in the majority of participating children. She also says that her autistic son became more sociable and flexible and less aggressive on the supplement. She does warn that during the initial phase of treatment, hyperactivity and tantrums may increase. However, researcher Stephen Fowkes notes that these side effects are only common with high doses, and asserts that they are rare with standard doses (both cited in “Letters to the Editor, Autism Research Review International, 1996).

I thought Bogdashina’s name was familiar.  I read her book on sensory issues in autism.  It is a good read, but it does not really tell you what to do.


Piracetam’s claimed possible methods of action
·        It is NOT a sedative or a stimulant

·        Piracetam is a positive allosteric modulator of the AMPA receptor.

·         It is hypothesized to act on ion channels or ion carriers; thus leading to increased neuron excitability

·         GABA brain metabolism and GABA receptors are not affected by piracetam.

·         Piracetam improves the function of the neurotransmitter acetylcholine via muscarinic cholinergic (ACh) receptors, which are implicated in memory processes

·        Furthermore, piracetam may have an effect on NMDA glutamate receptors, which are involved with learning and memory processes.

·        Piracetam is thought to increase cell membrane permeability

·        Piracetam may exert its global effect on brain neurotransmission via modulation of ion channels (i.e., Na+, K+).

·        It has been found to increase oxygen consumption in the brain, apparently in connection to ATP metabolism, and increases the activity of adenylate kinase in rat brains.

·        Piracetam, while in the brain, appears to increase the synthesis of cytochrome b5, which is a part of the electron transport mechanism in mitochondria.

·        But in the brain, it also increases the permeability of the mitochondria of some intermediaries of the Krebs cycle.

In 2005 there was an interesting review carried out in Poland; it is very readable.

"Piracetam is generally reported to have minimal or no side effects. It is interesting to note, however,  that piracetam is occasionally reported side effects of anxiety, insomnia, agitation, irritability  and tremor are identical to the symptoms of excessive acetylcholine/glutamate neuroactivity. In spite of these effects, piracetam is generally not considered to be a significant agonist or inhibitor of the synaptic action of most   neurotransmitters. The piracetam-type nootropic drugs might exert their
effect on some species of molecules present in the plasma membrane. It would seem that they act as potentiators of an already present activity, rather than possessing any neurotransmitter-like activity of  their own."

It would seem to me that we have come back to the vagus nerve and the Cholinergic system

I learnt in that post that there are two main classes of acetylcholine receptor (AChR), nicotinic acetylcholine receptors (nAChR) and muscarinic acetylcholine receptors (mAChR).  Mostly it seems to be the nicotinic type that is targeted by medical science, but piracetam has an effect on the other type of receptor.  This would explain excessive use of piracetam causing symptoms of too much acetylcholine.
If this is indeed the case, that would add yet another method of “correcting” the known biomarker of autism that is “diminished acetylcholine and nicotinic receptor activity”.  Of all the methods I have so far investigated, this might actually be the safest;  it is certainly inexpensive.

Effect on Comorbidities
My method of separating fact from fiction in autism now includes looking at the effect of therapies on the principal comorbidities of autism.  Most genuinely effective drugs seem to work across many comorbidities.  Epilepsy is the most prevalent comorbidity.
 


"CONCLUSIONS—This study provides further evidence that piracetam is an effective and safe medication in patients with Unverricht-Lundborg disease. In addition, it shows that a dose of 24 g is highly beneficial, more effective than lower doses and that a dose-effect relation exists. There is considerable variation in optimal individual dosage. "
Note:  Unverricht–Lundborg disease is the most common form of an uncommon group of epilepsy called the progressive myoclonus epilepsies.


Conclusion
Piracetam seems to be a safe supplement/drug that improves mood and reduces aggression (and SIBs).  I thought it was worthwhile testing and indeed I was not disappointed.  The dosage suggested is 50-100 mg/kg, but the optimal dose seems to vary by child.  If you follow my vagus nerve/neuroinflammation/ cholinergic way of thinking, then Piracetam would be acting (via acetylcholine) to reduce pro-inflammatory cytokines and hence reduce inflammation in the autistic brain.  This would mean that Piracetam would be a useful tool to control autism flare-ups, be they triggered by pollen allergy, intestinal inflammation, or even stress.  I shall use it as such.

As for why Piracetam seems more effective in the Ukraine than in Pittsburgh - that I can answer.  Much of what passes as autism in Pittsburgh, would be completely ignored in Kiev.  It would not be diagnosed as autism; only if it is disabling would it be called autism.  If you have "autism-lite", the symptoms are mild and you probably do not need Piracetam and it would likely have little effect.   The same would apply for the majority of ADHD/ADD cases, outside of the US they would not be diagnosed as such.
If you are on Ritalin for your severe ADHD, you might want to try Piracetam.  If you Google ADHD and Piracetam, you will find adults using Piracetam to avoid the side effects of Ritalin.
If your child suffers from SIBs (self-injurious behaviours) then Piracetam, along with nicotine patches, would be well worth investigating.

 
 
 

 


 

Monday 14 October 2013

IBS, IBD and Autism, leading to Cholinergic Signaling and the Vagus Nerve


This post is all about those stomach problems typical of many kids with ASD and some of their neuro-typical close relatives. Since Monty, aged 10 with ASD, does not have any of these problems, it is not something I have looked into earlier.  As you will see later in this post, by understanding the underlying science, we can move another step towards inhibiting systemic inflammation, which affects all people with ASD.
 
Irritable bowel syndrome (IBS) and Inflammatory Bowel Disease (IBD),
First of all we need to differentiate two common conditions with very similar symptoms.  IBS is the less serious condition, though it causes lots of discomfort.
 
Irritable Bowel syndrome - IBS
Irritable bowel syndrome (IBS) sufferers show no sign of disease or abnormalities when the colon is examined.

IBS does not produce the destructive inflammation found in IBD. It does not result in permanent harm to the intestines, intestinal bleeding, or the harmful complications often occurring with IBD. People with IBS are not at higher risk for colon cancer, nor are they more likely to develop IBD or other gastrointestinal diseases
The exact cause of IBS is unknown.   The most common theory is that IBS is a disorder of the interaction between the brain and the gastrointestinal tract, although there may also be abnormalities in the gut flora and immune system.

Inflammatory Bowel Disease -  IBD
Inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis

Crohn’s disease has a strong genetic component and is far more prevalent among smokers.  The usual onset is between 15 and 30 years old.
Ulcerative colitis is an auto-immune disease with no known cause.  The symptoms are very similar to Crohn’s disease, but there are some stark differences.  Ulcerative colitis is far less prevalent among smokers

Autistic Colitis / Ulcerative Colitis
The Inflammatory Bowel Disease (IBD) that seems to be relevant in Autism is ulcerative colitis, so much so that Wakefield and Krigsman sought to name a sub-type Autistic Enterocolitis.  Due to all the furore about vaccinations and autism, the research of these two gastroenterologists has been blacklisted.

Dr Krigsman has an informative website and has published some interesting research.
If you spend all day looking via the endoscope  at children with ASD, you are bound to notice a thing or two.  Ignoring what Krigsman observes is bizarre.

In case you are wondering what he does, he is going through the mouth to do an Upper Endoscopy; for the Colonoscopy he goes in from below.  He does both procedures under general anaesthetic.  That will be painless; I once had an endoscopy under general anaesthetic and you have no bad effects.  I had the misfortune to have another one without any anaesthetic, which was one of the most unpleasant experiences of my life.
Ulcerative colitis looks like a nasty condition but Krigsman finds it is generally treatable with some combination of anti-inflammatory medication, antimicrobials, probiotics, digestive enzymes and dietary restriction.

One thing he does not mention is nicotine, more of that later.

GERD
Gastroesophageal reflux disease (GERD) is a very common disease.  The acid within the stomach rises up into the esophagus and in doing so, damages its lining.

Most children will outgrow their reflux by their first birthday. However, a small but significant number of them will not outgrow the condition. This is particularly true when a family history of GERD is present.   It is estimated that 15% of adults of adults are affected by GERD.
Krigsman find that in kids with ASD and their siblings, GERD is relatively common.

 
Mechanisms linking IBS and IBD to Autism
I have already written about the link between food allergies, autism and behaviour.  In those posts it was histamine released from mast cells (along with cytokines and other nasties) that was the culprit.  The treatments included antihistamines and mast cell stabilizers (Ketotifen, Intal etc).  I would presume this would fall into the IBS category.

When it comes to IBD, things get interesting.
In 1936 the Nobel Prize for Physiology was awarded to Sir Henry Dale and Otto Loewi.  One had identified the neurotransmitter acetylcholine and the other had shown how the vagus nerve releases acetylcholine to control heartbeat.

It later became apparent how important the vagus nerve is.  The vagus nerve is a modulator of inflammation throughout the body.  Acetylcholine, the principle neurotransmitter released by the vagus nerve, can exert its anti-inflammatory effect via binding to nicotinic acetylcholine receptors (nAChRs), which are expressed on macrophages and other immune cells.
 
In a recent post I showed that autistic brain samples have diminished acetylcholine and nicotinic receptor activity.  I showed how this could be corrected either by drugs that mimic acetylcholine (eg nicotine or acetylcholine) or with an acetylcholinesterase inhibitor (Galantamine or Donepezil).

I found it very interesting that IBD can be successfully treated by mild smoking (3 cigarettes a day) or with nicotine patches. 
This then connects various comorbidities in a very useful way and opens up therapeutic directions.  The vagus nerve is also key to epilepsy.  Vagus nerve stimulation is currently used to treat epilepsy and depression.

Experimentally, vagus nerve stimulation is already used in autism.  

CONCLUSIONS:


Patients with ASD and intractable epilepsy respond as favorably as all other patients receiving VNS therapy. In addition, they may experience a number of QOL improvements, some of which exceed those classically observed following placement of a VNS device.

 

Kevin J. Tracey
A neurosurgeon and inventor, Kevin Tracey, is the man behind the inflammatory reflex.  The inflammatory reflex is a neural circuit that regulates the immune response to injury and invasion. All reflexes have an afferent and efferent arc. The Inflammatory reflex has a sensory, afferent arc, which is activated by cytokines, and a motor, or efferent arc, which transmits action potentials in the vagus nerve to suppress cytokine production. Increased signaling in the efferent arc inhibits inflammation and prevents organ damage.
We will be looking at his research and the Cholinergic anti-inflammatory pathway, in later posts