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Showing posts with label N-Acetylcysteine. Show all posts
Showing posts with label N-Acetylcysteine. Show all posts

Sunday, 7 April 2013

Conceptual Map of Behavioural Homeostasis in Autism

In the research there are various scales to measure how autistic a child is, for example the Childhood Autism Rating Scale (CARS).  They are very subjective, but clearly better than nothing at all. I read a study on older children with ASD that was highlighting that as the children get older, they become less autistic.  In the CARS scale there are 14 behavioural areas to grade and then there is number 15, which is the general impression of the clinician.  In effect, number 15 is how autistic the clinicians feel the subject to be;  you would expect that number 15 would be consistant with the findings in the first 14 areas.  In the test the older children all showed a big improvement in areas 1 to 14, but not in number 15, which is the one that really matters.  This really means that either the use of CARS was inappropriate or CARS is flawed.

As children get older the concept of "normal" changes.  So there is not much point comparing a 15 year old with ASD to a normal/typical 3 year old.  So I decided that kids with ASD deserve a better framework, so that clinicians and parents have a better way to understand many important issues, ranging from prognosis, to just what is autism and where its boundaries really are.

In the Peter Autism Scale (PAS), typical kids start at birth with a score of zero. After 12 months, typical kids show rapid development; they acquire an increasingly negative PAS score. After puberty has ended, the PAS score stops declining and gradually heads back towards minus 20.  Much later in life, after starting their own family, the PAS drifts back up towards minus 10.


Autistic children are likely born with a positive PAS score; as they show either regression, or just the emergence of ASD-type behaviours, the score will increase. At a score of 60, self injurious behaviour is exhibited; at a score of 80 there is serious aggression and violence. The scale stops at 100, where the child needs physical restraint and is likely to be sent to an institution (depending on which country they live in).


There has been an explosion in the number of children diagnosed with ASD, most notably in the US.  Undoubtedly a great deal of this is explained by a bizarre, ever-widening of the definition of autism.  At one end of the scale, what were formerly nerds/geeks are now "on the spectrum" and at the other end of the scale, cases of mental retardation (MR) are now labeled as severe autism.  This ever changing, ever stretching, diagnosis is extremely harmful to the search for genuine therapies.

Mild social difficulties and obsession with computers or music is nothing new; it may indeed be worthy of a diagnostic term, but I do not think it is autism, or ASD.  On the PAS framework, you will note a blue cloud.

Asperger's syndrome already has a nice name; in the PAS conceptual map it follows in parallel the general path of typical development but has a score 12 higher.  It passes through the lower edge of the blue cloud.



Now to the serious case of what I shall term "disabling autism".  These are children with a PAS score of greater than 20.  These children need immediate therapy and their parents need external training and support.  If this help is received, there is good chance that the PAS score will never reach 60, let alone 80.  If help is not received and the PAS reaches 100, there will not be a happy ending.

In a perfect world, the prompt intervention (both behavioural and pharmacological) will give the child a fighting chance of gradually heading south to that big blue cloud.



Monty no BU no NAC
This is my estimation of Monty's development with no drugs
 
Monty + NAC
This is my estimated outcome using NAC alone
 
Monty + BU + NAC
This is my curreent prognosis using Bumetanide and NAC
 
Monty + BU + NAC + Agent X
This is my optimal prognosis achieved by adding the unkown Agent X


Monty himself is the first subject to have a PAS assessment.  Clearly this is just conceptual and so is purely illustrative;  nonetheless I think it has value.

Monty was not born a typical baby; he was always a bit different.  These differences grew and it was in his fourth year that he really began to acquire and demonstrate lots of new skills.  Then, with a great deal of behavioral support, it was plain sailing until he was about 8 and a half years old, when almost overnight, his world fell apart.  His longtime assistant had to leave him and his cosy world was overturned.  All the behaviours that he had avoided earlier, such as head banging and aggression to others, emerged with a vengeance.  Nine months later things had finally returned to "normal", but at a higher plateau of autism than 12 months before.

Three months later I trialed Bumetanide (BU in the chart) and three months after that plateau I trialed NAC.  In the PAS framework, Bumetanide appeared to provide a one-off 40% reduction.  Then with NAC, I took a wild guess at a 25% one-off reduction in PAS score.

Now we are in sight of the blue cloud, but a lot of work remains to be done.

Within 12 months, I would like to have found Agent X, which would give another 25% reduction in PAS score.  I think that will be as much help as can be reasonably expected from drugs.     

If it was not for puberty, it would be plain sailing into the future.  In the prediction, I have forecast another behavioral meltdown (loss of behavioural homeostatis), but since we now have experience of such a shock, I hope to manage it better.




















  

Saturday, 30 March 2013

NICE Brits 281 and Californian Quacks 305?

I have to thank Paul Whitely  for a post on his website that I am hijacking today.  Click on Paul’s name to go to his blog.

National Institute for Health & Care Excellence (NICE)
NICE is an organisation in the UK, funded by the Department of Health.  They produce excellent guidelines on  most medical conditions for both doctors and patients.  They are all available free on line.

NICE & Autism
NICE are producing a guideline called:-  

Autism, The management and support of children and young people on the autism spectrum.  The guideline is still in the draft stage, but there are two versions:-
Full version (790 pages) 
Summary (40 pages)

You may wonder who on earth is going to read a 790 page document.  The 40 page document does not say a lot, you could summarize it as folows:-
  •  Carers (parents) are unsupported, miserable and financially strained
  • Children should have access to care and therapy, that does not currently exist
  • Local autism teams should have the skills to provide, or organize, the interventions and care recommended in this guideline, but they currently do not have these skills.
  • No magic cure exists
 


The NICE list of Dos and Don’ts  (Mainly Don’ts)

DO NOT:-

Do not use the following interventions for the management of core features of autism in children and young people: 

·         antipsychotics
·         antidepressants
·         anticonvulsants
·         exclusion diets (such as gluten- or casein-free diets)  -  sorry Paul

Do not use omega-3 fatty acids to manage sleep problems in children and young people with autism.

Do not use auditory integration training

Do not use the following interventions for children and young people with autism in any context:  
·         secretin
·         chelation
·         hyperbaric oxygen therapy 

DO:-

Consider a social-communication intervention for the management of the core features of autism in children and young people. For pre-school children consider delivering the intervention with parent, carer or teacher mediation. For school-aged children consider delivering the intervention with peer mediation.

Consider the following for children and young people with autism and anxiety who have the verbal and cognitive ability to engage in a cognitive behavioural therapy (CBT) intervention:  

·         group CBT adjusted to the needs of children and young people with autism
·         individual CBT for children and young people who find group-based activities difficult.  

For behavior that challenges, try antipsychotic medication.

  
The 790 page version  -   NICE Brits 281 and Californian Quacks 305
I was rather disappointed by the 40 page version of NICE, so I opened up the 790 page version.  I recommend you do too.  It is totally different.  Some people have spent many 1000’s of hours analysing all the scientific literature on a wide range of biological, social, psychological and educational aspects of autism.

The problem was on page 281.  This is the page where those clever guys over at Stanford 94305, get their research into Glutathione (GSH) mentioned. (94305 is their zip code) 

Then on pages 389/390 NICE give their verdict on the Stanford guys' findings.  They conclude that while NAC does nothing bad, it also did nothing good.



 


Now, I am no medical genius, but nor am I a complete moron. I read the full Stanford research paper as a highly sceptical, but informed, parent. I concluded, as did the Stanford team, that they had found something very important. To get the full report you have to pay $31.50 but I figured it was well worth it. So if this excellent research just gets sliced and diced, and then trashed, in this 790 page review, how much faith do I have in the other 787 pages?

I am with those Quacky Californians on this one.  Those NICE Brits can call me a quack too.


Tuesday, 26 March 2013

Glutathione (GSH) Part III - Say Goodbye to Obsessive Behaviours


Stereotypy is a word you may never have used, but it is there in the dictionary.  In the world of autism, they made up their own word for it; “stimming”.  Stimming does not appear in the Oxford English dictionary, but here is a nice definition from Urban-dictionary.
Stim, stims or stimming is short for "self-stimulation". Almost everyone does it (tapping feet, cracking knuckles, twiddling thumbs), but in autistic people these behaviours are more pronounced and may seem downright strange.

Stimming is an obsessive behaviour that can get in the way of doing anything else.  If you are wiggling your fingers 10 cm in front of your eyes, not surprisingly, you are lost to the outside world.

But there are plenty of other obsessions; here is an eclectic mix:-

·         Tearing up papers into tiny pieces

·         Jumping, rocking, trampolining

·         Roller coasters

·         Thomas the Tank Engine

·         Watching the same part of a cartoon over and over again

·         Going to the theatre

·         Eating a Big Mac every day for lunch

·         Always following the same route, walking to the park

Using behavioural techniques from ABA, you can go a long way to managing, and then dramatically reducing, these obsessive behaviours.

Now, thanks to some science, it seems that these obsessions can finally be got fully under control.

By implementing a program to increase GSH using NAC, the science of which was outlined in Glutathione (GSH) Part II -N-Acetylcysteine (NAC), we have witnessed a near immediate cessation of uncontrollable obsessive behaviours.  The obsessions remain, but they are now firmly under self-control.
 
 
 
 

Monday, 18 March 2013

Glutathione (GSH) Part II - N-Acetylcysteine (NAC)

Please take a look at Part I before reading this post.  Remember this is a blog, not medical research or medical advice.  Always read the full clinical study and then go talk to your paediatrician.
 

Here is the final part of my current research into GSH which, you will be pleased to learn, leads to where it should; a successful clinical trial.  This time it is not in France, the trial will be in Palo Alto, California, home of Stanford University.

You will recall, that while researching one evening in February, I had rather stumbled upon the subject of GSH.  In Part I you learned all about GSH, Redox and came across a funny type of stinky chemical called a thiol.  I asked you to make a note of one particular thiol called Cysteine.

 

1.     Brain region-specific glutathione redox imbalance in autism

 We now go inside the autistic brain.  Last year some very smart Americans did some research measuring GSH and GSH Redox  (the ratio of GSH/GSSG) in different regions of the brain of autistic subjects.  You will probably prefer not to know how they managed to do this.

 They were able to prove that in certain parts of the brain, GSH Redox was decreased by more than half in the autistic subjects, compared to typical subjects of the same age.  That means GSH was low and GSSG was high.  By consequence, the autistic brains had a much higher level of oxidative stress (always a bad thing) than the other subjects.

They suggested that this might leads directly to the neurodevelopmental abnormalities in autism.


 

2.    Regulation of cellular glutathione

So now I was on a roll, I had found a serious biological abnormality in autism, but would it lead me to another Epiphany? Highly unlikely I thought, but onwards I went.

The next step was to find out a bit more about GSH

This part is both interesting and rather complicated, so I am going to give you just the highlights.


  • Glutathione synthesis and metabolism
The way GSH is synthesized in the body seems well understood in the literature.  While hoping to simplify this text I do need to point out I just noticed another odd coincidence that I have to follow up on later (NADP/NADPH the actual chemical required for the GSH Redox chemical reaction to take place also has other known functions in human biology NADPH is used for processes such as lipid synthesis, cholesterol synthesis and fatty acid elongation.  I have another parallel investigation into omega 3 and autism, where I have learnt that in autistic children  there is a proven lipid metabolism disorder that causes high cholesterol and low omega3/omega6 ratio.  So have to add NADP/NADPH to my list of things to investigate).

GSH is all over your body - brain, lungs, liver, kidneys and in all these places some of it gets converted to GSSH.  But on balance, if your body is in good shape GSH should be greater than 99% and GSSH less than 1%.  If not, bad stuff will happen.

There are five known ways to increase the level of GSH (a good thing to do):-

1.    Enhancement of uptake of cystine

2.    Reduction of cystine to cysteine  (add a reducing agent such as NAC)

3.    Provision of alternative sources of cyst(e)ine

4.    Provide a GSH precursor (γ-Glutamylcysteine) directly

5.    Add GSH directly (intravenously, not by eating it)

 
3.    Clinical trial of glutathione supplementation in autism spectrum disorders

I came across a study from 2011 when some well-meaning folk wanted to test GSH supplementation in autism.  Now the problem is that they neglected to spend 4 hours on Google Scholar before they started.  Now, if you think I am beginning to sound smug, well you are entirely correct.  It seems Peter, doing research in the spare room, knows more about something than some white coated researchers.

They just had to look on Wikipedia to learn that “Raising GSH levels through direct supplementation of glutathione is difficult.  Research suggests that glutathione taken orally is not well absorbed across the gastrointestinal tract”  They quote research from 1992, so it must be widely known by 2011.

The study used oral GSH and a commercial transdermal GSH preparation called KIRKMAN Reduced L-Glutathione Lotion (50 g will set you back  EUR 45)

 But at least the idea behind the trial was good.

 

4.     Glutathione precursors to raise GSH levels in plasma (N-acetylcysteine, whey protein)

Going back to hard science, you quickly find that there are already well established methods to successfully raise GSH levels, via the administration of certain supplements.

 ·         Whey protein, as used by body builders, but not so cheap

 ·         N-acetylcysteine, otherwise known as NAC and pretty cheap.

 
So I follow up both and later opted for NAC.


5.     N-acetylcysteine (NAC)  in the Emergency Room and  Psychiatry

NAC has been used as a precursor to GSH for more than 30 years.  It is the standard Emergency Room treatment in the case of paracetamol overdose.

It turns out that NAC is another little wonder.  It is already used in obsessive compulsive disorder, schizophrenia, trichotillomania (a new one to me) and bipolar disorder.  It is even used in HIV therapy.

But no mention of Autism.

NAC is available as a drug or as a supplement without prescription.


6.    A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism

Finally, the bit you have been waiting for.  When I found this clinical trial at the end of  my 4 hour Googling session, I would have fallen off my chair, had I not been lying down at the time.

A eureka moment perhaps;  I found a clinical trial testing just what I wanted to test -  a serious study of NAC on the behaviour of kids with autism.  This study was carried out by Antonio Hardan at Stanford University, California.

Enough said.


  

 
If you want the full version they expect you to pay $31.50.

Well that was a productive 4 hours, but it set me back another $31.50.

Sadly, finding all the references again and writing my two posts on GSH has taken another 4 hours.

That was of course a few weeks ago.  The rest is history.  I suggest that you turn on your speakers., and click the link below.

 

 
1965 was an important year.  One of them was that this song was produced and is apparently  #89 in  Rolling Stones list of the 500 greatest songs of all time.