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Sunday, 29 September 2013

Autism in Iran: Piracetam, Periactin & Pentoxifylline

This may sound like a very odd subject for my blog.
 
In 2002 US President George Bush first used the term “Axis of Evil” to refer collectively to Ian, Iraq and North Korea.  Later that year the then-Undersecretary of State John Bolton gave a speech entitled "Beyond the Axis of Evil"; in it he added three more nations to be grouped together: Cuba, Libya and Syria. Finally, in 2005 Bush’s Secretary of State came up with “Outposts of tyranny” to refer to Cuba, Belarus, Burma and Zimbabwe.

Many readers of my blog are from the US and may think that not much good can be going on in Iran.  The reality is quite the reverse, at least in the field of autism.

In spite being under all kinds of economic sanctions, Iran has generated a substantial body of insightful research.  There are 75 million Iranians which is just under the population of Germany.  I do not recall seeing much German research into autism. 

One particular researcher, Shahin Akhondzadeh, has done several very interesting studies. His CV lists 128 research papers, including autism, ADHD, schizophrenia, Alzheimer’s and other conditions.  He also writes about herbal medicine for mental health, which I know is popular among readers of this blog, so I included links to some of those papers.


Piracetam, Periactin/ Cyproheptadine & Pentoxifylline

Akhondzadeh is unusual in that he actual makes repeated clinical trials of existing drugs that the science shows could be effective.  In the case of autism he trialled three interesting drugs (with similar names):-

·        Piracetam

·        Periactin/Cyproheptadine

·        Pentoxifylline

Unfortunately his three trials combined them with an anti-psychotic.  But I think it is still interesting to look at the net impact of each of the three drugs.  I did just that.

You have to look at the data and compare the impact after 8 weeks to be consistent and you have to adjust for the fact that in the Periactin/Cyproheptadine trial at week 0 the placebo group was out of line with the trial group.
 
Net improvements:-
 
Piracetam                                        7 points on ABC

Periactin/Cyproheptadine           7 points on ABC

Pentoxifylline                                 3 points on ABC

 
This tells us that Piracetam and Periactin had the greater incremental impact over the antipsychotic and that the change was 7 points on the aberrant behaviour checklist (ABC).  The ABC is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54. It is a 58 item checklist. There are five subscales: a) Irritability and Agitation b) Lethargy and Social Withdrawal c) Stereotypic Behavior d) Hyperactivity and Noncompliance and e) Inappropriate Speech.

 

 



 
 
 
Periactin/Cyproheptadine

I have written about this drug in my recent post on Serotonin.  Periactin is an old first generation H1 antihistamine that happens to have additional anticholinergic, antiserotonergic properties.  It is the effect on serotonin that appears to reduce aberrant behaviours in autism

Periactin is available OTC in the UK.  In the US it is sometimes prescribed to increase appetite.
 
The link to Akhondzadeh’s full study is later in the post.

  

Piracetam

Piracetam was first synthesized in 1964 by scientists at the Belgian pharmaceutical company UCB; struck by its apparent ability to boost mental functioning in even healthy individuals and by its safety, they coined the term nootropic to describe it and other substances. Piracetam (trade name "Nootropil") was launched clinically by UCB in the early 1970s, and currently is in use in many European countries.

Piracetam is a cyclic derivative of the neurotransmitter GABA.

Akhondzadeh writes:-

In addition to serotonergic abnormalities, the strongest evidence implicates the glutamatergic and GABAergic systems are important biochemical factors in autism. One current hypothesis is that autism is a hypoglutamatergic disorder. This hypothesis is based on neuroanatomical and neuroimaging studies and supported by similarities between symptoms produced by N-methyl-D-aspartate (NMDA) antagonists in healthy subjects and those seen in autism. If there is deficient glutamatergic transmission in autism, the most logical treatment would of course be a glutamatergic agent. In the treatment of schizophrenia, that has many similarities with autism either D-cycloserine (glycine agonist) or Piracetam showed promising results. Indeed, autism and schizophrenia have some similarities regarding the role of serotonin and glutamate in their pathophysiology.

 
Piracetam is a member of the nootropic class of drugs, which have cognition enhancing effects, it appears to modulate AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acids)-sensitive glutamate receptors positively and has been used in many countries in the management of dementia. Although its mode of action is not certain, it is said to protect the cerebral cortex against hypoxia and has been used following trauma or surgery and in a variety disorders including senile dementia and behavioral disorders in children. In addition, it is used in the treatment of dyslexia and some type of myoclonus in adults. Indeed. Piracetam is the most studied nootropic in children.


Piracetam was freely available in the US as a supplement until three years ago.  You will see on the web that people were using it, combined with another supplement called choline, to improve their mental functioning.  It had been shown to work in rats, as you can see in this trial.
In the Ukraine it seems that Piracetam has long been given as a therapy in autism.  No mention of choline.

The full study is listed later in this post.

 
Pentoxifylline

Pentoxifylline is a drug that targets the immune system, well established to play a key role in autism.  It is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNF  and leukotriene  synthesis, and reduces inflammation and innate immunity.

So it would be fair to classify it as an immunological treatment for autism.

It is hard to find much about Pentoxifylline and autism.  It was trialled in the 1970s in Japan.


Japanese Journal of Child Psychiatry, Vol 19(3), 1978, 137-144

Describes the successful use of Pentoxifylline (150–600 mg/day) with 3–15 yr old children with abnormal behaviour (e.g., self-mutilation, aggressiveness, and hyperkinesis) and with autism. It is noted that while the drug was effective in reducing symptoms of autism, developmental factors in the disorder should not be ignored. (English abstract)

 
Unfortunately I gave not found the full text version of Akhondzadeh’s study on this drug.

 
Autism in Iran

A paper actually entitled “Autism in Iran”, makes very interesting reading and was co-authored by  Akhondzadeh.

 

Links to my selection of Akhondzadeh’s Research

 

 
Herbal medicine and women's mental health



 

Autism spectrumdisorders: etiology and pharmacotherapy

ONLY ABSTRACT
 
Herbal Medicine in the Treatment of Alzheimer’sdisease

Cyproheptadine in the treatment of autism 


Authors: GUDARZI S., YASAMYM. and AKHONDZADEH S Eur. Psychiatry, Vol.17, Year. 2002, Page: 230-231,    NO ABSTRACT

A Double-blind Placebo Controlled Trial of Piracetam





Conclusion

All three drugs would seem worthy of further investigation, but particularly Piracetam and Periactin.  Both seem to be widely used with children and were/are OTC.


 

2 comments:

  1. Pentoxifylline is an oral medication that improves the symptoms of blood flow problems, such as intermittent claudication. Pentoxifylline is also used to improve blood flow to the brain, prevent strokes, reduce muscle pain during exercise, manage sickle cell disease, as well as relieve nausea and headaches associated with high-altitude sickness.Pentoxifylline allows blood to flow more easily.

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    1. Interesting. I once took a medicine to prevent altitude sickness when crossing the Himalayas, maybe this was it. I also found that Pentoxifylline is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNF and leukotriene synthesis, and reduces inflammation and innate immunity. Perhaps the effect in ASD is caused by anti-inflammatory properties. It is a pity that such drugs are not fully investigated for ASD. It is another inexpensive generic drug, supposedly well tolerated.

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