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Tuesday 29 July 2014

Steroids for Regressive Autism

As we have seen at various points in this blog, there is mounting evidence to support the use of steroids in autism, particularly in regressive autism.


Since long-term steroid use has side effects, there have been no large long-term trials.  There is plenty of anecdotal evidence, particularly from the US.  We saw a paper on Immunomodulatory Therapy, by Michael Chez, which discussed the benefits of Prednisone, a very cheap oral steroid.




In the days before inhalers for asthma, it was low dose oral prednisone that kept many sufferers from an early death.  It did result in reduced height, but this is probably a price worth paying to stay alive.

A paper was recently published by specialists at Harvard Medical School on the subject of steroids and regressive autism.


It pretty much concludes the same as Chez and others have been saying for many years; corticosteroids can have a profound effect on some types of autism.  It remains unlikely that there will ever be large scale trials, due to the scaremongering about side effects.  Much is known about how to minimize the side effects of steroids, for example tapering and pulse dosing.

Here are some key points from the paper:-

·        Up to a third of children with Autism Spectrum Disorder (ASD) manifest regressive autism (R-ASD).They show normal early development followed by loss of language and social skills. Absent evidence-based therapies, anecdotal evidence suggests improvement following use of corticosteroids
·        Twenty steroid-treated R-ASD (STAR) and 24 not-treated ASD patients (NSA), aged 3 - 5 years, were retrospectively identified from a large database.
·        Star group subjects’ language ratings were significantly improved and more STAR than NSA group subjects showed significant language improvement. Most STAR group children showed significant behavioral improvement after treatment. STAR group language and behavior improvement was retained one year after treatment. Groups did not differ in terms of minor EEG abnormalities. Steroid treatment produced no lasting morbidity
·        Steroid treatment was associated with a significantly increased FMAER response magnitude, reduction of FMAER response distortion, and improvement in language and behavior scores. This was not observed in the non-treated group. These pilot findings warrant a prospective randomized validation trial of steroid treatment for R-ASD utilizing FMAER, EEG, and standardized ASD, language and behavior measures, and a longer follow-up period.
·        Referring physicians often enquire about the utility of adrenal corticosteroids or glucocorticoids to treat patients with R-ASD

Prednisone is already a treatment used in PANS, PANDAS and Landau-kleffner syndrome, which all have autism-like symptoms.


  
'Wicked'

Slightly off-topic but, the following is relevant.  

There was a recent documentary by the BBC about US-style DAN autism therapies now being sold to parents in the United Kingdom.  The UK has a government funded institute (NICE) that publishes lengthy advice to doctors as to what drugs to prescribe for almost all conditions, including autism. UK doctors will get into trouble if they do not follow NICE guidelines.

Commenting for the BBC, on the DAN-type treatments, Francesca Happe, a professor of cognitive neuroscience at King's College London and apparently one of the world's leading researchers into autism, said practitioners who "peddled" treatments without proof were "wicked".

But how much proof do you need?  And who is to say which published researcher is serious and which is a charlatan.  The lay autism parent might (falsely) assume that if a researcher is publishing papers, they must be serious and the conclusions reliable.  The reality is that some of the papers are indeed flawed and the conclusions are nonsense.  That is why I keep a list of the researchers who I believe in.

At the extreme are bodies like the UK’s NICE, who conclude that absolutely none of the hundreds/thousands of drugs/supplements proposed for treating core-autism should be used.

The short version of the NICE clinical guidelines is below.  The much longer version reviews in detail many of the papers I have reviewed in this blog, but comes to a very different conclusion.


I read the same papers as NICE and concluded something entirely different.  I found several drugs that do indeed work.  The difference is that my standard of proof is lower than that of NICE and professor of cognitive neuroscience at King's College London.

The DAN/TACA/MAPS/ARI doctors from the US are also hopefully read all these papers, but they come up with ideas of the sort that do fall into the “wicked “category mentioned above.  

Autism parents are not surprising bewildered.  It is the parent that ends up deciding where to draw the line between what treatment is genuine and what is fantasy, perhaps like this one.



Conclusion

Yet again, we have a therapy based on solid science that is in use by a very small number of serious mainstream doctors.  It has not crossed into general use due to a lack of large scale trials.

As a result, medical science continues to tell families that there are no drug therapies for core autism, except some anti-psychotics, anti-depressants and anticonvulsants most of which have serious side-effects and/or cause dependence.

In the case of prednisone, this is a cheap generic drug that does have side effect with prolonged use.  Severe regressive autism can also have side-effects, like complete loss of speech and cognitive impairment.

The answer might be parents signing a waiver to get open access to drugs that have been used successfully in experimental use for autism, without the doctor worrying about losing his license, or being blamed for any side effects.




Friday 25 July 2014

Carnosine for Autism – an Alternative to N-Acetylcysteine (NAC)? or is it Complementary?


Several people have mentioned to me a supplement called L-Carnosine, so I thought it was worthy of its own post.

The first thing to note is lots of supplements have very similar names and indeed two entirely different substances are abbreviated to NAC.

·        Carnosine
·        Carnitine
·        L-Carnosine
·        L-Carnitine
·        N-Acetylcysteine    (abbreviated to “NAC”)
·        N-Acetylcarnosine  (also abbreviated to “NAC”)

In this blog, and in most literature on autism, NAC refers to N-Acetylcysteine.

This post is about Carnosine and L-Carnosine, but there is also research on the use of Carnitine and L-Carnitine regarding autism and Retts syndrome.  So double check what is on the label, if you do indeed order some.


Vladimir Gulevich, Carnosine (and Carnitine)






Vladimir Gulevich  received the degree of doctor of medicine in 1896 from the department of medicine of Moscow State University. From 1900, he rejoined the Moscow State University where he was rector for a brief period of time in 1919. He was a full member of the USSR Academy of Sciences since 1929.

Gulevich discovered both Carnosine and Carnitine in his work in Moscow.  Even today his university is a centre of research for both these substances.

Carnitine and carnosine are composed of the root word carn, meaning flesh, alluding to its prevalence in animal protein. A vegetarian (especially vegan) diet is deficient in adequate carnosine, compared to levels found in a standard diet.

Researchers in Britain, South Korea, Russia and other countries have shown that carnosine has a number of antioxidant properties that may be beneficial.

Carnosine has been proven to scavenge reactive oxygen species (ROS) as well as alpha-beta unsaturated aldehydes formed from peroxidation of cell membrane fatty acids during oxidative stress.

Carnosine can chelate divalent metal ions.  DAN Doctors probably do not know what divalent means, but in Hg2+ the “2” means divalent and Hg means mercury.

Carnosine was found to inhibit diabetic nephropathy.

Carnosine-containing products are also used in topical preparations to reduce wrinkles on the skin.

Some studies have detected beneficial effects of N-acetylcarnosine in preventing and treating cataracts of the eyes.


Carnosine and Autism

Small studies, including this one by Michael Chez, have shown the benefit of L-carnosine in autism.  By the way, Chez seems to be one of the handful of genuinely knowledgeable autism clinicians anywhere on the planet.


Abstract

L-Carnosine, a dipeptide, can enhance frontal lobe function or be neuroprotective. It can also correlate with gamma-aminobutyric acid (GABA)-homocarnosine interaction, with possible anticonvulsive effects. We investigated 31 children with autistic spectrum disorders in an 8-week, double-blinded study to determine if 800 mg L-carnosine daily would result in observable changes versus placebo. Outcome measures were the Childhood Autism Rating Scale, the Gilliam Autism Rating Scale, the Expressive and Receptive One-Word Picture Vocabulary tests, and Clinical Global Impressions of Change. Children on placebo did not show statistically significant changes. After 8 weeks on L-carnosine, children showed statistically significant improvements on the Gilliam Autism Rating Scale (total score and the Behavior, Socialization, and Communication subscales) and the Receptive One-Word Picture Vocabulary test (all P < .05). Improved trends were noted on other outcome measures. Although the mechanism of action of L-carnosine is not well understood, it may enhance neurologic function, perhaps in the enterorhinal or temporal cortex.


As Dr Chez points out, nobody is 100% certain why it is of benefit.  It could just be the anti-oxidant properties of carnosine or it could be something related to the interaction between carnosine and GABA in the brain.  GABA is an important neurotransmitter in the brain.

Other GABA related drugs show a positive effect in types of autism.  These include Baclofen, Arbaclofen, Bumetanide, Clonazepam and even Valproic acid (VPA).  The underlying mechanisms do differ, but all relate, in one way or the other, to GABA.

The Carnosine dosage used by Dr Chez was 800mg per day.

The body deploys a range of enzymes, called carnosinases, to break down carnosine.  In order to maximize the effect, and out-smart the  carnosinases, it might be wise to split the dose into two per day.

In a perfect world it might be simpler to inhibit the carnosinases and just rely on the carnosine from meat in the diet.

You cannot patent naturally occurring substances, so nobody can patent carnosine and no drug firm will therefore research it.  A carnosinase inhibitor could be patented and therefore could be made into a drug.


Carnosine and GABA

It looks like Moscow State University is still the centre of knowledge for Carnosine and Alexander A. Boldyrev recently published a book called:-


Book Description:

The main aim of this new book is to summarize the knowledge on the metabolic transformation of carnosine in excitable tissues of animals and human beings and to analyze the nature of its biological activity. At the beginning of monograph, the short history of the problem is stated. Distribution of carnosine in tissues, its appearance in ontogeny of vertebrates and correlation between carnosine content and functional activity of tissues are discussed. Chemical properties of carnosine and its natural derivatives and their ability to bind heavy metals and protons in water solution are documented. Special attention is paid to free radical quenching ability and to anti-glycating action. Biological activity of carnosine and carnosine containing compounds was tested using biological models of several levels of complexity, starting from individual enzymes and acellular mixtures and finishing to living cells and survival animals. Effects of carnosine on the whole animals under ischemic, hypoxic and other extreme conditions are described. In conclusion, the ability of carnosine to protect brain and muscular tissues from oxidative injury during exhausting exercise, extreme loading or neurodegenerative diseases is demonstrated. Based on these properties, carnosine is postulated to be a potent protector of human beings from oxidative stress.

You can preview much of the book on Google Books

We know from many autism researchers that oxidative stress is a feature of many people’s autism.  Anything that reduces this stress should have a positive effect on behaviour.

Common antioxidants used in autism include:-

·        N-Acetlycysteine (NAC)
·        Alpha Lipoic Acid (ALA)
·        All the many “chelating” substances used by DAN Doctors

Carnosine may be just an alternative anti-oxidant.

However, when you look through Boldyrev’s book, it does look possible that the chemical relationship between GABA and Carnosine many also play a role.


Conclusion

People currently taking Carnosine for Autism might well want to try N-Acetlycysteine (NAC) and see if they notice an additional benefit.  Conversely, the current NAC converts, like my son Monty, aged 11 with ASD, may well want to give Carnosine a try and see what happens.

One blog reader with Asperger’s finds Baclofen highly beneficial; he might as well give Carnosine a try, based on the GABA relationship.

Current research indicates 2,400 mg of NAC and 800 mg of Carnosine. 

It would be nice if one day somebody would do a controlled trial of NAC vs Carnosine vs Carnosine+NAC;  but don’t hold your breath.

Some people with diabetes are already taking ALA (Alpha lipoic acid) or Thioctacid for neuropathy, but find it also increases insulin sensitivity; this means they need less insulin.  They might well find both NAC and Carnosine will further increase insulin sensitivity.  Generally speaking it seems that low insulin sensitivity is bad and high insulin sensitivity is good; but I am no expert on diabetes.

In some counties Carnosine is not available, but you simply can buy it online on Amazon, ebay or many other sites. 






Wednesday 16 July 2014

Verapamil for a Broader sub-group of Autism and even Diabetes?



This blog is about science rather than medicine, and believe me there is a much bigger difference than you might hope for.
Many aspects of the research literature indicate the potential of certain calcium channel blockers, like Verapamil, to be useful in treating autism.  As we have seen, there are many different causes of autism and what treatment works in one type may be totally ineffective in another type.

For almost a year Monty, now age 11 with ASD, has taken Verapamil to control the behavioural effects of allergy that are driven by so called “mast cell degranulation”.  His pollen allergy makes his summertime behaviour dramatically worse; a reaction that is almost entirely reversed by Verapamil.

In my page in this blog on Allergies and Autism I raised the question as to whether Verapamil would be effective in treating the many people with autism who have food allergies leading to gastrointestinal (GI) problems.  Many people with autism have symptoms like Irritable Bowel Syndrome (IBS) or Inflammatory Bowel Disease (IBD) and these are widely associated with worsening autistic behaviours.  Monty has no GI issues or food intolerance.  I was very interested to receive some lengthy comments from a mother with a son who does have autism plus GI problems.  She found Verapamil highly effective in treating both his GI problems and the autism.  This is rather significant, since while I do receive the odd comment that H1 antihistamines have an unexpected beneficial effect on autism, which supports some of my own findings and theories, the issue of GI problems is very common in autism.  Could a pill called Verapamil be the little wonder for them as well?  The science does indeed support this, even if current medicine does not.

 

How can medicine be so disconnected from science?  It does seem to happen far more often than it should.

I did wonder if I was missing something about Verapamil.  It is an L-type calcium channel blocker and in autism there is a known genetic dysfunction (CACNA1C) that affects the calcium channel (Cav1.2) blocked by Verapamil.  It also turns out that Verapamil has been shown to be a highly effective mast cell stabilizer.  I did a little more digging and found something very surprising, the effect of Verapamil on the pancreas.  The pancreas makes all kinds of enzymes as well as insulin.  In some people with an auto-immune dysfunction the body destroys its own insulin producing cells and diabetes results.  In some people with autism (also an auto-immune condition) the pancreas seems not produce some of the other enzymes and there are various DAN-type treatments for this; and the new CUREMARK drug CM-AT seems to target this dysfunction.

Science has remarkably shown that Verapamil had the potential to reverse diabetes, if intervention is early.  Given that type 1 and type 2 diabetes are becoming increasingly common and account for a substantial part of national healthcare costs, it seem odd that medicine has not taken full note.



It appears that older people on Verapamil for hypertension, strangely do not develop type 2 diabetes, which supports the claim for Verapamil.

There is no mystery as to why this is happening.  Calcium channels are widely expressed in pancreas, just as they are in the heart and the brain.  The effect of aberrant calcium channel signalling does no good for the brain in autism and in some other people, with a tendency to auto-immune problems, it would appear to be the pancreas that suffers.

You will recall that autism is amongst, other things, an auto-immune condition.  If you look at the extended family you will likely notice other auto-immune conditions like diabetes, thyroid problems, and arthritis.  (I would myself add fibromyalgia and even some types of chronic headaches to this list)

Recall that several drugs that help autism have a beneficial effect in diabetes and that the key type 2 drug for diabetes seems to have a positive effect on autism.

PPAR alpha, beta and gamma in Autism, Heart Disease and Diabetes


In the above post we saw that PPAR gamma (PPARγ) is a nuclear hormone receptor which modulates insulin sensitivity.  The following autism study looked at the effect of a common diabetes drug, pioglitazone (Actos), an FDA-approved PPARγ agonist used to treat type 2 diabetes, with a good safety profile. 
 

Pioglitazone is currently in Phase 2 trials for autism.

Another comorbidity of autism that is an auto-immune condition is asthma.  Here again, Verapamil was shown many years ago to hold promise.

Verapamil in the prophylaxis of bronchial asthma

A single oral dose of verapamil 80 mg was shown significantly to inhibit histamine-induced bronchoconstriction in 8 out of 16 asthmatic subjects (maximum increase in PD20FEVHi 416%). There was still significant protection (Δ PD20FEV1Hi>100%) in the responders 5 h after the oral dose.

I also noted in earlier posts that anti-oxidants seem to reduce the insulin required by diabetics and also improves one of the big problems that occurs along with diabetes that is peripheral neuropathy.  These antioxidants, like ALA, NAC, Thioctacid etc are also chelators of heavy metals.  While the planned study of chelators in autism in the US was effectively “banned”, a large study was carried out on heart patients.  Chelation was shown to be remarkably beneficial, but chelation is really just a shock dose of antioxidants.

Effect of Disodium EDTA Chelation Regimen on Cardiovascular Events in Patients With Previous Myocardial Infarction The TACT Randomized Trial


My take on this is that in many medical conditions, oxidative stress is present and therefore any antioxidant will be beneficial, but some more so than others.  In the well-researched world of asthma they concluded that the most potent, safe antioxidant was NAC (N-acetylcysteine).  NAC is my choice for autism.


Conclusion

If you have autism and suffer from chronic GI problems, Verapamil might well offer significant relief.

If you have unexplained autism flare-ups, like aggression, in summer this may well be driven by a pollen allergy, Verapamil is likely to help.

If your older relative has hypertension already and looks likely to be heading towards type 2 diabetes, maybe suggest they talk to their doctor about Verapamil;  it may well treat both.

Incidentally, if you have a child with autism and suffer yourself from chronic headaches or fibromyalgia, you might want to try some Verapamil yourself.

Verapamil is a very cheap generic drug; one tablet cost a couple of cents/pence. 


Opinion

I continue to be surprised how far medicine is behind science.

In the case of autism there is now a great deal of “actionable” research that is available for anyone to read.  This blog is about autism, but it seems that in many other areas of medicine the same is true, for example diabetes and types of cancer.   

The idea is that you should wait for clinical trials.  But who do you think is going to do them? There is no financial incentive for drug firms to do trials on old generic drugs for new uses.  Prepare for a long wait.

The medical practitioners involved with autism, mainly psychiatrists if anyone, show little interest in any novel treatment that has not yet been approved.  With such little interest from clinicians, novel treatments will remain well kept secrets for decades to come.

The “alternative” practitioners dealing with autism, like DAN doctors, are mainly in the US; but they are not fully grounded in science and seem overly interested in unorthodox expensive lab tests and costly supplements.

So you really do have to figure out autism for yourself, if you want to control it.