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Showing posts with label GABAb. Show all posts
Showing posts with label GABAb. Show all posts

Wednesday 16 December 2015

Long Term use of Low Dose Clonazepam and More Science on the Excitatory/Inhibitory Imbalance in Schizophrenia and ASD


   
A small number of readers of this blog have followed Professor Catterall’s ideas and trialed low dose clonazepam for autism.  

This post summarizes my findings from using it long-term; it would be a good place to collect the findings of other people.


The science part of this blog is courtesy of a reader who highlighted the full-text version of a paper I mentioned.  Perhaps it was the author?

For information on Catterall’s clonazepam research, go to the “Index by Subject” tab and click on Clonazepam.






Before getting to that, I do get asked how I know, for sure, these therapies really do work for Monty, aged 12, with classic autism.  As I told Ben-Ari, the Bumetanide researcher, the best way to convince the doubting public will be to measure IQ, not autism.  If you can add 30 to 50 points to your IQ result, even the sceptics would pay attention.

I am not measuring IQ directly, but I do note things like spelling tests, math tests and handwriting.  The first pleasant surprise was actually reaching the point of sitting the same tests as the NT kids. Piano playing is another interesting proxy.

Monty’s one to one Assistant (and pal) from age 3 to 9 came to visit the other day and could not believe what his handwriting now looks like.  She had spent hundreds of hours with him practicing fine motor skills, like pencil control.  The end result was handwriting, but even then not like that of his peers. 

Cursive handwriting is now great.  Spelling tests and “quick-fire” math tests are also great.

As we now know, 20% of people diagnosed very young with quite severe autism seem to make wonderful progress.  This has happened by 5 or 6 years old, while the brain is still highly plastic.  Spontaneous accelerated development thereafter rarely seems to happen.  Monty started his Polypill therapy at the age of 9 years, in December 2012.

This is a spelling test from school, given to NT (neurotypical) ten year olds and 12 year old Monty (on paper without lines).  It is not rocket science and big brother could probably have got 20/20 in this test when he was eight years old.  But when Monty was eight years old, he was trying to break the windows of my car with his head and his handwriting did not look like this.





I have all the proof I need that modulating the excitatory/inhibitory imbalance in Monty’s autism is well worth the effort.  The effects are reversible if you stop the therapy, as should be the case.


Clonazepam

Here I am repurposing an existing drug for a different use, at a dosage so low it is highly unlikely to cause side effects.  This is mirroring the use of the same drug, at similar low doses, in mouse models of autism by Professor Catterall.

Clonazepam at “high” doses is widely used already in people with autism, to treat seizures and extreme anxiety.  

Catterall showed that the drug has a totally different effect at very low doses (less than 10% of normal), via a specific mechanism which he has identified, the positive modulation of the α 2,3  subunits of GABAA receptors. 

GABAA receptors are made up of five sub-units, the strict composition does indeed vary over time, just to make things even more complicated.  The most common GABAA receptors have two αs, two βs, and one γ 2β2γ). For each subunit, many subtypes exist (α1–6, β1–3, and γ1–3). It is these subtypes of the subunits that Catterall showed to be key.  Clonazepam was one of the substances that he showed to be effective (in mice).

At “high” doses Clonazepam does have side effects, people build up tolerance to it and so take ever higher doses, and then they get hooked on it.

At very low doses the reverse seems to occur.  Over time you become more sensitive to it and need lower and lower doses.  This was a surprise to me.

The other surprise was that slightly above the effective “low dose” you get some anxiety and irritability.  When I first wrote about this I did wonder if this was just a coincidence, but it is not.

My chart from back then:-




Another interesting point was that some other readers found the effective dose was even less than mine.

When you read about the use of Clonazepam at regular, much higher doses, it is clear that there are wide variations in people’s sensitivity to this drug.  So much so that there is standard lab test to measure blood concentration of this drug, so that the clinician can vary the dose to achieve the desired level in blood.



It is not an expensive test and I did wonder if this could be used by clinicians to find the effective low dose in their patients with autism.

It did sound a clever idea, but then I read that even the same blood concentration of clonazepam (at high doses) can have markedly different effects in different people.  Still it is better than doing nothing and would reduce some of the guesswork with dosage.



The effective dose

In my n=1 example, the effective dose started out at 40mcg a day.  The half-life is very long and so you need three days to reach a stable level.

Other people contacted me to say that in their case 25mcg a day was effective and in one case, dosage once every two days was optimal.

In my case 40mcg, now gives the negative effects I has originally discovered at higher doses.

Currently the effective dose is 20 to 25 mcg.

This is a tiny dose, technically sub-clinical, but it really is better than giving none.  I have discontinued on several occasions.  There is cognitive loss, which is then regained when re-starting. 

The incremental cognitive effect is not as great in magnitude as I found with Bumetanide, but in people not using Bumetanide, the effect seems to be much greater.  Put more simply, Clonazepam plus Bumetanide is more beneficial than Bumetanide alone, at least in my case.

At this dose the annual cost of the therapy is one dollar/euro/pound. So it will not break the bank.

Tablets are available as 0.5mg  (giving 20 days of use) and 2mg (giving 80 days of use).  A bottle of 2mg tablets will last someone a few years.

I wish they made 0.025 mg (25 mcg) tablets.

I see no reason why, in ten to twenty years’ time, low dose clonazepam will not be a mainstream therapy for some autism; the only problem is the variability of the effective dosage.



Science

For those diehards who have made it this far, now I move from the Peter-reviewed science to the Peer-reviewed science, but from yet another Peter, Peter Penzes from Northwestern University, close by the Windy City.




Abstract: Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism.
Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.


This study really shows how the common genetic dysfunctions in both schizophrenia and autism come together to produce the Excitatory/Inhibitory (E/I) imbalance.  Numerous different dysfunctions result in the same imbalance, some relate to GABA and some to NMDAR, but the end result is the same.

It is a really good paper, mentioning many of the genes we have encountered in this blog, plus many of the pathways like mTOR and even PAK inhibitors.

The study does not cover any therapeutic methods to correct the E/I imbalance, but this blog has those in spades.  They relate to modulating GABAA, GABAB and NMDA receptors.

Low dose clonazepam is modulating GABAA , as does Bumetanide and as should Acetazolamide (Diamox).  More of that in 2016.









Thursday 23 April 2015

Buy Arbaclofen for Autism? Perhaps try Pantogam Aktiv?


             
An Enantiomer is like a mirror image,
so there are two versions of the “same” molecule one called R- and one called  S-


Some people are still looking to obtain Arbaclofen to treat autism and Fragile-X, they regularly stumble upon this blog.

A couple of years ago there was a lot of interest in Arbaclofen (R-baclofen), a GABAB drug, which is, in effect, a special version of a cheap existing drug called Baclofen.  Baclofen is generally used to treat spasticity, but also alcoholism and even hiccups.

As we saw in earlier posts, the drug Baclofen is a mixture of R-Baclofen and S-Baclofen. The research showed that their action is different and that S-Baclofen reduced the effect of R-baclofen.  So in some modes of action, pure R-Baclofen would have much greater effect than the regular Baclofen mixture.

If you use the "index by subject" on this blog, which is a tab at the top, you can find the posts that relate to Arbaclofen.

Arbaclofen

Arbaclofen Research in Autism/Fragile X

This very expensive episode was triggered by one child with autism being prescribed regular Baclofen, for an unrelated issue.  That child’s autism had dramatically improved, this then led to the interest of Seaside Therapeutics, who already had another prospective autism drug.

After tens of millions of dollars spent, everything stopped a couple of years ago.  The developer, Seaside Therapeutics, appears to have been shut down, although in its clinical trial a substantial minority found the drug was effective.  The way the trial had been structured, the drug did not achieve is “primary endpoint” and so Roche, the potential follow-on investor, deemed the trial a failure.

This led to many unhappy parents seeking alternative sources of R-Baclofen, which they believed had been effective.


Baclofen for Asperger’s?

At least one regular reader of this blog finds that Baclofen is very helpful for himself.

Yesterday before completing this post I had some exchanges with a UK pediatrician (spelled paediatrician in the UK) who is prescribing Baclofen to eight children with Asperger’s to treat anxiety. The results are very positive.  I do wonder is this a 100% response rate,  or are the eight a subset of all the children that have tried the drug?

One of our Australian readers of this blog is very interested in minimizing anxiety in his child with high functioning autism.  He did forward me some research, a while back,  that links GABAB to Somatostatin, also called Growth Hormone Inhibiting Hormone (GHIH) .  The research from Carnegie Mellon shows that GHIH changes the way the brain functions. 
This does get very complicated the more you dig and, until today, I did not start to write up my findings.  This is just some initial thoughts/links for scientists.
“Furthermore, by silencing certain parts of the neuronal network, the activity of the somatostatin neurons also can change the way the brain functions, heightening some perceptual pathways and silencing others.” 

“If the levels of human growth hormone in circulation in the brain and the blood get too high, then special cells called somatostatin neurons detect this. These neurons then trigger the creation of more GHIH in the brain. This then in turn slows down the secretion of human growth hormone.”

 “Mature interneurons from this brain region mainly express either parvalbumin or somatostatin, which serve as markers of these subtypes. Parvalbumin neurons tend to fire quickly in response to signals, whereas the somatostatin ones respond more slowly.
In control mice, the ratio of these two subtypes is about 50:50. By contrast, the mutant mice show a dramatic decrease in the number of interneurons expressing somatostatin. This results in an excess of abnormally large cells expressing parvalbumin.
Despite an overall loss of interneurons, the mice have more inhibitory signals than controls do, skewing the signaling balance to excitation.” 

We do know that the various growth factors in people with autism can be disturbed, but in different types of autism that disturbance varies, just to complicate things.

Various therapies based on this are under development (one uses IGF-1 and NNZ-256 is another).  We also know that many people with classic autism have accelerated growth (both body and head) in the first two years.  We also know that brain growth is also accelerated.

We know from the genetic research that many of the anomalies relate to GABA.

We know that targeting the GABAA receptor can be hugely beneficial in classic autism (bumetanide and micro-dose clonazepam).  We can also fine tune the structure of the GABAA receptor and potentiate it using allosteric modulators (like Pregnenolone or progesterone).  This also gets very complicated.



Baclofen for Classic Autism?

Baclofen is a spasticity drug:

Spasticity (from Greek spasmos-, meaning "drawing, pulling") is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles.

People with (classic) autism as opposed to Asperger’s can have all sorts of fine and gross motor issues, particularly as young children.

They can “toe walk”, walk with their feet pointing in different directions, they can have “claw hand”.  They can struggle to control a pencil and even when they learn, their handwriting can be very sloppy.

Are these spasticity issues?  I think they probably are.

When people’s autism flares up, an early sign is worsening handwriting.

When my son’s Polypill begins to wear off in spring/summer at school at around 11 am, the claw hand returns.

I did indeed try Baclofen about a year ago.  There is an effect - no claw hand.

The problem with Baclofen is tolerance, the more you use it the higher the effective dose becomes, just like benzodiazepines.

So I noted that there was an effect, but chose to move on.


Meanwhile over in Russia

For many years in Russia they have had their own GABAB drug, similar to Baclofen, it is called Pantogam.  Pantogam has been used for years as a therapy for neurological conditions including autism.

Just as Baclofen is “racemic mixture” of left-baclofen and right-baclofen, so is Pantogam.  There is S-Pantogam and R-Pantogam.


Enantiomers

There is nothing strange about these left and right versions of a drug


Enantiomers of each other often show different chemical reactions with other substances that are also enantiomers. Since many molecules in the bodies of living beings are enantiomers themselves, there is sometimes a marked difference in the effects of two enantiomers on living beings. In drugs, for example, often only one of a drug's enantiomers is responsible for the desired physiologic effects, while the other enantiomer is less active, inactive, or sometimes even responsible for adverse effects.
Owing to this discovery, drugs composed of only one enantiomer ("enantiopure") can be developed to enhance the pharmacological efficacy and sometimes do away with some side effects. An example of this kind of drug is eszopiclone (Lunesta), which is enantiopure and therefore is given in doses that are exactly 1/2 of the older, racemic mixture called zopiclone. In the case of eszopiclone, the S enantiomer is responsible for all the desired effects, though the other enantiomer seems to be inactive; while an individual must take 2 mg of zopiclone to get the same therapeutic benefit as they would receive from 1 mg of eszopiclone, that appears to be the only difference between the two drugs.

Another good example is a common antihistamine:-
Levocetirizine (Xyzal) and cetirizine (Zyrtec)
Cetirizine, an effective H1-receptor antagonist, is a racemate mixture of two enantiomers: levocetirizine (R enantiomer) and dextrocetirizine (S enantiomer).  Chemically, levocetirizine is the active enantiomer of cetirizine. It is the L-enantiomer of the cetirizine racemate.
Cetirizine is sold as Zyrtec and Levocetirizine is sold as Xyzal.

If you prefer Claritin:
Claritin is loratadine.  The active half of this mixture is desloratadine.
So they have separated this out and produced a single-enantiomer drug made exclusively of desloratadine.  You can buy this as Clarinex/Aerius, depending on where you live.

In many cases the single-enantiomer drug works no better, it just costs more and may allow for a patent to be extended, which may mean billions of extra dollars.

Single-enantiomer drugs: elegant science, disappointing effects.
Abstract
Most new drugs are marketed as single enantiomers but many older agents are still available in racemic form. As these drugs reach the end of their patent life manufacturers become interested in marketing single enantiomer equivalents. This is called 'chiral switching' and it has been claimed that it will bring clinical benefits in terms of improved efficacy, more predictable pharmacokinetics or reduced toxicity. We reviewed the clinical evidence and prices for three recently marketed single enantiomer versions of widely used racemic drugs: escitalopram, esomeprazole and levosalbutamol. Claims of increased efficacy were based on comparisons of non-equivalent doses and any advantages seemed small and clinically unimportant. Prices of esomeprazole and levosalbutamol were higher than their racemic alternatives and we predict that these prices will remain high despite the market presence of generic versions of the racemates. Patent protection and a perception of superiority based on promotion rather than evidence will maintain price premiums for single enantiomer drugs that are not justified on the basis of clinical performance


Back to Russia

In Russia they have now marketed the single enantiomer drug of Pantogam, which is called Pantogam Aktiv.
Does Pantogam Aktiv work “better” than Pantogam, or does it just cost more?
Is Pantogam Aktiv equivalent to R-baclofen (arbaclofen)?

How would those eight kids with Asperger's in the UK fare on Pantogam Aktiv, as opposed to Baclofen?  Is tolerance an issue with Pantogam Aktiv? 

“Failed” Arbaclofen Trial
Rather than spend tens of millions of dollars on Arbaclofen, why did not someone just think of first trying Pantogam and Pantogam Aktiv on that very first child who responded to Baclofen?
When they closed the trial (and the company) why did they not suggest to those unhappy parents to try Pantogam and Pantogam Aktiv?

Pantogam Research
Most research is in Russian, but there is some in English.  Interestingly this drug affects both GABAA and GABAB.
While its main effect is on GABAB. like Baclofen, it also has the effect of modulating the GABAA response.  This effect means that when combined with benzodiazepines, where normally people build up a tolerance, and so the dose needs to be increased, no tolerance develops.  We saw this very effect on GABAA with tiny doses of other drugs in earlier posts.

 A total of 32 children aged 6–12 years with attention deficit hyperactivity disorder (ADHD) were monitored during prolonged (6–8 months) treatment with Pantogam (homopantothenic acid) at daily doses of 500–1000 mg. Treatment results were assessed using the DSM-IV core ADHD symptom scales and the WFIRS-P (parental) scale every two months. Decreases in core symptoms on the DSM-IV core ADHD symptom scale were seen at two months of treatment. Significant changes on the WFIRS-P scale took longer: improvements in self-concept, socialization, and social activity were seen at four months and in behavior and schoolwork, basic life skills, along with decreases in risk-associated behavior, at six months. Thus, in contrast to regression of core ADHD symptoms, overcoming impairments in social-psychological adaptation required longer treatment periods.




Conclusion
Arbaclofen (R-Baclofen) failed its clinical trial, so it is no wonder drug for Fragile X and classic autism, but is was effective in a minority of people. 
It is possible that it would have been much more effective on people at the other end of the spectrum, those with Asperger’s – like the reader of this blog and the UK pediatrician using cheap Baclofen.
The people behind the Arbaclofen trial were super-brainy types from MIT, dig a bit deeper and I recall family links to Fragile-X.  So objectivity went out of the window, along with all those millions of dollars.
I do not suppose Pantogam and Pantogam Aktiv are autism wonder drugs, but they must help in some cases, otherwise the Russians would not be prescribing them. 
For those who found Arbaclofen really did help, why not try Pantogam and Pantogam Aktiv?  Just use Google:- “Buy Pantogam” in place of “Buy Arbaclofen”.
You would have thought someone smart at the US NIMH would have thought of this.  There are some very clever Russians and they do have autism over there too.