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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.





23 comments:

  1. Another Russian GABA-B agonist that is similar to Baclofen is Phenibut.

    http://en.wikipedia.org/wiki/Phenibut

    We only tried L-Theanine which is a GABA agonist as well - we didn't see much from it although our son is not the ADHD - anxiety phenotype.

    Both Phenibut and L-Theanine can cross BBB.

    K



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    1. Thanks.

      I see that it is widely used for anxiety and while a drug in Russia, it is a supplement elsewhere.

      Another option for those with anxiety

      Delete
  2. Thanks for that study, Peter. I am interested that they used it for ADHD, as there are already a number of effective treatments for that condition, we have several licensed medications in the UK already.

    I should clarify that I tried 13 relatively high functioning autistic children on baclofen. In 9 it was effective - parents reported a lot fewer tantrums, better sleep, a more relaxed child. One teenage boy refused to continue taking it as he didn't like the way it calmed his behaviour! The other 4 did not respond. Two of these were complex children whose diagnosis was uncertain, two were already on treatment for ADHD - but so were some of the respoonders. So a bit of a mixed bag, & not a 100% response rate by any means.

    I was trying to target children whose behaviour difficulties were rooted in anxiety, but in a population of young children (aged 6 to 13) who all had some degree of communication problem, this was always going to be difficult. Possibly in some the baclofen was treating a different problem - your theory of muscle tension in children with autism is very valid, in fact prescribing baclofen on this basis would actually be using it for its licensed purpose, whereas prescribing it for anxiety is using it off label.

    One child has been on the same dose for a year with continued benefit & no sign of tolerance.

    It really needs a research project or a clinical trial to take it forward, & I am not in a position to undertake this sort of work. I am still hoping to find some research already completed which would support my prescribing.

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    1. I think there will be a study on autism, but in Russian. It is a standard in Russia for Autism and people claim cognitive improvements.

      Delete
  3. Hi Peter,

    Yes I am the reader that forwarded you the research linking GABAb to Somatostatin. I'm still very interested in finding ways to reduce our child's anxiety, although with your recommendations, he and we are in a much more favourable position now than 6 months ago.

    The Propolis is definitely providing a cognitive boost - my highly critical wife's words.The Broccoli is allowing him to engage socially much more with more and more unprompted expression. The NAC is reducing his repetitiveness. This three pronged attack is working wonders. There are many examples of these positive changes and believe me we notice every one of them as any Autism parent would. One such example as recent as yesterday was the ability (for the first time) of our child to shift his thoughts and actually consider what someone else was thinking. It was a Mr. Bean video where he is on a very high diving platform and the pool inspector calls him out. Our child actually asked me, 'what is the inspector thinking that Mr. Bean is going to do?' This was huge! Never has our child considered anyone but himself. His teachers describe him as very egocentric - and he is, but not at all in a nasty way. There are just many more examples like this since we started on these three supps in particular. They seem to work better together, that is, the sum is greater than the total of parts.

    The anxiety still holds him back though, albeit to a lesser extent. With us he's fine, but the introduction of someone new overwhelms him and you can see everything just tighten up very rigid-like. And yes he does have very low muscle tone.

    One area I might have overlooked is the effect that results when he has just eaten. He receives what I could only describe as a 'turbo' like burst or pulse of energy. Almost like taking a 'Proton' pill - think Roger Ramjet. He is not a hyperactive child but after he has eaten, it's like the food has gone to his head and it doesn't really matter what he's eaten. For one thing, he just does not like chocolate or sweets at all, only savoury. He just has to expend this energy and then he calms down and is fine again. It really is quite astonishing to see.

    Have you any thoughts on this Peter?

    How available is Baclofen? Do you need a script?

    Regards,
    D&G

    ReplyDelete
  4. Did you ever check your son's fasting blood sugar level?

    Baclofen is an inexpensive prescription drug, but you may struggle to obtain it.

    The Russian equivalents, Pantogam and Phenibut, might be easier to obtain, as drugs here:-

    http://rupharma.com/products/pantogam

    Phenibut is widely sold as a Nootropic supplement in the US, UK and Australia.
    Drugs have the advantage of serious quality control, I am not so sure about Nootropic supplements.

    Pantogam is an autism drug, at least in Russia.

    What dose of Propolis are you giving?

    ReplyDelete
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    1. Hi Peter,

      Thanks for the reply. We are giving 2x10 drops during the week and 3x10 on weekends of Propolis. It does provide a cognitive boost as mentioned but it does taper off.

      We did carry-out some blood work recently and I don't recall the blood sugar level standing out for any reason but I will revisit the results to confirm.

      Thanks again.

      Regards,
      D&G

      Delete
    2. Baclofen is easily available from online pharmacies & is generally of reliable quality from these sources - as Peter says "supplements" are of unreliable quality.

      When Peter says "Pantogram is an autism drug, at least in Russia" I am not sure we know what the Russians use Pantogram for. This site is all about "treating autism", which I gather implies improving core function in children who have significant deficits in communication, social interaction & flexibility. My own prescribing of baclofen is to treat anxiety in children with autism who are relatively high functioning. I would not recommend it as a "treatment" for autism.

      This is just to clarify my own post above in case there is any misunderstanding.

      Best of luck to all of you with your own treatment regimes.

      Delete
  5. Hi, My son has been using Pantogam Active for the past 3-4 months with great success in the area of overall calming and sleep. I am sensing that he might be building up a tolerance and that we should take a break (as recommended on the enclosed literature with the drug).
    Does anyone have any suggestions as a replacement drug/supplement that can act as a GABA-b agonist, which I assume the Pamtogam is?
    Thanks very much.
    Nancy

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    1. Nancy, drugs that might have a similar effect include Baclofen, Phenibut and Gabapentin. All these drugs are slightly different and so may, or may not, help. Phenibut is another Russian drug, that was sold as a supplement in the US, but that may no longer be the case. Baclofen is a cheap generic drug.

      Delete
    2. Just to note Phenibut and Gabapentin have to be careful cycled up and down, big withdrawl issues for both if you're not careful.

      Phenibut is consistently rated one of the most impactful "nootropics" in the community.

      Delete
  6. Baclofen is a novel emerging therapeutic treatment in aberrant behaviors associated with dysfunctional GABAb receptors in autism. It should be furthered researched and tried as a last resort in treatment resistant patients. As for side effect of seizures, it is only contratindicated for patients with absence seizures, not other seizure disorders.

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  7. Ive been following this with great interest, as my son, who was in the study mentioned above, improved dramatically whilst on the arbaclophen.
    You make the same valid points as I've come to, and if you would like to pick my brains- feel free. I never stop.

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    1. What exactly was the effect you got from Arbaclofen? Did you ever try standard baclofen?

      Delete
    2. He improved dramatically. Cognitively,it removed a great deal of anxiety thought by some to be the major stumbling block to learning difficulties regarding those with FXS. Once, we accidently changed his dose while in the trial to a higher dose. This brought on extreme aggravation, but once I located the error, I was able to calm him by explaining the dosage error and the time it would take for it to diminish. It was completely understood. I am highly aware of the placeobo effect- even the difficulties from a truthfully unbiased parent- which is one of the reasons it was not approved. However, considering it is now of interest again, this time by another pharmaceutical company, gives me doubts to the real reason it wasn't approved in Seaside's trial.

      Delete
    3. Also, to answer your first question - when the trial was discontinued, we were given Baclofen to wean him off of Arbaclofen, and while we still noticed great difficulties during the process, we came to the conclusion that the Baclofen was 'better than nothing' regarding his regular meds (sertraline and B vitamins compounded)that he also had to stop while in the first phase of the trial. I have obtained some of the Russian Pantogam Aktiv but have not tried it yet. The dosage is hard for me to calculate as we weren't told the amount of Arbaclofen he was on during the trial, and of course the overall anxiety of treatment without enough medical knowledge regarding chemical compounds and the effects on the brain. If we knew the exact dose he was given during the trial I would be less trepidacious as I am dying to try it, but am afraid to as we saw first hand how one higher dose effected him. Anyone with advice or encouraging words about this dilemma would be greatly appreciated.

      Delete
    4. Arbaclofen is far more potent than baclofen. Pantogam is in effect the Russian equivalent of Baclofen, targeting GABAb receptors. From the people selling it:-

      "The general dose is 300-900mg (1-3 capsules) 15-20 minutes after meal 2-3 times per day (preferably in the morning and at day time). Maximum dose is 2400mg (8 capsules)."

      The whole idea of arbaclofen was to make a super-potent baclofen. So it must have been more potent than the standard dose of baclofen, probably many times more potent.

      So you might as well compare the standard dose of Pantogam to see how it compares with the standard dose of Baclofen.

      Incidentally you might want to consider why arbaclofen worked.

      GABAB-mediated rescue of altered excitatory–inhibitory balance, gamma synchrony and behavioral deficits following constitutive NMDAR-hypofunction

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410621/

      It is likely that your son has reduced NMDAR signaling.

      There are plenty of ways other than Baclofen to treat this. You need to upregulate NMDA receptors.

      Delete
    5. S, you might want to consider the numerous other Fragile-X trials that "failed". Most of these use readily available drugs targeting then same E/I imbalance as Arbaclofen.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396424/table/t1-tacg-8-075/

      Delete
  8. There is also CGP7930, Gaba b receptor agonist, a positive allosteric modulator, being tested with promising results for its anxiolytic, antidepressant effect and also possibly effective for tinnitus and addiction. It doesn't have the adverse side effects of baclofen. Maybe helpful for Asperger's anxiety?

    ReplyDelete
  9. Has anyone looked into or know of using ketamine infusions to decrease glutamate for ASD? Perhaps even in combination with Baclofen?

    ReplyDelete
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    1. Intranasal ketamine is currently being trialled in autism. If you use the "search this blog" function in this blog you can see what I previously wrote about it. Look at the top right of the page.

      Delete
  10. My son was involved in the autism R Baclofen studies. He experienced extreme improvement with his life limiting social anxiety issues. He crashed hard when the study was discontinued and returned to being a shut in. We saw more gradual improvement with straight Baclofen, but now he is able to work, shop, and socialize in public. He takes 20 Mg 4 every 6 hours. The only downside is that he begins to experience withdrawal symptoms if a dose is only a few hours late.

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    Replies
    1. That is interesting. What kind of autism does he have? Is it more like Asperger's, since you say he is able to work.

      Delete

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