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.