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Showing posts with label Arbaclofen. Show all posts
Showing posts with label Arbaclofen. Show all posts

Monday, 3 April 2017

Different Types of Excitatory/Inhibitory Imbalance in Autism, Fragile-X & Schizophrenia


There is much written in the complex scientific literature about the Excitatory/Inhibitory (E/I) imbalance between neurotransmitters in autism. 

Many clinical trials have already been carried out, particularly in Fragile-X.  These trials were generally ruled as failures, in spite of a significant minority who responded quite well in some of these trials.

As we saw in the recent post on the stage II trial of bumetanide in severe autism, there is so much “background noise” in the results from these trials and it is easy to ignore a small group who are responders.  I think if you have less than 40%, or so, of positive responders they likely will get lost in the data. 

You inevitably get a significant minority who appear to respond to the placebo, because people with autism usually have good and bad days and testing is very subjective.

There are numerous positive anecdotes from people who participated in these “failed” trials.  If you have a child who only ever speaks single words, but while on the trial drug starts speaking full sentences and then reverts to single words after the trial, you do have to take note. I doubt this is a coincidence.

Here are some of the trialed drugs, just in Fragile-X, that were supposed to target the E/I imbalance:-

Metabotropic glutamate receptor 5 (mGluR5) antagonist

·        Mavoglurant

·        Lithium

mGluR5 negative allosteric modulator

·        Fenobam

N-methyl-D-aspartic acid (NMDA) antagonist

·        Memantine

Glutamate re-uptake promoter

·        Riluzole

Suggested to have effects on NMDA & mGluR5 & GABAA

·        Acamprosate

GABAB agonist

·        Arbaclofen

Positive allosteric modulator (PAM) of GABAA receptor

·        Ganaxolone


Best not to be too clever

Some things you might use to modify the E/I imbalance can appear to have the opposite effect, as was highlighted in the comments in the post below:-



So whilst it is always a good idea to try and figure things out, you may end up getting things the wrong way around, mixing up hypo and hyper.

The MIT people who work on Fragile-X are really clever and they have not figured it all out.


Fragile-X and Idiopathic Autism

Fragile-X gets a great deal of attention, because its biological basis is understood.  It results in a failure to express the fragile X mental retardation protein (FMRP), which is required for normal neural development.

We saw in the recent post about eIF4E, that this could lead to an E/I imbalance and then autism.




Our reader AJ started looking at elF4E and moved on to EIF4E- binding protein number 1.

In the green and orange boxes below you can find elF4E and elF4E-BP2.

This has likely sent some readers to sleep, but for those whose child has Fragile-X, I suggest they read on, because it is exactly here that the lack of fragile X mental retardation protein (FMRP) causes a big problem.  The interaction between FMRP on the binding proteins of elF4E, cause the problem with neuroligins (NLGNs), which causes the E/I imbalance.  Look at the red oval shape labeled FMRP and green egg-shaped NLGNs.

In which case, while AJ might naturally think Ribavirin is a bit risky for idiopathic autism, it might indeed be very effective in some Fragile-X.  You would hope some researcher would investigate this.




Can you have more than one type of E/I imbalance?

Readers whose child responds well to bumetanide probably wonder if they have solved their E/I imbalance.

I think they have most likely improved just one dysfunction that fits under the umbrella term E/I imbalance.  There are likely other dysfunctions that if treated could further improve cognition and behavior.

On the side of GABA, it looks like turning up the volume on α3 sub-unit and turning down the volume on α5 may help. We await the (expensive) Down syndrome drug Basmisanil for the latter, given that the cheap 80 year old drug Cardiazol is no longer widely available. Turning up the volume on α3 sub-unit can be achieved extremely cheaply, and safely, using a tiny dose of Clonazepam.

It does appear that targeting glutamate is going to be rewarding for at least some of those who respond to bumetanide.

One agonist of NMDA receptors is aspartic acid. Our reader Tyler is a fan of L-Aspartic Acid, that is sold as a supplement that may boost athletic performance.  

Others include D-Cycloserine, already used in autism trials; also D-Serine and L-Serine.

D-Serine is synthesized in the brain from L-serine, its enantiomer, it serves as a neuromodulator by co-activating NMDA receptors, making them able to open if they then also bind glutamate. D-serine is a potent agonist at the glycine site of NMDA receptors. For the receptor to open, glutamate and either glycine or D-serine must bind to it; in addition a pore blocker must not be bound (e.g. Mg2+ or Pb2+).

D-Serine is being studied as a potential treatment for schizophrenia and L-serine is in FDA-approved human clinical trials as a possible treatment for ALS/Motor neuron disease.  

You may be thinking, my kid has autism, what has this got to do with ALS/Motor neuron disease (from the ice bucket challenge)? Well one of the Fragile-X trial drugs at the beginning of this post is Riluzole, a drug developed for specially for ALS.  Although it does not help that much in ALS, it does something potentially very useful for some autism, ADHD and schizophrenia; it clears away excess glutamate.


Fragile-X is likely quite different to many other types of autism

I suspect that within Fragile-X there are many variations in the downstream biological dysfunctions and so that even within this definable group, there may be no universal therapies.  So for some people an mGluR5 antagonist may be appropriate, but not for others.

Even within this discrete group, we come back to the need for personalized medicine.

I do not think Fragile-X is a good model for broader autism.


Glutamate Therapies

There are not so many glutamate therapies, so while the guys at MIT might disapprove, it would not be hard to apply some thoughtful trial and error.

You have:

mGluR5

     ·        mGluR5 agonists (only research compounds)

·        mGluR5 positive allosteric modulators (only research compounds)

·        mGluR5 antagonists (Mavoglurant, Lithium)

·        mGluR5 negative allosteric modulators (Fenobam, Pu-erh tea decreases mGluR5 expression )

Today you can only really treat too much mGluR5 activity.  It there is too little activity, the required drugs are not yet available.  I wonder how many people with Fragile-X are drinking Pu-erh tea, it is widely available.


NMDA agonists

D-Cycloserine an antibiotic with similar structure to D-Alanine (D-Cycloserine was trialed in autism and schizophrenia)

ɑ-amino acids:

·         Aspartic acid (trialed and used  by Tyler, suggested for schizophrenia)

·         D-Serine (trialed in schizophrenia)




NMDA antagonists


·        Memantine (widely used off-label in autism, but failed in clinical trials)


·        Ketamine (trialed intra-nasal in autism)


Glutamate re-uptake promoters via GLT-1


·        Riluzole


·        Bromocriptine


·        Beta-lactam antibiotics









Saturday, 1 August 2015

NMDAR hypo-function causing E/I imbalance in Autism and Schizophrenia – Baclofen, Sodium benzoate and Cinnamon (again)


Click on figure to enlarge

Interpretation, extrapolation and graphic - Peter  


Today’s post is not the one I intended.

It nearly got tucked into long complicated one, that most people might not read.

I should caution that I am perhaps over-simplifying something that is extremely complicated, but no one fully understands the subject.

There is much talk in autism about the imbalance between excitatory and inhibitory processes. In this blog this is normally all about the inhibitory neurotransmitter, GABA, not functioning properly.

There is of course another side to the story.  The excitatory neurotransmitter Glutamate signals via receptors including the NMDA receptors.  If signaling via these receptors is either up or downregulated, the delicate balance between excitatory and inhibitory can again be lost.

What caught my interest was an experiment on mice that caused downregulation of (excitatory) NMDA signaling. This caused the famous E/I imbalance and resulting autistic behavior.

The interesting part is that the researchers normalized the imbalance and the autism not by targeting NMDA but by targeting GABA.  They used baclofen that acts on GABAB receptors.  So they made the mouse autistic by adjusting NMDA (Glutamate) signaling, but recovered the mouse by adjusting the GABA signaling.  This is really quite compelling and made me look into the E/I imbalance again.

It also neatly explains why anti-epileptics, like valproate, when given during pregnancy can result in autistic off spring.  The Valproate increases GABA signaling, i.e. it inhibits neurons from firing too easily.  This reduced the tendency towards seizures.  It will unfortunately also enter the blood stream of the unborn child.  Here again it will shift the E/I balance towards inhibitory, but unlike in the mother, the E/I balance in the child was perfectly fine.  The valproate shifts the E/I balance out of the “safe zone” into the inhibitory danger zone.  This then can affects critical processes in the developing brain leading to autism.
   


NMDA hyper/hypo function

In earlier posts we have already seen that in autism NMDA activity be hyper (too much), hypo (too little) or normal.  There are drugs that can increase NMDA activity and others that reduce it.

In this post the research shows that reduced NMDAR signaling has been associated with schizophrenia, (some) autism and intellectual disability. 

A person with autism might be in this group, but as we saw in earlier posts on NMDA they might be in the opposite group and so have excessive NMDAR signaling.  A bit of trial and error would reveal whether the person was hyper, hypo or just right.  All three are possible in autism.   


GABA/Glutamate imbalance in Autism

The neurotransmitter GABA is supposed to be inhibitory and it is kept in balance by the excitatory neurotransmitter Glutamate. Glutamate binds to NMDA receptors and AMPA receptors.  GABA binds to GABAA and GABAB receptors.

In 2003 John Rubenstein and Michael Merzenich published a paper suggesting that autism might be the result of an E/I imbalance that disrupted both the development of the brain at critical periods and also was the underlying cause of some on-going autistic symptoms, including epilepsy (found in 30% of “old” autism) and what I refer to as pre-epilepsy (odd epileptiform activity without seizures – another 40% of “old” autism).  Plenty of subsequent research has supported their hypothesis.


Once well-established theory for the development of autism is that the balance of various neurotransmitters is out of balance.  GABA, the key inhibitory neurotransmitter in the brain, ceases to inhibit the firing of neurons as it should.  The result is chaos in the brain.

In this blog we have concentrated one cause of this so called E/I (excitatory/Inhibitory) imbalance.  That cause is the presence of the NKCC1 transporter in the brain beyond the first few weeks of life.  This transporter leads to an excess of chloride inside the cells and this shifts GABA away from inhibitory to excitatory.  This then results in a GABA/Glutamate imbalance.  This impairs cognitive function and logically may be a cause of some seizures.

As Rubenstein and Merzenich observed, the hypothesis of E/I imbalance gives hope that drugs correcting this balance may treat autism. This has already been proved to be the case.

But there are other possible causes of E/I imbalance.  Today’s post is about one of those.  People who respond to the prescription drug Baclofen and the experimental drug Arbaclofen most likely are affected by this kind of E/I imbalance.

This blog has extensively covered the GABAA-related cause of E/I imbalance, for which the prescription drug Bumetanide is effective.

Baclofen affects the GABAB receptor.  One reader of this blog did tell us that in her patients with Asperger’s and anxiety did respond well to Baclofen.  They quite possibly have an E/I imbalance of the type covered in this post.  If so the underlying cause may well be NMDAR-hypofunction.

Reduced NMDAR signaling has been associated with schizophrenia, autism and intellectual disability.  By definition people with Asperger’s do not have and intellectual disability, but the Reduced NMDAR signaling may still be holding back their ever higher potential cognitive function.

As we will see, there may be a simple way to treat the NMDAR-hypofunction.

We have already covered this in an earlier post, when I talked about sodium benzoate and schizophrenia.

Sodium benzoate has multiple effects.

Sodium benzoate is a D-amino acid oxidase inhibitor. It will raise the levels of D-amino acids by blocking their metabolism and in doing so enhance NMDA function.  In doing so the E/I balance is shifted towards excitatory.


Sodium benzoate also increases the expression of a protein called DJ-1.  This is well known gene/protein because of its role in Parkinson’s disease.  The DJ-1 protein plays a supporting role to a key anti-oxidative stress defense called Nrf-1.

At times of oxidative stress, the body activated Nrf-1 which in then turns on key genes that need to respond to the stress.  In the absence of enough DJ-1, Nrf-1 is unable to sound the alarm and turn on those genes.

Sodium Benzoate is a common food additive (people with histamine intolerance “should be” allergic to it) but it is also a byproduct of eating cinnamon.  This is why cinnamon was shown to have therapeutic value in Parkinson’s disease.  Rather surprising it has also been shown to be beneficial in early Alzheimer’s disease.

In the earlier post we also saw that cinnamon had other useful effects like lowing cholesterol and improving insulin sensitivity.

We saw in the earlier post that it is important to use the “purer” cinnamon that come from Sri Lanka, since the related species from China that is commonly used by bakers does actually have side effects in large doses.

The Sri Lankan cinnamon may cost a bit more, but a one year supply is only about $15.






            Abstract

Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30–80 Hz) oscillatory abnormalities, phenotypes common to these disorders. However, circuit-level mechanisms underlying such deficits remain unclear. This study investigated the relationship between gamma synchrony, excitatory–inhibitory (E/I) signaling, and behavioral phenotypes in NMDA-NR1neo−/− mice, which have constitutively reduced expression of the obligate NR1 subunit to model disrupted developmental NMDAR function. Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABAB-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits. These data demonstrate a clinically relevant, highly translatable neural-activity-based biomarker for preclinical screening and therapeutic development across a broad range of disorders that share common endophenotypes and disrupted NMDA-receptor signaling.





IMPORTANCE In addition to dopaminergic hyperactivity, hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has an important role in the pathophysiology of schizophrenia. Enhancing NMDAR-mediated neurotransmission is considered a novel treatment approach. To date, several trials on adjuvant NMDA-enhancing agents have revealed beneficial, but limited, efficacy for positive and negative symptoms and cognition.
Another method to enhance NMDA function is to raise the levels of D-amino acids by blocking their metabolism. Sodium benzoate is a D-amino acid oxidase inhibitor.

OBJECTIVE To examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia.

DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer.

INTERVENTIONS Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo.

MAIN OUTCOMES AND MEASURES The primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment.

RESULTS Benzoate produced a 21% improvement in PANSS total score and large effect sizes
(range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms–20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health’s Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects.

CONCLUSIONS AND RELEVANCE Benzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia.



Abstract 
This study underlines the importance of cinnamon, a widely-used food spice and flavoring material, and its metabolite sodium benzoate (NaB), a widely-used food preservative and a FDA-approved drug against urea cycle disorders in humans, in increasing the levels of neurotrophic factors [e.g., brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3)] in the CNS. NaB, but not sodium formate (NaFO), dose-dependently induced the expression of BDNF and NT-3 in primary human neurons and astrocytes. Interestingly, oral administration of ground cinnamon increased the level of NaB in serum and brain and upregulated the levels of these neurotrophic factors in vivo in mouse CNS. Accordingly, oral feeding of NaB, but not NaFO, also increased the level of these neurotrophic factors in vivo in the CNS of mice. NaB induced the activation of protein kinase A (PKA), but not protein kinase C (PKC), and H-89, an inhibitor of PKA, abrogated NaB-induced increase in neurotrophic factors. Furthermore, activation of cAMP response element binding (CREB) protein, but not NF-κB, by NaB, abrogation of NaB-induced expression of neurotrophic factors by siRNA knockdown of CREB and the recruitment of CREB and CREB-binding protein to the BDNF promoter by NaB suggest that NaB exerts its neurotrophic effect through the activation of CREB. Accordingly, cinnamon feeding also increased the activity of PKA and the level of phospho-CREB in vivo in the CNS. These results highlight a novel neutrophic property of cinnamon and its metabolite NaB via PKA – CREB pathway, which may be of benefit for various neurodegenerative disorders.

There are several advantages of NaB and cinnamon over other proposed anti-neurodegenerative therapies. First, both NaB and cinnamon are fairly nontoxic. Cinnamon has been widely used as flavoring material and spice throughout the world for centuries. Cinnamon is metabolized to NaB. NaB is excreted through the urine, if in excess.

Second, cinnamon and NaB can be taken orally, the least painful route.

Third, cinnamon and NaB are very economical compared to other existing anti-neurodegenerative therapies.

Fourth, after oral administration, NaB rapidly diffuses through the BBB. Similarly, after oral administration of cinnamon, we also detected NaB in the brain

Fifth, glycine toxicity is a problem in different neurological diseases because for movement disorders, glycine is one of the factors for inhibiting motor neurons. When impaired, glycinergic inhibition leads to spastic and hypertonic disorders such as featured in PD, multiple sclerosis (MS) and spinal cord trauma. NaB is known to combine with glycine to produce hippurate, a compound that is readily excreted in the urine. Because PD and MS patients exhibit significant elevation in plasma level of glycine, NaB and cinnamon may have added benefits for MS and PD.




Benzoate, a D-amino acid oxidase inhibitor, for the treatment of early-phase Alzheimer disease: a randomized, double-blind, placebo-controlled trial.

Abstract 

BACKGROUND: 
N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission is vital for learning and memory. Hypofunction of NMDAR has been reported to play a role in the pathophysiology of Alzheimer disease (AD), particularly in the early phase. Enhancing NMDAR activation might be a novel treatment approach. One of the methods to enhance NMDAR activity is to raise the levels of NMDA coagonists by blocking their metabolism. This study examined the efficacy and safety of sodium benzoate, a D-amino acid oxidase inhibitor, for the treatment of amnestic mild cognitive impairment and mild AD.

METHODS:
We conducted a randomized, double-blind, placebo-controlled trial in four major medical centers in Taiwan. Sixty patients with amnestic mild cognitive impairment or mild AD were treated with 250-750 mg/day of sodium benzoate or placebo for 24 weeks. Alzheimer's Disease Assessment Scale-cognitive subscale (the primary outcome) and global function (assessed by Clinician Interview Based Impression of Change plus Caregiver Input) were measured every 8 weeks. Additional cognition composite was measured at baseline and endpoint.

RESULTS:
Sodium benzoate produced a better improvement than placebo in Alzheimer's Disease Assessment Scale-cognitive subscale (p = .0021, .0116, and .0031 at week 16, week 24, and endpoint, respectively), additional cognition composite (p = .007 at endpoint) and Clinician Interview Based Impression of Change plus Caregiver Input (p = .015, .016, and .012 at week 16, week 24, and endpoint, respectively). Sodium benzoate was well-tolerated without evident side-effects.

CONCLUSIONS:
Sodium benzoate substantially improved cognitive and overall functions in patients with early-phase AD. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for early dementing processes.


The implications

There are numerous implications, since cinnamon is very cheap and Sri Lanka Cinnamon is seen as very safe.

·        Take cinnamon to lower the risk of Parkinson’s and Alzheimer’s
·        Take cinnamon if you have got Parkinson’s or Alzheimer’s
·        Take cinnamon if you are type 1 or 2 diabetic to improve insulin sensitivity
·        Take cinnamon if you have high cholesterol (perhaps you do not like Statins)
·        Rather unexpectedly, it is suggested that cinnamon should also help multiple sclerosis (MS) because it reduces glycine toxicity which otherwise leads to spastic and hypertonic disorders
·        Trial cinnamon if you have Asperger’s, Schizophrenia, Autism, MR/ID and even COPD
·        Trial cinnamon if (ar)baclofen positively affects your cognitive or emotional function.


Note that some people diagnosed with “autism” have the opposite NMDA dysfunction, they have too much signaling rather than too little.

One method to enhance NMDA function is to raise the levels of D-amino acids by blocking their metabolism. Sodium benzoate is a D-amino acid oxidase inhibitor. Cinnamon is metabolized in the body to sodium benzoate.

Giving cinnamon to someone with hyperfunction of NMDA, should make their symptoms worse.

Sodium Benzoate/Cinnamon also increases the level of BDNF



It is thought that BDNF  increases excitatory synaptic signaling partly



“BDNF increases spontaneous network activity by suppressing GABAergic inhibition, the site of action of BDNF is predominantly postsynaptic, BDNF-induced suppression of GABAergic synaptic transmission is caused by acute downregulation of GABAA receptors, and BDNF effects are mediated by its TrkB receptor and require PKC activation in the postsynaptic cell.”


BDNF is commonly elevated in autism.


So you would then expect that some people with autism/schizophrenia would benefit while others would not.


Since some people are allergic to sodium benzoate it would wise to start with a tiny amount of cinnamon.


Cinnamon has been used medicinally for centuries.

Cassia cinnamon from China, Vietnam or Indonesia contains coumarin.  Courmarin is not good for you.  Cassia cinnamon is what is normally used in food products, to save money.


In an earlier post:



we saw that Clioquinol and  D-Cycloserine should help those with those with reduced NMDAR function.

Those with elevated NMDAR function would benefit from Memantine and Ketamine.

So logically Clioquinol and  D-Cycloserine should help schizophrenia:-



Nobody seems to have tried Clioquinol on schizophrenia.



Baclofen for Schizophrenia

It is would also be logical that if some people with schizophrenia do have reduced NMDAR signaling then Baclofen should also help them, just as Sodium Benzoate has been shown to do and therefore cinnamon should.

Going back to 1977 Baclofen was indeed found to be effective in some types of schizophrenia





Conclusion


I think that Cinnamon is a better bet than Sodium Benzoate, because you actually may have other substances involved, not just NaB.

The dose at which cinnamon shows tangible biological effects in humans (lowing cholesterol etc.) is around 3g a day.  For those who can swallow capsules, that would be 3 large (size 000) gelatin capsules a day, otherwise you have to find a way of eating a teaspoonful of cinnamon a day.

According to the research “cinnamon has been widely used as flavoring material and spice throughout the world for centuries. Cinnamon is metabolized to NaB. NaB is excreted through the urine, if in excess.”  So it looks a safe therapy, whether it helps autism will depend on the specific biology of that individual.










Wednesday, 13 May 2015

Arbaclofen Given a Second Chance by the Simons Foundation


 Light at the end of the tunnel, for some


I did recently write about autism drugs that target the GABAB receptor.

Western doctors have Baclofen and a few did have experimental use of the more potent version called Arbaclofen, or R-Baclofen.  We saw that Russian doctors have a wider choice.

The rights to use Arbaclofen have been acquired by the Simons Foundation, and they intend to restart autism trials in humans.



  
Arbaclofen was found to be effective in some people with Fragile-X and autism, but it failed its clinical trial and the developer, Seaside Therapeutics, went out of business.

The Simons Foundation, for those who do not know, is probably the best thing to ever happen to people with autism.  The founder of the foundation is an American multi-billionaire, former fund manager and mathematician.  He has a daughter with autism and decided to do something about it.

Having already funded a great deal of research, including by some of the scientists on my Dean’s List, it looks like he is going one step further and taking ownership over the trial drugs themselves.  Being a mathematician he is not averse to funding the most complex areas of research which include genetics and ion channels.  Being a fund manager he understands risk.  Being rich also helps, but you also need to be philanthropic.

Given the poor performance to date of developing practical therapies from the vast wealth of existing autism research, this is a very encouraging development.

There is now a large industry being made out of autism research, but the only coordinated part of it seems to be the Simons Foundation.  Interestingly the Simons Foundation focuses its effort on the very best scientists and not the existing autism researchers.  Apparently they want Nobel Laureates and future Nobel Laureates.  That sounds good to me.

Some people are concerned that by focusing on specific areas like genetics, the Simons Foundation may miss other possibly fruitful avenues.  But it is usually the case that an intelligent person's well thought out strategy is better than no strategy, and, at the end of the day, Simons’ billions are his to spend as he pleases.

Hopefully Simons will do for autism, what Bill and Melinda Gates are doing for polio and malaria.






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.