Bumetanide – Maths Test ✔✔✔ Clinical trial ✖✖✖

 

Memantine, Arbaclofen and now Bumetanide stumble in clinical trials

(also the less well known Balovaptan, which Roche dropped in 2020).

Place your bets on Suramin, anyone?

 

Plus ça change, plus c'est la même chose

The more things change, the more they stay the same

The first week of the school year brought two big surprises. 

Monty, aged 18 with autism, came top of the class in the math test.  This is a big win for bumetanide treatment, because 9 years ago Monty was effectively innumerate.  With a huge effort by his Assistant, he had learnt how to read and write, but even the most basic maths was beyond him.  That all changed in 2012 thanks to Professor Ben-Ari’s published research on Bumetanide in autism.

The sad news that week was that the Phase 3 clinical trial of Bumetanide for autism had been terminated early.  

Servier and Neurochlore announce the main results of the two phase 3 clinical studies assessing bumetanide in the treatment of Autism Spectrum Disorders in children and adolescents

Paris, 7 September 2021 – Servier and Neurochlore announce that no sign of effectiveness was observed in their two phase 3 clinical studies assessing bumetanide versus placebo in the treatment of Autism Spectrum Disorders (ASD) in children and adolescents. As a consequence, Servier and Neurochlore have decided, by mutual agreement, on an early termination of the two clinical studies in progress.

“The results of the phase 3 clinical studies are a major disappointment,” declares Professor Yehezkel Ben-Ari, President of Neurochlore. “Neurochlore’s teams will now analyze in detail the results of the studies and potentially explore new approaches based on artificial intelligence, which may enable us to identify sub-populations of people suffering from Autism Spectrum Disorders, for whom bumetanide could be effective.

 

Bumetanide also did not pass the NEMO clinical trial, as a treatment for neonatal seizures back in 2015.  This then made it a bit awkward to suggest that children with severe autism might lower their risk of developing epilepsy by taking bumetanide. Since this is a blog, I can speculate.  I would imagine children with severe autism, who are bumetanide-responders, and who are treated from early childhood through to adulthood with this drug, will have a low incidence of developing seizures. Seizures develop in about 30% of those with severe autism (DSM3 autism) and are the leading cause of their early death.  

 A Poorly Constructed Trial?

If such an effective therapy shows no benefit in a trial with 400 participants, something has gone seriously wrong.

I did ask one researcher friend, who just replied bluntly that the trial must have been poorly constructed.  I thought that was a bit brutal, even by my standards.

 

Be honest and admit your limitations

Monty, aged 18, came top in maths among 15 neurotypical 16 year olds.  But the 45 pupils in the year had been split into sub-groups. Two groups of 15 taking extended maths and one group of 15 taking core maths.  For some reason, because Monty has autism they put him in the lower group.

Not to worry, after his coming top in the math test, the school agreed that he can move to one of the upper groups taking the wider math curriculum.

So Monty is no maths genius, he came top among the weakest group of typical kids.  That is the whole truth, which is different to the partial truth.

In a similar way, autism researchers need to accept that there may never be a unifying therapy for autism, one that benefits everyone.

Concentrate on the responders to your treatment and forget the rest.  If you over-sell your therapy, you will fail.

As I have said in this blog many times, most people with an autism diagnosis are not bumetanide-responders.  However, a significant minority of those with severe autism are responders to bumetanide and they will experience a transformative benefit.

Going from a basket case to a Maths Whizz even?

 

Apply common sense and don’t outsource everything

In previous clinical trials of bumetanide, critics said it was all a placebo effect because the parents knew when they were giving bumetanide rather than a placebo.  The bumetanide pill causes the diuresis and placebo does not.

Why can you not use a different diuretic as the placebo?  Answer that one!

Many people using bumetanide give up because of the diuresis.  With schoolkids, the parents will receive complaints from school about excessive toilet breaks.  There will be wetting of trousers, car seats etc.  There will be anxiety caused by urgently needing a toilet, when none is nearby.

So you need a strategy in advance of how to deal with the diuresis.

I was told that people in the one trial centre I know about, were told nothing about the diuresis and how to cope with it.  I was even told the clinician basically told the parents that it was a stupid trial.  Not a good way to ensure compliance with the trial protocol.

So what happens? Some parents will decide to stop giving the diuretic drug, at least on school days.  Maybe they think that a “double-dose” at the weekend will make up the difference.

Clinical trials are a business these days and are outsourced to companies that do this and nothing else.  Don't outsource the most critical part of your work, or at least supervise it.

 

Why, oh why, oh why?

I was contacted by a mother from the southern hemisphere who managed to get Bumetanide prescribed by a pediatrician, based on Ben-Ari's earlier publications.  The diuresis is proving a problem for her family, but the positive effects are clear, for example her son now uses the word “Mummy”, but only while taking Bumetanide.  If you are a Mum/Mom, that is a big deal.  He also now responds to his own name and is "more present", the hallmark sign of a bumetanide-responder.

She saw me on YouTube and sent me a long email, including the “why, oh why, oh why?” are more people not giving bumetanide to their child with severe autism.  There is no good answer.

This Mum, now realizing she is not alone, plans to continue Bumetanide therapy.

Good for her!

 

Who dares wins, or at least stands a chance

I was recently sent an email version of an old post I had written on myelination. The sender had read it and convinced her doctor to prescribe her son Clemastine.

Her son has a single gene autism that is known to feature impaired myelination.

I pointed out that in my blog there are many references to therapies shown to benefit different aspects of the myelination process, clemastine is just one.  Some of these therapies are OTC, like alpha lipoic acid (ALA) and the N-Acetyl glucosamine (NAG), that Tyler brought to everyone’s attention.

Is the young man in question going to improve in function taking one or all of these 3 therapies? At least the mother in question is going to give them all a good shot.

Good for her.

 

Conclusion

I have received quite a few comments and messages about the Bumetanide trial failure.  Many are along the lines of “what do we do now?” and “how long will we have to wait?”

It looks like it pays to be an early adopter, rather than having faith that clinical trials will be structured and implemented properly. 

It has been suggested in the research that a large, 10g, daily dose of the OTC supplement TMG (trimethylglycine) may have an equivalent chloride lowering effect to bumetanide.  There is only anecdotal evidence to support this, but it seems to work for our reader Nancy's adult son - good job Nancy!  The other potentially chloride lowering drugs are more difficult to obtain than bumetanide itself.

There likely will never be a single unifying therapy for autism, just like there can never be for cancer.  In both conditions it is all about specific sub-types.

You would think that the previous trial failures in autism would have caused people to learn this important lesson.  

Hopefully, in the future Suramin clinical trials, where two competing companies are using the same therapy, it will not be assumed that everyone must be a responder for the therapy to be valid.  From the data, it does look like Suramin improves symptoms in a significant percentage of those with severe autism; but the same can also be said of Bumetanide, based on the earlier trials

In December Monty will commence his 10th year of Bumetanide therapy. We have made short breaks periodically to check it is still needed. For our case of autism, Professor Ben-Ari clearly got the science right and transformed a little boy's future life, something Ben-Ari can always be proud of. 

The Kynurenine Pathway in Autism and its modification using Sulforaphane or the probiotic Lactobacillus Plantarum 299v

 

 A pathway to somewhere, hopefully

Today’s post was prompted by our reader George’s observation that the probiotic Lactobacillus Plantarum 299v increased speech in his adult son.  This widely available probiotic is commonly used to treat IBS (Irritable Bowel Syndrome) and I did mention it in a recent post about Eubiotics.

Eubiotics for GI Dysfunction and some Autism

Increased speech is a target for many people treating autism and this probiotic is known to be safely used long term - so it is interesting.

Since I already had this probiotic at home, I made a trial and I observed a very similar effect to what happened several years ago when Monty started to use Sulforaphane / broccoli sprout powder. 

The effect of broccoli powder was a brief period of euphoria about 20 minutes later and a then a marked increase in verbalization.  The effect on mood was seen by some other readers, but not the majority. I recall back then a very happy parent who was feeding broccoli powder to his child via a G-tube. A gastrostomy tube, often called a G-tube, is a surgically placed device used to give direct access to your child's stomach for supplemental feeding, hydration or medication.  Some children with autism will not eat and so are fed via a G-tube.

Broccoli powder tastes pretty bad, but this is one problem you will not experience when taking it via a G tube.

I was surprised that even some people with mild autism found broccoli powder beneficial. In diabetics it improves insulin sensitivity and so reduces the amount of insulin they need to inject.

This post is about the science, but before reading all the science, I made my trial of Lactobacillus Plantarum 299v.  One capsule a day works very nicely. The science is optional.

I wondered what might be the shared effect of these two very different therapies - broccoli and L.P. 299v.  There is indeed a plausible explanation, the Kynurenine pathway.

 

Click on the graphic, to enlarge

This may all look rather complicated, but there are some terms we are already very familiar with. We know that Serotonin is the happy hormone and we know that Melatonin is the sleep hormone.

It all starts with Tryptophan, one of those amino acids. It is essential in humans, meaning that the body cannot synthesize it and it must be obtained from the diet. Good sources include milk, turkey and bananas. If you take bumetanide, you likely already eat a lot of bananas due to their potassium content.

95% of tryptophan is metabolized to Kynurenine, a very odd sounding word. So it must be that less than 5% becomes Serotonin and Melatonin. Two enzymes, namely indoleamine 2,3-dioxygenase (IDO) in the immune system and the brain, and tryptophan dioxygenase (TDO) in the liver, are responsible for the synthesis of kynurenine from tryptophan.

The so-called kynurenine pathway of tryptophan is altered in several diseases, including psychiatric disorders such as autism, schizophrenia, major depressive disorder and bipolar disorder.

The supplements Tryptophan and 5-hydroxytryptophan (5-HTP) are widely used for many conditions ranging from depression to autism.

 

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD⁺).

 

NAD⁺ is very important.

 

Increasing the level of NAD is itself an autism therapy in the research. 

New Preclinical Study Finds Niagen® Corrects Social Deficits in Mouse Model of Autism

First-of-its-kind preclinical study shows that Niagen® (nicotinamide riboside) resolves social deficits and anxiety-like behaviors in male mice

The amount of Tryptophan that ends up as the cute-sounding Picolinic acid is determined by how much of the enzyme ACMSD is present.

Quinolinic acid (QUIN) and Kynurenic acid (KYNA) are two neuroactive KP metabolites that have received considerable attention for their modulation of the NMDA receptor. While QUIN shows neurotoxic effects by over activation of the NMDA receptor, KYNA offers neuro-protection by blocking receptor function. Emphasis has been placed upon the importance of maintaining a balanced ratio between these two metabolites.

Picolinic acid (PIC) also shows antagonistic properties towards the toxic effects of QUIN via an unknown mechanism.  There are a number of biological factors that can potentially affect PIC levels and synthesis in the CNS including age, circadian rhythms and hormonal and nutritional factors.

 

 Source: The Physiological Action of Picolinic Acid in the Human Brain

Anthranilic acid (AA), once thought to be vitamin L, is very elevated in schizophrenia, and also in type-1 diabetes and arthritis.  AA is seen as a treatment target in these conditions. 

Now for the interesting part, the effect of the probiotic Lactobacillus Plantarum 299v on the Kynurenine pathway:

 

Probiotic Lactobacillus Plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: A double-blind, randomized, placebo controlled study

Highlights

· There was an improvement in cognitive functions in group of depressed patients receiving probiotic Lactobacillus Plantarum 299v (LP299v) compared to the placebo group.

 · There was a significant decrease in kynurenine concentration in the LP299v group compared to the placebo group.

 · There was a significant increase in 3-hydroxykynurenine : kynurenine ratio in the LP299v group compared with the placebo group.

· Decreased kynurenine concentration due to probiotic could contribute to the improvement of cognitive functions in the LP299v group compared to the placebo group.

  

And, the effect of Sulforaphane on the Kynurenine pathway: 

 

Altered kynurenine pathway metabolism in autism:Implication for immune-induced glutamatergic activity

Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, Quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased Quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD.

 

QA = Quinolinic Acid

KP = Kynurenine Pathway

 

The increased concentration of QA in ASD is also likely to be associated with increased oxidative stress. We previously showed that QA can significantly potentiate oxidative stress in human primary neuron cultures and that oxidative stress markers are increased in children with ASD.  Recently, a clinical study effectively used sulforaphane derived from the broccoli sprout to treat ASD resulting in improved behaviour.  Interestingly, sulforaphane was shown to attenuate the effect of QA-induced toxicity in rat brain by enhancing the antioxidant, glutathione. This study is coherent with our current finding of increased QA in children with ASD and our previous work showing decreased glutathione in the children with ASD.  Hence, the possibility that sulforaphane may act by attenuating QA-induce oxidative stress in ASD warrants further investigation.

 

Conclusion

Too much Quinolinic Acid (QA) does appear to be a damaging feature of autism and is produced by a malfunctioning Kynurenine pathway (KP).

The exact relevance of each part of the KP in diseases of the brain is still a work in progress, but it is clearly disturbed in a specific way in each particular CNS disorder, autism being just one.

Modifying the KP does look like a useful therapeutic avenue to follow, but it is not so simple to understand all of it.

It appears that Lactobacillus Plantarum 299v may improve some people’s autism via a mechanism that includes modification of the Kynurenine pathway (KP). It may also be the case that sulforaphane / broccoli powder has an effect that counters the disturbed KP. For whatever biological reason, the visible/audible effects of the two therapies appear to be remarkably similar.

As usual, you do not have to fully understand biological pathways, like the KP, to benefit from them.  In effect, it is all a question of where all the Tryptophan from your diet ends up – and for some people it does seem to matter.

Lactobacillus Plantarum 299v and sulforaphane / broccoli are not wonder autism therapies for most responders, but if there is an incremental benefit available, you may want to take it.

Another low hanging fruit?