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Tuesday 10 September 2013

Bumetanide in Autism and Epilepsy – Drug Licensing Status

In Europe, drugs have to be licensed by the European Medicines Agency, or each country’s national drug’s agency.  In the US ,the regulatory body is the Food & Drug Administration (FDA).

Drug approval is a slow and costly process and results in different drugs being available in different countries, or the same drug being licensed for different age groups or illnesses in different countries.

Bumetanide has been licensed around the world for many years for use in adults.

 
Bumetanide

Bumetanide is a loop diuretic originally licensed more than 30 years ago to treat heart failure.  It has a secondary function; in the brain bumetanide blocks the NKCC1 cation-chloride co-transporter, and thus decreases internal chloride concentration in neurons. In turn, this concentration change affects the action of the neurotransmitter GABA, which has been shown to be useful for treatment of neonatal seizures, that quite often are not responsive to traditional GABA-targeted treatment. Bumetanide is therefore currently under evaluation as a prospective antiepileptic drug.

Bumetanide is also being investigated by a French researcher, Dr Ben-Ari, for use in treating childhood autism.

Bumetanide was developed with older patients in mind and was never licensed for children, let alone babies.  Experimentally, Bumetanide has been used in babies for many years.


Bumetanide in Neonatal Seizures – NEMO project

You may have read in earlier posts about the research done using bumetanide to treat neonatal seizures.  There is now a 15 strong consortium including Duke University in the US, Great Ormond Street Hospital in the UK and Dr Ben-Ari’s INMED in Marseille, who have joined forces to bring this therapy to the market. The initiative is called the NEMO project and they have a slick website explaining their work.

The clinical trials are being carried out at 7 sites across 5 European countries.  The phase 1 study has been completed.

The objective is to develop a bumetanide formulation for neonatal seizures and obtain a drug license called a Paediatric Use Marketing Authorization (PUMA), from the European Medicines Agency.  The drug can then be prescribed to babies within Europe.

 
Bumetanide in Autism

Dr Ben-Ari is soon to conduct a phase 2 clinical trial of the use of bumetanide for autism in multiple European centres.  This study follows on from the already completed initial studies in France.

Some parents, mainly in France, are already using bumetanide for their children with ASD.  Most others clearly want the drug to fully certified for use in childhood autism before trying it, or are unable to obtain it, since it is a prescription only medicine.

Dr Ben-Ari informed me that he expects his bumetanide formulation is likely to be licensed for prescription in Europe to autistic children within four years’ time.

The FDA has more onerous (costly) requirements than its European counterpart and so the drug will only be licensed in Europe as a therapy for childhood ASD.




 

11 comments:

  1. Note that a recently published comprehensive review on the use of bumetanide in the treatment of neonatal seizures indicates that theres is no evidence to support the use of this drug in the treatment of central nervous system disorders via the NKCC1-dependent mechanism described above, as at the very low doses that are given to infants and children bumetanide does not reach sufficient levels in the brain.

    direct link to the original review:
    http://onlinelibrary.wiley.com/doi/10.1111/epi.12620/pdf

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  2. Thanks for this. There may be better drugs that cross the BBB more freely in the future. As the paper states at the moment Bumetanide is the only such drug available. I can tell you that in a 33 kg child with autism, 1mg of Bumetanide is potent enough to cross the BBB and affect the excitatory/inhibitory behavior of GABA. In some other children it has no such effect.

    I have no direct experience of neonatal seizures, but if Bumetanide can cross the BBB in autistic children, it probably can do in babies. There is a great deal of research currently taking place regarding bumetanide and neonatal seizures. Those researchers might well dispute the findings of your paper.

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    1. Your claim ("potent enough to cross the BBB") is based on what? The fact that you see CNS effects, does not mean that the primary site of action of a drug is the CNS.

      Your statement "I can tell you that in a 33 kg child with autism, 1mg of Bumetanide is potent enough to cross the BBB and affect the excitatory/inhibitory behavior of GABA." is for sure not based on scientific evidence.

      Delete
    2. If you want to doubt the science, then go and argue with Yehezkel Ben-Ari, who is the scientist proposing Bumetanide for Autism, rather than the person using it.

      I just read the research and then trial what I believe looks plausible. I made a trial of Bumetanide and it did exactly what Ben-Ari claimed. For me that is all evidence I need. 1 mg does the job required in a 33 kg child, for some reason that displeases you. Maybe people in Finland are different.

      If Ben Ari has got the mechanism all wrong, which is unlikely, I do not care. What matters is whether it works. If you want to argue why it works, go write to Ben Ari, but not as Mr Anonymous

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  3. Peter, Bumetanide has had a huge impact on my son's cognitive skills.
    It has given back his laser focus ability to deal with advanced mathematics and physics. He can't get enough of it.
    Also, unless there is an allergy, or something to that effect, so far he seems meltdown free.
    I just don't know what to say...doctors can give different kinds of antidepressants, anxiolytics, neuroleptics, but they can't prescribe Bumetanide?

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    1. Petra, that is great to hear. I thought it would have less effect in Asperger's, maybe in your son he just has a small dysfunction and so it is a case of "fine tuning", whereas in Classic autism the dysfunction causes a more profound cognitive impairment.

      Anyway, it is great that it works. Tell your biotin researcher doctor and also see if it helps your nephew.

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  4. Petra, also if one of your doctors will give you a prescription you will find it easy to acquire in another country. In Germany they will happily dispense against a prescription from another country, even a supply for one year. You could buy from an "official" online pharmacy in the UK (so no customs duty or VAT). If it is not available in Macedonia or Bulgaria, you can buy it very cheaply in Serbia and, with a prescription, if you ask for 40 packs they will just order it and have it the next day, all for less than 100 euros.

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  5. Thought some might find this interesting:

    The effects of Ginsenoside Compound K against epilepsy by enhancing the γ-aminobutyric acid signaling pathway
    https://www.frontiersin.org/articles/10.3389/fphar.2018.01020/abstract

    GCK enhanced the expression of GABAARα1 in the brain and exhibited a tendency to decrease the expression of NMDAR1 protein in the hippocampus. The expression of KCC2 protein was elevated by the treatment of GCK after status epilepticus, while the expression of NKCC1 protein was reversely down-regulated. These findings suggested that GCK exerted anti-epileptic effects by promoting the hippocampal GABA release and enhancing the GABAAR-mediated inhibitory synaptic transmission.

    Note, compound k is mainly from panax ginseng, there are many different types of ginsengs and only panax ginseng is considered true ginseng.

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  6. Peter, I could use your help. I am trying Bumetanide again. I had good results last year but on day 60 there was a switch to extreme aggression. I mean extreme. Prior to that switch bumetanide was giving my son global improvements. He has high functioning autism and is 8 years old.
    I started the bumetanide again 6 days ago and the gains are very noticeable, less robotic speech, happiness, joking, enjoying kids movies (which is something that he previously could not do) Joining in on family conversations, making his bed, forgetting to ask for screen time, these are all new. I am ONLY giving him bumetanide 1mg in the morning and 1mg in the afternoon, potassium, magnesium and nothing else. Can you tell me what I might do if the aggression starts again? Lower the dose of bumetanide if it happens? He is normal weight and height for an 8 year old 50 pounds 54 inches tall. Also do you have any idea why this might have happened? Have you heard of this with bumetanide?

    Thanks in Advance

    Pierrette

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    Replies
    1. Pierrette, bumetanide changes the level of your electrolytes and will cause dehydration. So if both of these are not fully countered by drinking much more and adding back the electrolytes, strange things may occur.

      The only way to know if you are giving enough potassium is to measure the level in his blood. Most people require only a small supplement, but others may require up to 1,500 mg a day.

      Dehydration seems to be more common that you would think. You have to drink a lot of water to replace 2 daily sessions of diuresis. He needs 9 glasses of fluid a day.

      Another possible cause is that it was just a coincidence, something else triggered the aggression. In my son it is allergy or something else pro-inflammatory occurring. The solution to that is treating the allergy/inflammation.

      So I would check his blood electrolytes and make sure potassium is in the top half of the reference range and make doubly sure he has adequate fluid intake.

      If aggression returns then you need to check whether the cause is the bumetanide. If you stop bumetanide and aggression stops the next day, then you know that bumetanide is the problem. The great majority of bumetanide's side effects are caused by low electrolytes and/or dehydration.

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  7. Ok Thank you for that information I will continue to give the potassium and I have a MAPS appointment and I will have his electrolytes checked including potassium. His aggression did go away as soon as I stopped the bumetanide, about a day later and I was still supplementing potassium so the potassium must have gotten too low! This time around I will be more proactive in knowing the levels.

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