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Monday, 20 March 2017

Progress towards the Approval of Bumetanide as a Drug to treat Core-Autism


This blog is seen by many as being  bumetanide-inspired, so it is only fair to highlight the recently published Bumetanide for autism Phase IIb results. This study probably will not get the attention it should get in the media, in part because it is French and not American. 




This was a trial based on 90 days of taking the drug, while some readers of this blog have been using bumetanide for years. 

Nonetheless, there are some interesting things in the study, most importantly is that you can see the guiding hand of the drug approving agency (the European Medicines Agency).  They have specified how to measure the results (the CARS rating scale), the level of severity of autism to test the drug on (severe) and the age group (2-18 years old).

In this blog we know that autism is very heterogeneous and that while bumetanide can be highly effective, there is a large group that do not respond.  This trial did not use any kind of biomarker and so it contains a broad mix of responders and non-responders.

The good news is that even though only about 30-50% of people with an autism diagnosis seem to be responders, this was more than enough to make the drug look effective in a trial of just 88 people.

The small sample size does throw up anomalies, like giving the impression that 0.5mg twice a day  is more effective than 1mg twice a day, on some measures. 

The most effective treatment, judged by the authors, was 2mg twice a day, but it was ruled out for the Phase III trial because of side effects.  

“Clearly this trial must be viewed as a source of data on the safety and dose-ranging usage of bumetanide and it provides further support to justify a large multisite European Phase III trial.

We report here the results of a multicenter phase II dose-ranging study conducted according to a pediatric investigation plan approved by the EMA to determine the optimum bumetanide dose in ASD children and adolescents aged 2–18 years. To achieve these aims, the study population was divided into four subgroups receiving three doses of bumetanide (0.5, 1.0, 2.0mg twice a day) or placebo. The distribution of age was the same in the four groups (2–4, 5–9, 10–13, 14–18 years old). The results of this trial confirm and extend our earlier observation that bumetanide improves the symptoms of ASD and that too in the full age range targeted. 

EMA imposed the age range from 2 to 18.

CARS has been selected by the EMA in their recent (2016) guidelines for evaluation of ASD core symptoms (Guidelines on the clinical development of medicinal products for the treatment of ASD, 25 December 2015).
The mean initial CARS scores were similar across all treatment groups in the six clinical centers and were above the cut-off for severe autism as required by EMA (>34). “

  
Placebo Effect

In the CARS scale, a score greater than 30 is the threshold for autism.  The higher the score, the more severe the autism. The regulator required that people in the trial had a CARS score greater than 34 to be eligible for the trial. The average CARS score for those in the trial was 41, so you would need an average improvement of 11 to potentially make them all “better” (this is a simplification).  This just shows the meaning of improving by 8 CARS points.  It is a big deal.

Here you see what happens when half a study group are not responders to bumetanide and you see a large group who either show minor improvement or get worse.  This is just the expected background noise in all autism trials.  There is even one person who improved greatly (>8 on the CARS scale) just by taking the placebo.




 Change in the completers of the total CARS score from screening to day 90 after bumetanide (blue bars; n=52) and placebo (orange bars; n=21). All changes were calculated from the initial values for each individual participant at screening. Note a significant amelioration of the CARS scale after the treatment period (>4) is almost entirely restricted to the bumetanide-treated patients (only placebo). CARS, Childhood Autism Rating Scale.


Thirty bumetanide- and five placebo-treated showed an attenuation of more than 4 of whom 23 treated and only one placebo showed an amelioration of more than six Childhood Autism Rating Scale (CARS) scores, and 13 of these and only one placebo showed an attenuation of more than 8 points. The differences between placebo- and bumetanide-treated patients having more than 4, 6 or 8 points attenuation are highly significant.




Side effects 

As we have seen in feedback on this blog the harmful side effects of bumetanide are dehydration and low levels of potassium. These side effects are entirely manageable, but that job is for the parents. 
I was interested in the chart below which measures the potassium levels during the trial of the four groups. I assume green (placebo), blue (0.5mg), red (1.0) mg, black (2.0mg)


  

 Points perhaps unbeknown to the authors

An important point we have seen on this blog is that intracellular levels of chloride vary under the influence of inflammation (which affects KCC2 expression).  This results in some people responding well to bumetanide at some times and apparently not at others.
We also noted that bumetanide does not cross the blood brain barrier very well and so in some people with high levels of intracellular chloride they may appear not to respond to bumetanide, not because they do not have elevated Cl-, but because it is just too high for bumetanide to show effect. 
Taken together the point is that if at any one time say 40% of people with autism are responders, there may be another x% who are potential responders to a similar but more potent therapy.
If you trial bumetanide in the summer and have a pollen allergy, it may appear not to work, as in the case of my son. Fortunately I did my trial in the winter.


New information


Dr Ben-Ari told Medscape Medical News that the phase 3 study, which is approved by the European authorities, will be performed in about 400 children in five EU countries. The patients will receive 1 year of treatment, and they will reflect the entire pediatric autism population.
"We hope to get the drug on the market in Europe for autism by the end of 2021," he said.
Source: http://www.medscape.com/viewarticle/877562#vp_2



As some wise older person told me many years ago, "things take time".  In the world of autism, things seem to take forever.





20 comments:

  1. Calcium is essential for both neurotransmitter release and muscle contraction. Given these important physiological processes, it seems reasonable to assume that hypocalcemia may lead to reduced neuromuscular excitability. Counterintuitively, however, clinical observation has frequently documented hypocalcemia’s role in induction of seizures and general excitability processes such as tetany, Chvostek’s sign, and bronchospasm. The mechanism of this calcium paradox remains elusive, and very few pathophysiological studies have addressed this conundrum. Nevertheless, several studies primarily addressing other biophysical issues have provided some clues. In this review, we analyze the data of these studies and propose an integrative model to explain this hypocalcemic paradox.

    Keywords: action potential, hypocalcemia, ion channel, neurophysiology, seizure, synaptic transmission

    We know that Bumetanide causes potassium loss and dehydration. Less discussed is the possibility of hypocalcemia, particularly for some who show such dysfunctions even without Bumetanide.
    I assume correcting hypocalcemia might make it more effective.

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  2. So are we talking about treating a channelopathy involving the chloride channel?

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    1. We are talking about a channelopathy, more precisely overexpression of NKCC1 which lets chloride into cells and underexpression of KCC2 which lets chloride out. This elevated chloride makes GABA act as excitatory rather than inhibitory. The usual balance between GABA and Glutamate neurotransmitters that controls when neurons fire is lost. The causes the so-called E/I imbalance and the visible features of autism.

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    2. I am waiting to see if the genetic testing I am getting done for my son will show anything in regards to a channelopathy or something with transporters. I made a mistake on his keto-diet when I made new menus erasing casein and recalculated all of the menus-I was focusing on ratio and did not focus on the calories. My son's seizure threshold changed and it gave me the chance to re-examine. I believe GABA is excitatory...It is as though GABA doesn't function the way it should or for him its a transporter issue? Observing him in a room with other children who do not have epilepsy I can see that he is entirely too excited without the ketogenic diet. I can actually see the effect the rapid firing has...sort of like the other end has to catch up. (His teacher noticed it too when we were talking about him) The drawback to the diet at least for him is that when the ketones are too high which happens for a couple of different reasons he can get moody and sad. If he is eating every 4 hours he is ok. Sometimes you have to give a little extra carbs when you see this. Now that his ketones are back to normal though I still notice a lot of darting around but overall it is slower and depends on whether its a new environment and he doesn't want to be in it.-Infinitybeyondlove

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  3. Hello Peter,

    This study looks quite encouraging indeed, at least for the responders. I mean a drop of beven 4 counts on the CARS score is no mean feat. I was wondering, given the observed diresct relation between dose and severity of side effects, and also, significant improvements even at 0.5 mg bid (though you frel it might be a data artefact), would a 0.5 mg dose a good place to start? I wanted to trial bumetanide once again during summer vacations. I was also thinking of supplementing with ca, mg and k and/or a good multimineral tonic instead of just potassium this time. Will that be a good idea or additional ca might be undesirable?

    Regards

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    Replies
    1. Calcium channel dysfunctions seem to be a part of autism so I would not add this to the mix. You could just see the effect good/bad/none from the extra calcium as a separate experiment.

      The big issue with bumetanide is loss of fluids and loss of potassium. I supplement potassium and magnesium, because that is how the supplement I use comes.

      You could start at 0.5mg twice a day for a month and then increase to 1mg twice a day. Then decide if either was beneficial.

      In my son 1mg once a day seemed much more effective than 0.5mg twice a day.

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  4. Dr Ben-Ari told Medscape Medical News that the phase 3 study, which is approved by the European authorities, will be performed in about 400 children in five EU countries. The patients will receive 1 year of treatment, and they will reflect the entire pediatric autism population.
    "We hope to get the drug on the market in Europe for autism by the end of 2021," he said.

    Source: http://www.medscape.com/viewarticle/877562#vp_2

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    Replies
    1. Peter,

      Things seem to be moving. Servier and Neurochlore have signed an agreement to develop and market bumetanide for paediatric autistic population...should be available by 2021. Since the drug is already there what does that imply....they might try an d make it safer by adding potassium or what? Whatever, I hope my phase 2 trial turns out successful too. Please son, turn out to be a clear responder!

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    2. Kritika, I think they will offer a liquid version, that is easier to give to young children. The main difference is that only when it is approved will doctors in the most countries even consider to prescribe it. Early adopters who have taken matters into their own hands will see no change, except perhaps they can acquire the drug in an easier way. What about the other partially effective autism therapies? If it takes ten years to repurpose bumetanide.

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  5. Do you think bumetanide would work for mild autism/aspergers? I have social deficits and hope this would help.

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    1. It is worth trying, many people with Aspergers use it. Also worth trying for Aspergers, much more so than more severe autism, is baclofen which seems to help the majority of people.

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    2. I tried baclofen before and it just made me sleepy. I didn't find it to work. Not sure if it's because I took it incorrectly, wrong dose, or whether I took long enough to give a verdict. Even if it works out isn't something I would take regularly because side effects include memory and cognitive problems.

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  6. What dosage Do people use for baclofen?

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    Replies
    1. You would be best advised by someone with Asperger's who takes Baclofen. As I understand it, they are using a moderate dose, which would be around 10mg three times a day in adults.

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  7. Hello Peter,

    I read somewhere that diuretics might cause thiamine deficiency. Will a good b complex or multivitamin suffice? I want to ensure to the best of my abilities that deficiencies do not crop up when I trial bumetanide this time. We had some odd neurological behaviour last time..but I am so confused about b vitamins. And then there is this whole overmethylator-undermethylator issue. How is any sane person supposed to navigate through this amazing maze. Except for B6 in combination with magnesium and to a certain degree zinc which surprisingly seems helpful for a variety of troubling conditions associated with autism ..methylation, metallothionein deficiency, pyroluria, the rest of the bs look quite unreliable. And the cherry on the cake seems histamine, the new yeast, so now there are some b vitamins and a whole range of food/supplements to steer clear off if you have histamine intolerance.

    Cry-baby act aside, what would a sensible b vit combination be to go with bumetanide or you think its not really required.

    Regards

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    Replies
    1. Kritika, in some people it is reported that diuretics may reduce levels of folate and thiamine, but these will be much older people.

      The most important thing to supplement is potassium and perhaps some magnesium while you are about it. Many potassium supplements include magnesium. Having a daily multivitamin, with a little of everything can do nor harm and may help. Our reader Maja has found that small deficiencies in common vitamins can have behavioral effects and has explained the likely mechanisms.

      This combination is inexpensive and would be a good choice to go with bumetanide.

      Zinc is interesting and you do not want to be deficient in it, but it seems that in autism the problem is the Zn2+ ions are in the "wrong" place, and supplementing will not change that.

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  8. So does anyone from Australia manage to get a doctor to off label prescribe bumetanide or are people sourcing from the internet if so any good options. Also what changes have people noticed over what period of time. Have 4 year old son who has ok cognition numbers letters words etc. But lives entirely in his own world no social skills no life skills dressing toileting etc welcome any replies

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    1. Very few doctors anywhere are prescribing bumetanide for autism, but it is worth asking your doctor. Most people are buying it without prescription, either online from Mexico, Taiwan, an island in the Pacific etc, or in person in a country that does not strictly enforce the prescription requirement (e.g. most developing countries and Spain).

      Bumetanide reduces the severity of autism in responders. Autism manifests itself so differently in particular people it is best to leave it at that. If you say it helps toilet training, an adult with Asperger's will assume it is no good for him, but it might well help him.

      You need to try it for a few weeks and normally within 10-20 days you will see behavioral changes. About half of people seem to be responders, some more than others.

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    2. I'm not confident that you'd be able to get bumetanide in Aus, as it's a med beyond what GPs and psychiatrist can prescribe. I feel like it's within cardiologists area and they can't prescribe stuff for autism

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  9. I just wanna share that the study is finally reaching grounds, as it's up on a renown news.

    https://spectrumnews.org/news/trials-repurposed-drug-shows-promise-autism/

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