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Saturday 29 February 2020

Clinical Trials – Bumetanide and Memantine & Making Sense of it all in a Single Book





This week I received a message: -

“Your Bumetanide treatment is on trial among 25 teenagers here and parents are loving it”

My reply, brief as usual (unlike my blog posts)

“Great!”

I did not mention that in the first phase of the trial 50% of the teenagers are going to be on the placebo.  It is Dr Ben-Ari’s treatment.

A clinician told me that all the parents of children, to whom she has prescribed bumetanide, think their children are responders and is wondering how to deal with the parental placebo effect.

I had another clinician telling me, “I guess from your experience with the blog, most people are not responders to Bumetanide”.  Then came an analysis of the recent tiny study in China that showed on average there was a measurable improvement on the CARS scale (Childhood Autism Rating Scale), but the question arose was “is this response large enough for parents to notice?”

Memantine (Namenda)

A few years ago, Memantine was also trialled at the University Hospital where we live, the same one that is part of the current Bumetanide study.

Memantine was subject to a rigorous multi-center study of nearly one thousand children a few years ago.  The FDA did not like all the off-label prescribing of Memantine for autism and asked the producer to carry out a serious clinical trial.

The first phase of the trial was to identify the responders, those responders then were to be enrolled to two follow-on trials to collect additional useful data.  The trial was terminated after the first phase was completed because in the subsequent trials the placebo produced as good results as Memantine.

So, we should assume memantine is no good for autism?

Or

In spite of spending millions of dollars and liaising with the FDA on the detailed structure of the trial, the producer did not know how to organize an autism trial properly?

I was just writing a part of my autism book that reviews all the drugs trialed to date in autism and I noted that Antonio Hardan (for me, Dr NAC from Stanford) has published a review of data from those expensive Memantine trials.


… the considerable improvements in mean Social Responsiveness Scale scores from baseline in the open-label trials were presumed to be clinically important.

I think that is Hardan-speak for “I think Memantine can be a useful therapy, for some people”.  I am not totally sure and I can see why Barney Rubble might be left scratching his head. 

Hardan is about to become Stanford's Dr Nexium, as he runs a clinical trial of the acid lowering drug esomeprazole (Nexium).  I am not sure why he thinks this will improve autism.  I think it will make some people's autism worse, because over time it will cause intestinal dysbiosis.

https://stanfordhealthcare.org/trials/a/NCT03866668.html

Intestinal Dysbiosis Secondary to Proton-Pump Inhibitor Use



Autism for Dummies?

Writing a comprehensive book about autism is quite a task.  If it is too complicated nobody will read it, but if you do not go into the how and why of autism, you have not contributed very much.

My elder son has suggested calling it “Autism for Dummies”; but that was not helpful suggestion.  We probably all count as Dummies, when it comes to autism, even Dr Naviaux, who I think knows the most.

I like the book written by a US Academic who treated his "untreatable" brain cancer (Gioblastoma, life expectancy 14 months), by reading the research and applying off-label therapies, using cheap generic drugs.  He has lived long enough to publish a second edition.  The first edition has a cover that looks like a medical textbook; he learned his lesson and the second edition looks more like a cookery book.

Before using pharmaceuticals to treat autism, we used a Peter-created, ABA-inspired, home therapy program.  Amongst many resources, we had two old, but excellent books - they were published nearly 40 years ago.  One was blue and one was yellow (code named by me and therapists as the yellow and blue books), one was about increasing good behaviors and the other was about reducing bad behaviors.  I could not leave them lying around at home, because in the tittle of these use cute looking books was in large print “SEVERE RETARDATION”.  The books are great and of course they should have been combined into a single book. 




I am not a fan of giving a nice name to somethings that is bad.

To me, intellectual disability sounds like not being very good at playing chess.

Accept bad news and move on.


Peter’s Book

I decided to have three sections in my book and have a nice cookery book style cheerful cover, so nobody can be embarrassed.  I will not be citing endless complicated research papers. 

I start with all the general issues that are relevant to understanding autism, that do not relate to complicated science.  I finish with a section on how autism can be treated based on applying the research findings to date, what ideas I came up with myself and other people’s ideas shared on this blog. 

Sandwiched in between easy reading section 1 and practical section 3, is a more heavy-going section 2; it is a simplified review of the biology and chemistry that is relevant to autism.  These are things you need to know to make any sense of those tens of thousands of published autism papers, that most people do not know exist.

Section 2 is not going to be a favourite for Roger, but I think he will like sections 1 and 3.  To really judge what to do in the therapy part (section 3), understanding at least part of section 2 is advisable and that is why it has to be there.

It is just like fixing your car, it does help to know a little bit about how it works, before you start tinkering with it.  Even the mechanic at the dealership does not know everything about how it works, but hopefully he knows enough.

If the mechanic cannot fix your car, you just sell it. You may feel a pain in your wallet, but no long-term guilt.

The autism is equivalent is putting your child into an institution, or group home.  You either feel guilty at this point, or later on when something goes terribly wrong. 

I am forever having to fix things - from cars to computers, to solar panels, air conditioners, blocked drains, a leaking swimming pool etc.  Once you realize the "experts" are often not so expert, you engage yourself to solve the problems; or at least tell the expert what you want him to do, like “I found the leak, here it is, now fix it like this”.

Don’t skip section 2, invest time to learn some biology.



21 comments:

  1. I do think the problem with bumetanide trial is that surely parents will be aware if their child is on the drug by the direus it causes vs the placebo. So not sure with all the bumetanide studies trials how relevant this is just wondering what you think this causes any kind of bias in the results

    ReplyDelete
    Replies
    1. The smart thing would be to use another diuretic as the placebo.

      Delete
    2. I am not 100% convinced NKCC1/KCC2 is what is causing the benefit of Bumetanide even though Ben-Ari's theory makes perfect sense since many other anecdotal autism symptom improving drugs also happen to be diuretics or related to lowering blood pressure. Knowing this information one way or another in a real clinical trial would be especially useful information.

      Delete
  2. Looking forward to your book, it will be a charttopper, hopefully available on Kindle. We started our daughter on Tavegyl and since we heard from several sources that Ibuprofen has interactions, we stopped Ibu. She is really a lot more anxious because of that and we will have to stop Tavegyl. What do you think?

    ReplyDelete
    Replies
    1. tpes, the interactions are well documented. Look at this link

      https://www.drugbank.ca/drugs/DB00283

      Ibuprofen is not listed as interacting with clemastine.

      Delete
  3. Peter. Do you think anyone that has a child with autism should try bumetanide? In your experience how much percentage of children respond to it

    ReplyDelete
    Replies
    1. Yes, I think all people with autism should trial bumetanide. I think about half of people with severe autism will be responders.

      Delete
  4. It is very exciting to hear that your book project has progressed this far! Do you think it will be suitable to put in the hands of doctors too, or is it only for parents?
    Using the phrase 'mental retardation' will certainly put off a number of potential readers. I've read it too many times in scientific literature to care anymore, but I never use it when speaking to others.

    Among the most important things that you've taught me with your blog Peter is that autism is a severe condition, that it can get much worse, and that you most likely won't get any help from medical advisors.
    As a parent you don't want to hear these things. You want to hold on to your hopes and beliefs that things will get better, that with enough therapy it will all be OK and that professionals really are professional. You took these illusions away from me very early on, but instead offered other paths to hope. I feel much more confident now, knowing that change relies on me, knowing how to approach the task of finding solutions and knowing what can be accomplished.
    It's huge.

    /Ling

    ReplyDelete
    Replies
    1. Ling, The old terminology was simple, if you want to refer to an IQ<70 you just say MR.

      The term intellectual disability (ID) first appears in 2013 in DSM5.

      In countries that follow the World Health Organisation, and use ICD-10, they now call MR a learning disability (LD), about 2% of the population; but they also have learning difficulty (also LD) which includes dyslexia and ADHD etc, which may be 15%-20% of the population.

      In the US a learning disability, or learning disorder refers to weaknesses in certain academic skills. Reading, writing and math are the main ones. Often these people have average to high IQs.

      If you use the term ID in the UK, nobody knows what you are talking about.

      It is as if confusion was the objective.

      I don't think many doctors want to read a book about autism, unless they have a personal interest.

      Delete
    2. I still have hope that a lot of doctors wish for ways to treat their pediatric patients. The problem is that the number of approved drugs is very tiny. Risperidone is for example widely prescribed, but it's far from perfect. So you have to choose between not treating, or treating with a drug with less nice side effects (or treat off-label, which is risky andand requires a lot of research).
      /Ling

      Delete
    3. Ling, in many countries doctors are no longer allowed to prescribe off-label.

      I recall many years ago (25+) that my GP mother told me that she was prescribing placebo pills to some older patients. They genuinely felt better, the pill cost almost nothing and did no harm, but this was banned.

      Anti-psychotics have serious side effects, but not for the doctor.

      If a doctor prescribes Verapamil to a child and something bad happens, he/she is going to be in serious trouble.

      Delete
    4. I think you've got your mothers heart and creativity, Peter.
      :)
      /Ling

      Delete
  5. I am trying to do aba, even if in italy there are not experienced consultants...parents doing aba are familiar with data and taking data , maybe it lessens the parental placebo effect, who knows..carla marta

    ReplyDelete
    Replies
    1. If you work with your child, doing ABA or particularly maths, you will notice small but significant changes. Maths is my favourite measure of cognitive change. You can detect even nuances. Afobazole reduced anxiety in my son but reduced his maths ability.

      Delete
  6. Good afternoon Peter, Friends, and Community,

    I found the following paper earlier today and wanted to share as it adds yet another piece to the ASD puzzle:

    https://www.cell.com/neuron/fulltext/S0896-6273(20)30065-9

    The researchers have found the reducing Tau levels appears to positively impact ASD for at least some causes. It appears to do so, as Tau negatively regulates PTEN.

    In fact, Peter has noted PTEN in numerous posts (including one recently from January).

    The actual full paper is quite interesting.

    As usual, this pathway may be relevant to some and not others, but this latest connection between Tau (which I almost always read about in connection with Alzheimers) and PTEN is certainly interesting.

    AJ

    ReplyDelete
    Replies
    1. Thanks AJ!

      Since I'm still not finished with this theme I'm into I'm going to add a 3 months old paper published in Nature to be glanced at after reading yours above:

      NLRP3 inflammasome activation drives tau pathology
      https://www.nature.com/articles/s41586-019-1769-z

      "NLRP3 activation induces tau hyperphosphorylation and aggregation [..]
      Here we provide evidence that tau oligomers and monomers have direct effects on microglia by activating NLRP3. As non-fibrillar tau can actively be released by neurons, it could thereby contribute to chronic microglial activation in tauopathies. This pathway could potentially be blocked by NLRP3 inhibitors"

      /Ling at your service

      Delete
    2. Hi Ling!

      Well, your paper certainly adds another layer to the potential issues with Tau...

      So NLRP3 activation drives Tau hyperphosphorylation, too much Tau (or potentially Tau hyperphosphorylation) drives reduced PTEN, and PTEN regulates the PI3K/Akt/mTOR pathway.

      I'll have to go back to the new paper I posted earlier (full version) to see what it says about Tau (i.e. too much Tau or Tau hyperphosphorylation, or both) but it seems like a few pathways we've become familiar with are connected in interesting ways.

      Great find Ling!

      Hope all is going well, and I'm sure you're making incredible headway on your relevant pathway.

      Have a great evening Ling!

      AJ

      Delete
  7. Just a practical side note on introducing Tavegyl: We used Aerius before and thought, ok lets replace that with Tavegyl. We neglected to realize that the antihistamine effect lasts only 12h. Lets just say, the past few days have been interesting :-))). Especially with spring at the door...Since the two antihistamines don’t mix and aerius lasts 24h, and tavegyl would make her sleepy given also mornings, we will do tavegyl 2x week in the evening and give a half dose of aerius that day in the morning, whereas the day after we can already give the full dose since clemastine lasts 12h only. (a and c together both have QTs prolongation effects)

    ReplyDelete
    Replies
    1. Antihistamines can potentially prolong QT (In long QT your heart muscle takes longer than normal to recharge between beats).

      The research does show that in clinical use, this is usually not a practical concern, either with Aerius or Clemastine. Just look up each specific drug in the research, like for example:-

      “The disparity between clemastine's potent IHERG inhibition and a lack of QT-prolongation in normal clinical use underscores the need to interpret HERG IC50 data for novel compounds in the context of information from other safety assays.”

      Also look at the both the half-life and the claimed effectiveness of drugs. I have not found any antihistamine that is effective for 24 hours.

      I give 1mg clemastine in the evening and in the allergy season add a second antihistamine for the daytime.

      Some people with mast cell conditions use very much higher doses of multiple antihistamines. In theory they should not be doing this.

      We did ECG and ultrasound with a cardiologist, which I think is a good idea for children with autism being treated with off-label therapies.

      Delete
  8. We did all possible organ ultrasounds and ecg maybe 10 days ago, especially because recently she has been complaning about pain everywhere - what she actually means is that she wants pressure everywhere, but we did the exams and all is perfect. We will combine the two then.

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  9. my kid took 15mg calcium folinate for 1-1.5 years as part of a broad spectrum MTHFR therapy, and we saw nothing special. 15mg at 20kg weight should be enough to produce an effect, but it was just okay.

    ReplyDelete

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