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.
Hi Peter,
ReplyDeleteI have been following the Arbaclofen and Bumetanide saga for 2 years now. I read about how sfari has purchased the rights to Arbaclofen in an article on http://sfari.org/ a couple of weeks ago. Immediately, I emailed every address I could find on the website inquiring about the trial. Amazingly, I actually heard back from the director of clinical research that we would be considered for the Arbaclofen trial. They are targeting 2016 to start. I still have not been able to find a physician that will try Bumetanide, but I will keep searching.
What are your thoughts on taking Bumetanide and Arbaclofen? Would that go even further to stabilize GABA?
If it was me and I lived in the US, I would order Bumetanide online from Mexico. I would try 1mg twice a day for three weeks, while adding extra potassium in the form of a banana a day and a K+ supplement.
DeleteIf I noticed a big increase in awareness and cognitive function, I would then check K+ levels in the blood and find a long term source of bumetanide.
I think Arbaclofen might also help, but it looks like the odds are higher for Bumetanide and the effect seems to be greater and indeed different.
One doctor who reads this blog gives her child the micro dose of Clonazepam, that I suggested, which should do something similar to Bumetanide. There is no loss of K+ and the dose is so small that a pack of 50 tablets, 0.5 mg will last a year. I just bought 2 mg x 30 tablets, it will last us 3 years and cost less than $3.
Physicians are not comfortable with any of this, but as you see, when it is their child they can be less cautious.
Thanks to Bumetanide, in particular, my son has been able to acquire academic skills at the same rate as his NT classmates for the last two and a half years. Prior to Bumetanide, even with 40+ hours of 1:1 help, he was falling further and further behind. So aged 8 he had the academic skills of a 4 year old. Now aged 11 he has the academic skills of an 8-9 year old. His NT classmates are 8-9 year old.
Who do I email for the arbaclofen trial?
DeleteA good place to start would be to call the Simons Foundation and ask them.
DeleteHi Peter,
ReplyDeleteWhat do yo think about Phenibut?
It is a Gaba B agonist mainly .it has similar effects than baclofen.
Thanks
Olga
It is worth a try as is Pantogam, the other Russian drug. If you can get Bumetanide, that would be my first choice though, as a GABA drug.
ReplyDeleteHi Peter! I am amazed by your knowledge and your effort to help your son and other ASD kids. My son has been diagnosed with Asperger's, anxiety disorder and Tourette's syndrome. He is 13 years old and his tics have been on the increase lately! The problem is that he can't concetrate at school, he is very anxious, he gets aggressive sometimes and displays inappropriate behaviour sometimes (i.e laughing with no reason, repeating lines of films he has seen or mottos from advertisements. Of course, his tics (motor and vocal) are a real disability for him. We've tried biomedical approach, he's on B COMLEX, Tyrosine, p-5p, fish oil, Magnesium and unfortunately Risperdal. His tics are still there, nonetheless. What shall i do? I'm in total despair! How can i help him?
ReplyDeleteThe tic is likely a form of OCD, like the repetitive stimming in kids with autism. If this was the case then the cause is likely oxidative stress and you can treat it very easily with NAC (N-actely cysteine). We 4 x 600mg of NAC spread through the day. If your son can swallow pills then best to try the sustained release from, just google "NAC sustain". Anxiety is very common is Asperger's, but I think people do not always mean the same thing. In some people Sulfurophane has a big impact on mood and it takes effect within 30-40 minutes, it is really quite amazing. In other people it has zero impact. Some types of broccoli powder produce Sulfurophane, but most do not. We one called Supersprouts, you need a tiny amount and do it is not an expensive intervention.
DeleteOne Pediatrician reading this blog told us that he/she treats people with with Asperger's and anxiety úsing Baclofen, with great results. About 70% of patients responded well.
There are lots of other anxiety drugs, but Baclofen is interesting because it directly affects GABAb receptors which are implicated in genetic studies of autism.
I think drugs like Risperdal may do more harm than good.
Hi Peter, I cant get Bumetanide until december, I could try Clonazepam with Valproate. With Valproate 500 mg, which dose of clonazepam would be right for my son with photosensitive epilepsy?
ReplyDeleteThanks for all
I am using a tiny dose of Clonazepam. It is 0.05mg per day. This is a different use of the drug to the traditional much higher doses. You have to dissolve a tablet in water and then use a syringe to measure out the correct amount. So I dissolve a 0.5mg tablet in a 100ml bottle, mix very well and then give 5ml twice a day. The drug has a long half life and so it will take 3 days before the effect should be visible. If you give a bigger dose the effect is lost, just as research suggested it would be.
DeleteI was wondering if baclofen wouldnt be a better choice, in addition to valproate and nac. I am afraid of combining 2 aintiepileptics drugs, Y read that the combination of clonazepam and valproate can induce absence seizers. My son is very similar to georgia^s son with asperger
DeleteI think you have to be careful because these are all experimental uses of drugs. You really need to figure out what the biological dysfunction might be in order to know how to treat it.
DeleteIt is best to use drugs that do not have side effects and contra-indications. The big attraction of micro-dose clonazepam is that while it can be effective, the dose is tiny. At the usual doses, Valproate is quite a potent drug.
It was interesting that Olga found that by using Bumetanide her son has a big reduction in epileptic seizures. So perhaps the seizures are caused by the excitatory/inhibitory imbalance of GABA. This would mean that you could treat autism and certain epilepsy with the same drug, and a very safe drug at that.
I think there are two key words here, that are playing together causing permanent anxiety, movments and tics in my son : gaba and gut. I agree with you that gaba is very related to seizures, or in this case , with electrical activity. So,Bumetanide, nac and probiotics could be a solution.Do you agree?
DeleteYes, that would seem a good combination. Try it and see what happens.
DeleteYes,we started Bumetanide one month ago.
ReplyDeletei have seen any improvement but it has improved epilepsy.before bumetanide he had an episode every week ..do you think he needs two dose (1mg+1mg)instead of one?
I'm thinking about adding other gabaergic drug...or AED low do se
I tried valproate low dose and I havent seen any improvement either.
Regards,
Olga
Yes, I would try 1mg twice a day and keep going for a few more weeks. If it helps the epilepsy, things must working.
DeleteSo, I initially learned about PANDAS in one of your blogs. I kept saying, he was NOT born autistic. He was so snuggly and responsive to calling his name. Eye contact was totally there. We have been struggling with everything for about 5 years. I even got to try Bumetanide. We saw one good day with him. Then, he got an ear infection in both ears and he was put on antibiotics. All of a sudden I had a different kid. His aggression was totally gone. He is more "present". Hyperactivity is gone. And, the one huge red flag, a beautifully colored picture of a tree and some flowers from after the antibiotic. All of his other pictures had come home with careless scribbling. So, I finally asked the question of his doctor. Is it possible he could have PANDAS? He nods and says it's possible. We got the test results back yesterday, and it sounds like it is PANDAS. I have him all set to go on Curemark's CM-AT clinical trial (chymotrypsin levels are no longer a possible excluder for this trial), and I'm worried about PANDAS excluding him from the clinical trial. Do children just have PANDAS and treatment will get him to where he needs to be (I still haven't seen the scholastic improvement I was hoping for) or is autism a possible comorbid part of PANDAS?
ReplyDeleteI think that PANDAS is just one possible trigger of autism-like behaviors. I expect in reality there will be PANDAS-like syndromes and cases of PANDAS plus autism. The tests for PANDAS appear to be subjective.
DeleteThere is quite a large group of people with ASD who improve on antibiotics. In my earlier post on antibiotics I suggested people narrow down the problem by using an antibiotic that can only treat the GI tract, because it is not absorbed in the blood. If that antibiotic had no effect, but a broad spectrum antibiotic did have an effect, you could rule out all the GI-related possibilities. I would suggest you read up on antibiotics improving autism.
If you have PANDAS and this triggered an altered immune state in the brain, then you might benefit from the immunomodulatory therapies. But there are some clever doctors researching how to treat PANDAS, so you would hope trial and error would be less necessary.
I would stay on the CM-AT trial.
Having treated the PANDAS you would have to see what is left of the "autism". I also wonder if some of the dysfunctions will remain. It might be better to consider it as PANDAS triggered autism. So first you treat the PANDAS and then treat whatever is left. For example perhaps when PANDAS has been controlled, bumetanide will then give the cognitive boost you want. This is all speculation of course.
That is something that frustrates me about PANDAS. The subjectivity bothers me, but he does have strep antibodies. I did notice the N of One organization the one guy did for the antibiotics. He tests average in two areas and in another two it was just below average, but his verbal is pretty bad, so I'd imagine with kids with autism you need to bump the scores two percentiles to get to where they really are. We are at "the top of the list" for the CM-AT trial, so we haven't started it, yet. Interestingly enough, I did NAC (the high quality effervescent BioAdvantex ones)-nothing. I tried carnitine - nothing. I tried the broccoli sprout powder that you recommended from Australia) - again, nothing. I tried bumetanide...and I think we saw two days of responding to it, but now I wonder if those two days were more related to something with the PANDAS. I also had him gain weight on Bumetanide and I was a little puzzled because I didn't think that was a side effect, but his teacher also commented that he was "hungrier". So, PANDAS could be a big light at the end of my tunnel of "he doesn't respond to autism treatments". Thanks for always responding.
DeleteDid you check for mitochondrial disease? This can be accurately diagnosed.
Deletehttps://www.tacanow.org/family-resources/autism-and-mitochondrial-function/
In the case of one reader of this blog, nothing worked until he finally did a detailed metabolic analysis. Having got the diagnosis, he follows Dr Kelley's therapy from John's Hopkins and after a few months things started to get better. But it takes months. So unlike in my son where things work in a day or two, much more patience is needed.
Bumetanide should only make you thirsty and so I think his weight gain may be a coincidence. Indeed one company used to add bumetanide to their pills for weight loss, before they got found out and banned.
What is a "detailed metabolic analysis"?
DeleteDiagnosis of mitochondrial dysfunction in ASD:
DeleteThere are many different tests that can be done to look for signs of mitochondrial dysfunction. Some common first-line tests include
•Blood testing: Complete metabolic profile (Chem 20), lactate, pyruvate, amino acids, creatine kinase, ammonia, total and free carnitine, acylcarnitine profile
•Urine testing: organic acids
http://www.ucsfhealth.org/tests/003468.html
Well, I just feel like I got confirmation of PANDAS. Dad just got put on antibiotics for a strep infection and my son has become a raging lunatic again. :(
DeleteGood detective work. Now it would be a good idea to check your son for strep, so you can convince your doctor.
DeleteIn some people antibiotics are effective, but in others IVIG is needed; so you will need a medical diagnosis to get the best treatment.
Hello again! I thought about PANDAS myself because i know deep inside that he was not born autistic. Until the age of about 4 he was a typically-grown child. There was no language delay, he was very sociable and loving and extremely smart. Now he is a slow writer, can't concetrate at all, needs 1:1 support at school, has fears and of course tics! I had tested him for PANDAS in the past but the doctor said his indicators was nothing to worry about. We live in Greece and i think that paediatricians are not very well aware of such ''new'' diseases. What would you suggest i should do? Any special blood tests? Any specific antibiotic i should try? He can't shallow pills. In case the symptoms ease with antibiotics, could that be a proof that it is PANDAS? In that case, should he take antibiotics for ever?????? Sorry for the multiple questions but i think that many kids with Asperger's don't really have Asperger's.....
ReplyDeleteI think people like the idea of PANDAS because it looks to be treatable, but apparently it is rare. I think if your child has ever had a penicillin-type antibiotic for a common problem, you would have noticed a behavioral change if it was PANDAS.
DeleteI think your best bet is to try and control the OCD/tics with NAC. This should happen within a couple of days, if the problem is oxidative stress. NAC you can probably buy in Greece at a pharmacy as Fluimucil, which is a tablet that dissolves in water and tastes fine. If you buy the capsules, you can open them and put them in juice. The taste is bitter, but it is much cheaper than Fluimucil. You need a lot of NAC for it to work.
I would not expect any help from a typical pediatrician. All autism therapies are experimental.
Try NAC and let me know if it helps. Do this before thinking about experimenting with antibiotics.
Hello again! Having read closely all the comments about PANDAS i need to add something. I 've read that colostrum could have positive effects on such disorders. So, would NAC, GABA supplements and COLOSTRUM be a good idea???
ReplyDeleteAccording to Wikipedia ...
Delete"Supplementation with colostrum, which is rich in IGF-1, can be a useful part of a weight reduction program.Although IGF-1 is not absorbed intact by the body, it does stimulate the production of IGF-1 when taken as a supplement."
This is interesting because the growth factor IGF-1 is actually being researched used as an autism therapy, but you have to inject it every day.
Baclofen also stimulates the growth hormone-IGF-I axis.
Recently it was shown how GABAb dysfunction will affect the production of Growth Hormone Releasing Hormone (GHRH or somatostatin) in the brain. This might explain why Baclofen/Arbaclofen help some people. But they might also benefit from the IGF-1 injections or by your colostrum.
There is data showing how much Baclofen increases IGF-1/GH, but I have no idea how much colostrum you would need to eat. It might be a huge amount.
So I would class it as "plausible".
Hello Peter,
ReplyDeleteI was reading much about PANDAS while trying to explain periodic episodes of neuropsychiatric symptoms in my son a long time ago. I was told then by an experienced doctor here that acute flares of symptoms worsening associated with documented Strep infection (at the same time) are needed to confirm this diagnosis. Both PANDAS and PANS however can be diagnosed also by “Cunningham Panel”, a set of autoimmune antibodies tests, including anti-dopamine receptor autoantibodies. Although it’s not included into official diagnostic criteria it makes sense to me as it refers to the core problem: autoimmune process. The test is very expensive, but can be done also in Europe (via Wieslab in Sweden, you can send blood sample there). Well, there would be a good question, what to do if PANDAS is confirmed. I know a mother of ASD/PANDAS teen boy here, who benefitted much from IVIG, but not antibiotics. It is difficult to get such treatments in my country, perhaps easier with a well confirmed diagnosis. As my son’s episodic issues resolved with valproate started together with food allergy treatments, I haven't continue with PANDAS tests.
Now valproate (high dose) happens to be the only drug that I found able to prevent this flares - with headaches and autonomic symptoms - in my son (via influencing sodium channels? or T-type calcium channels?), so I may face the question whether one can combine it with Bumetanide for long term. Do you know anybody using them both? This episodes are severe, but on the other hand, I remember too well the times before Bumetanide to give it up.
It is very interesting that Bumetanide helped with seizures for Olga’s son. I wonder if it was given together with any other AED? Bumetanide alone corrected abnormal slowing in the awake EEG in my son, while he still has spikes while asleep. I am not a neurologist, but I suspect that it could be of much benefit for some people with ASD/epilepsy, whose seizures are not well controlled with typical treatment (if not alone then combined with other drugs as proposed here http://www.ncbi.nlm.nih.gov/pubmed/21167788).
That paper "Combined effect of bumetanide, bromide, and GABAergic agonists: An alternative treatment for intractable seizures", you highlighted is very interesting. Perhaps, in some people with autism, bumetanide appears ineffective because it is not sufficient. Potassium Bromide is an epilepsy drug used in Germany for children. I will raise this with Ben-Ari.
DeleteI do not know about anyone using Bumetanide and Valproate long term.
I think you may need to find an immuno-modulatory therapy, very specific for your son. I would not rule out things like Minocycline, that was trialed to reduce microglial activation. In the more rare cases of autism it might indeed work. In my son's case the Sytrinol/Tangeretin really does have the effect I was hoping for and it is something that is cheap and low-risk. In your son's case it looks like you need something more potent, or very targeted. I would also look at things that work in Crohn's disease and arthritis.
Pioglitazone looks interesting and was trialed in autism. While most people would not like the idea of the TSO therapy, it might be worthwhile finding out more about the sub-type who benefit. I have no idea if Low Dose Naltrexone works; most doctors are hugely skeptical. Being low dose it should be both safe and cheap to try. I think these kinds of treatment are likely to be ineffective when trialed on "all autism", and therefore rejected. But in very specific cases, as suggested by anecdotal evidence, some do seem to work.
For now, my son is on a good path and so I will not be trying things like TSO or Naltrexone; but I think they are worthy of investigation.
Thank you Peter for these suggestions.
DeleteIt would be great if prof Ben-Ari commented this issue. Perhaps Bumetanide should be considered for trial in people with ASD and epilepsy (or epileptiform EEG). Such children were excluded from the French study, but I think that was done for scientific clarity reason only. Otherwise those who called this research “controversial” could tell that Ben-Ari and Lemonnier treated epilepsy and autism improvement is just secondary.
In the paper about Bumetanide and seizures they wrote “Concomitantly with the inflammation, changes in expression of NKCC1 and KCC2 co-transporters have been observed that resemble the immature brain”. This is with regard to epilepsy, but I think that it may explain also what happens when bumetanide stops working in autism, as you suggested, due to other things like inflammatory exacerbation. In our case: for a few weeks without antihistamines.
You are right about the immuno-modulatory therapies, thanks for these comments. I do consider LDN.
Have you seen the study, which - in vitro and not for autism though - “screened 1040 compounds with the aim of identifying inhibitors of microglia to reduce neuroinflammation”? http://www.ncbi.nlm.nih.gov/pubmed/24047520
Ben Ari replied that things are more complicated than suggested in the paper your found (http://www.epilepsybehavior.com/article/S1525-5050(10)00695-5/fulltext ) and that he published a paper ( I think this one http://jn.physiology.org/content/101/6/2878.long) showing that bumetanide is not a good prophylactic drug, at least for severe seizures and in chronic seizures. He also suggests that it would be is ethically and technically impossible to give prophylactically a drug.
DeleteI think he is really considering epilepsy per se, rather than autism+epilepsy, or indeed just autism. If you are already taking bumetanide for autism, it would be nice to have a "bonus" prophylactic effect.
While bumetanide may indeed not be a good prophylactic drug for all types of seizures, we are really only interested in the ones that occur in autism. We only have one piece of data, Olga from Russia, suggesting an effect.
I found a case study of the use of potassium bromide 150 years ago to treat epilepsy in a girl with severe autism: -
https://books.google.co.uk/books?id=PBSG-_45jdwC&pg=PA8&lpg=PA8&dq=bromide+autism&source=bl&ots=BSpHBq6e3O&sig=JRykEW4cbBzYKvZl5T2VNzYJu1U&hl=en&sa=X&ei=ReFZVeiQOYauygONtYDIBw&ved=0CGIQ6AEwCDgU#v=onepage&q=bromide%20autism&f=false
the use of potassium bromide not only treated the epilepsy, but also resulted in age-appropriate play with a doll (for the first time).
Potassium bromide is still used in Germany for epilepsy in humans. In the rest of the world it is used in dogs. Too much bromide is not good for you. There was a trial showing positive effect in Dravet’s syndrome.
I wonder what the effect of a low/safe dose of KBr would have when combined with bumetanide, in those who respond to Bumetanide alone; and indeed in those who fail to respond to Bumetanide alone.
Regarding your other paper, Spironolactone has been suggested for autism for mainly different reasons (http://www.ncbi.nlm.nih.gov/pubmed/17150311). Since it increases K+ it would go well with bumetanide. I did briefly try it, but saw no effect.
I believe in what Ben-Ari says although his paper is quite difficult for me... But I think that his findings do not exclude possibility of bumetanide potential specifically in autism+epilepsy, as you pointed. Maybe it’s not sufficient alone, that’s why I wonder if Olga’s son received also other AED.
DeleteDr Chez seems to give effective seizure prophylaxis in ASD, according to his book, long ago highlighted in your blog. He wrote that his patients with asymptomatic spikes in sleep treated with high dose of valproate did not develop epilepsy in the follow-up. He seems to treat many children, so the number might be significant enough.
A year ago I wouldn’t dare to think if there could be better ways to achieve this than what Chez suggests. But maybe there are.
This issues are important for more kids than my son, as abnormal, epileptiform sleep EEG is a common finding in ASD children. And unfortunately neglected by many.
I am quite shocked by the book you referenced. Apart from the bromide successful use, it seems that a hundred years ago they were more aware of GI/autism associations - even without labelling the problems - than it sometimes happens today. This dr Dickinson luckily did not learn at medical school that autism is untreatable psychiatric condition to the benefit of his patient. This is a very interesting story.
Do you recall the dose of Spironolactone you used? Did you use it together with Verapamil? I can’t increase Bumetanide dose as my son goes hypokalemic easily.
I think I used the 25mg tablets and just once a day. Perhaps this dose was too low. This was before I used Verapamil. Diuretics are often combined to avoid hypokalemia.
DeleteAnother diuretic that might have a similar effect on Cl- levels is Diamox, although not via NKCC1. It will have a secondary effect of changing the PH of the blood so that it carries more oxygen. Some children have cluster-similar headaches that respond to oxygen. If their blood carried more oxygen, they might not get the headache to start with. Diamox is also used to avoid altitude sickness. I showed in an earlier post that it would reduce chloride levels within the cells via a different transporter/exchanger. I do not know about its effect on K+ levels. In some countries bumetanide has KCl added to it to avoid hypokalemia.
It looks like they should have added KBr. A small amount of KBr might be good for your son, both the K+ and Br- should do something helpful. Germany is the best place to get the human variety. High doses are not good, but a fraction of their dose might give the effect of bumetanide an extra boost, just as the Brazilian paper suggests.
I think the effect I saw with a tiny dose of valproate was in effect the GABA agonist effect also suggested by the Brazilians. This makes me think that once GABA is shifted back to inhibitory, I could just add GABA itself for this effect.
Thanks!
DeleteI remember we discussed Diamox briefly few months ago and also KCC2, neuroligin etc. Your earlier post about modulating GABA A receptor is my favourite of all and helped me much with understanding the basis for these treatments.
I once read a DAN case report about a young adult man with autism, who improved on Diamox (given for presumed other reason). Do you know what is Ben-Ari opinion on this drug?
It is suggested that GABA itself can’t cross blood-brain barrier. In my opinion this may not be relevant to BBB in autism though. Also you wrote about some Russian GABA-ergic drugs, which may be helpful and can cross BBB. Phenibut and Picamilon also may be interesting. I always ask myself the question about safety of such treatments for children, but from what I can read on our polish parental message boards, these drugs are given by neurologists for ASD kids in Russia or Ukraine.
There’s also l-theanine, which I found looking for mast cell stabilizers and seems to have other good properties as well:
http://www.ncbi.nlm.nih.gov/pubmed/17928735
http://www.ncbi.nlm.nih.gov/pubmed/21344174
http://www.ncbi.nlm.nih.gov/pubmed/25896423
According to the ever-useful Wikipedia:-
Delete"Theanine increases serotonin, dopamine, GABA, and glycine levels in various areas of the brain, as well as BDNF and NGF levels in certain brain areas"
So L-theanine certainly should have an effect. Whether good or bad will depend on exactly what the dysfunctions are. That it had a good effect in schizophrenia, suggests that it may also be beneficial for some types of autism, but if you look at reviews many people who tried it for autism were not impressed. It does not appear to have safety issues.
The Russian drugs are interesting; I suppose you can get them in Kaliningrad. They are GABb drugs, but seem to have a smaller effect on GABAa.
I will ask Ben-Ari about Diamox, but he is clearly focused on NKCC1, and may not like the idea of a rival transporter/diuretic combination.
As I suggested, Ben Ari is very focused on Bumetanide. He says that to trial Diamox would cost another 5 to 8 million euros. So he stays with Bumetanide.
DeleteHe is not really thinking about what might work, rather how to get a therapy approved.
For me, I am just concerned with the optimal therapy and that it is safe. I am not concerned with approvals. In the same way he is not interested in the micro-dose clonazepam, or verapamil, let alone NAC, Sulforaphane, Atorvastatin etc.
I really appreciate the French research and what Ben-Ari, Lemonnier et al have already done. It’s rather exceptional in the current autism science/medicine world. It will be of great benefit for many to have bumetanide therapy approved.
DeletePersonally I share your view and so I am grateful for your blog. Diamox seems really interesting, so I might try it in the future. Didn't know that it's also used for hypokalemic paralysis. I was amazed to quit a kind of auditory aura in my son few days ago with an extra K dissolved in water. I read about your experiments with potassium, this is all very interesting and helpful.
Do you mean that a tiny dose of valproate with high dose plain gaba could have the same effect as high dose valproate? sorry but as i have nearly the same questions as Agnieska, i am geting into your convesrsation! My name is Valentina.
ReplyDeleteValentina, here is a nice picture showing valproate (typical doses) mechanisms of action, I found it helpful:
Deletehttps://www.pharmgkb.org/pathway/PA165959313
There's excellent Peter's earlier post regarding this issues:
http://epiphanyasd.blogspot.com/2014/09/gaba-receptors-in-autism-how-and-why-to.html
I found 50 mg prolonged release valproate formulation in UK (Epilim Chronosphere). Depending on child's weight it can be used as low dose. It's very comfortable, but expensive.
The first step ,to switch gaba to inhibitory, for how long would be?, because it would be interesting if i could give him gaba high and valpraote low dose and nothing more to treat his subclinical epilepsy or epileptiform activity
DeleteThankyou
Valentina
Valentina, your child has subclinical epilepsy but does he have autism? If he does, what kind of autism?
DeleteIf he has autism, it is very well worth trying bumetanide to treat it. It may, or may not help the epilepsy.
He was diagnosed with HFA but now he is 9 he became Asperger, according to what you say and what you know about my son, would be a possibility to give him both bumetanide and valproate?, i know that iam repeating this question and Agnieska asked you the same, but could i keep the dose of 500 mg valproate? with the usual dose bumetanide? thanks, Valentina
DeleteAgnieszka many thanks for the information! I also rely on valproate , but I want to minimize side effects by lowering the dose without removing the effect , so the first questions to Peter about combine it with Bumetanide , which is not advisable. Now I asked him about plain gaba for what he said about the brazilian paper, , if could be another possibility, in addition to valproate . About your info, ,on drug interactions , it is said something about NAC and toxicity that i did not understand , can be combined nac with valproate ?
ReplyDeleteValentina,
ReplyDeletePeter is far ahead than me with these issues, but as I understand it: Bumetanide is the only drug studied in children with ASD, thought to restore GABA inhibiting properties. Low dose clonazepam is supposed to do this also, but in different mechanism. It was shown in “autistic“ mice and a few people use it. It was all described earlier by Peter.
Brazilians suggest KBr and Bumetanide for better effect. It seems plausible, but I don’t know if anybody has tried this in autism.
If Peter doesn’t mind, I can write you here about my experience as valproate (ex)user. Valproate abated severe headaches, misdiagnosed at first as mood disorder in my son and improved his sleep EEG. He had spikes before, but never overt seizures. However valproate did nothing good for autism, so I changed it for bumetanide, which helped my son with awareness, learning and sensory issues. So perhaps bumetanide did its job and switched GABA to inhibitory. In our case this was not enough to correct epileptiform sleep EEG and prevent headaches though. Later I added back valproate, but it was a very low dose (1-2mg/kg). This was associated with nice social effects in my son, but it did not helped him with headaches so I quit it. I did not see any significant side effect of that combination and regular lab tests in my son were normal, had not done EEG then.
I once read much about using NAC together with valproate and NAC seems to improve safety of the latter: http://www.ncbi.nlm.nih.gov/pubmed/21175036. It has been suggested that NAC may even increase antiepileptic effect of valproate. So for sure it’s a good combination.
Agnieszka, thankyou so much for the clarity of your explanation. I have only a question, if you left valproate , what do you use to lower the electrical activity ? because bumetanide would be for autistic behaviors and not very sure for epileptiform activity, more if it is resistent . Would be good to know what Peter thinks about this. Many greetings, Valentina
DeleteValentina, if your son's autism responds to bumetanide it is certainly possible that so will his epilepsy. It is thought that about 50% of people with ASD do respond to bumetanide; so it is certainly worth trying out bumetanide. You cannot know the effect on his epilepsy without trying it; it all depends what is the underlying cause of his epilepsy. If it is GABA being overly excitatory, then bumetanide should improve it.
DeleteI see that valproate dosage should be reduced only very slowly to avoid seizures, so if you choose to experiment with bumetanide you should do things slowly. Another reader of this blog, from Morocco, had exactly the same question as you, he wonders if bumetanide might mean he can stop high doses of valproate. His son may react differently to your son, since the underlying dysfunction will likely not be same.
Bumetanide dosage is 1mg twice a day and it will take 2-3 weeks to show effect. There should be a very obvious behavioral and cognitive effect, if your son is in the 50% of responders.
Can I make de process of lowering valproate dosage introducing Bumetanide at the same time? because if he responds well to bumetanide, the transition would be slowly and less problematic and perhaps i could see a diference from the start (after 2 or 3 weeks) and could get to the optimal dosage of valproate. Or is not a good idea? thanks,Valentina
DeleteBest to try Bumetanide for three weeks, with your current valproate dosage. Then you see if there is a behavioral/cognitive change. If there is a positive change then you know your son is a responder. This then would mean that Bumetanide might also help the epilepsy. Then you could slowly lower the valpraote dose to see if he now needs less valproate to manage the epilepsy.
DeleteIt looks like you need to lower the valproate dose very slowly, because the body has got used to it and then the epilepsy trigger is just the valproate withdrawl itself.
You may find the bumetanide helps the autism but not the epilepsy, but that still would be a big success.
Valentina,
DeleteI have added clonazepam low dose, actually because I wanted to target sodium (Nav/SCN) channels in case this is the problem for my son.
When tapering off valproate I asked his neurologist how long we should lower the dose. And did it twice as long than was told, just to be on the safe side. Started bumetanide together with 100 mg valproate.
and did you notice that bumetnaide was replacing the lack of valproate or did you add clonazepam immediately? valentina
DeleteNo, I saw different effect with bumetanide and valproate, can’t say one replaced another. Valproate abated headache (mood) episodes, but had no effect for autism symptoms. Ten days after bumetanide, without valproate, got a series of positive comments from teachers about my son’s engaging with classmates and his speech. 3 weeks later my husband noted in our “treatment diary”: “it seems that we can teach him something” - and this was after lack of almost any progress for 2 years before. My son was exactly like in Peter’s post here:
Deletehttp://epiphanyasd.blogspot.com/2014/08/double-tap-autism-perhaps-important.html
So I don’t know if our children’s issues are similar. I have more detailed information about my son, treatments and also a kind of short “bumetanide vademecum” but written in polish, where are you from?
I added clonazepam only two weeks ago.
I understand, perhaps in this cases of autism is dificult to generalize a treatment, what helps one, doesn t help to another, bumetanide helps you and peter with your sons autism symptons but for olga was the opposit situation, and now, neither of them. I treat my son with an argentinian neurologist, last time he told me that he wanted to take out valproate, but was afraid of a regression.´that means that could be a posibility to convince him of trying bumetanide. But you know the position of neuroligists, and how they medicate. I dont know.Do you konw Punta del Este? Iam from Uruguay.
DeleteValentina,
DeleteI think one has to consider many things with such decisions and only sometimes there’s a clear way to go. In my son EEG abnormalities were minor, so the risk of seizure associated with valproate withdrawal was of little concern. I would discuss this risk in details with neurologist as this depends on many individual factors. The advantage of drugs as bumetanide, diamox or low dose clonazepam (and also verapamil) is that they are for sure safer than many typically used in ASD children, so the risk of trying them is low. Good luck! My Spanish is worse than English unfortunately, I am from Poland.
Hi Agnieska, thanks for your advise, i think that its time to cross the river to Argentina, to visit the neurologist and look for another treatment or medicaton, see how is his epilepotiform activity. Y suspect that is worse.He has made a huge intelectual progress but his inestability or anxiety movments hasnt been controlled yet. My english is terrible! you write very good!! I will be in touch, Valentina
Deletehello Peter
ReplyDeleteBumetanide apparently has stopped working for epilepsy after 1,5months...
Do you know what could be the reason of it?
In my son Bumetanide has not improved ASD symptomes but helped with partial epilepsy...
NAC and sulphoranane didnt work ...
Do you think a good idea introducing Verapamil todo restore the effect of bumetanide?
olga
Several people have commented that these drugs (bumetanide, NAC etc) "stop working".
DeleteReally it is the case that something else has "started working". But what?
If your son has any kind of allergy (pollen, food etc) this could be the problem. If this is the case then Verapamil is well worth a try. If he has even a very mild pollen allergy then also use H1 antihistamines. The older ones may indeed work better than the new "non-drowsy" ones. I use Allergodil (Azelastine) nasal spray, by Meda Pharma.
Even if you detect no allergy, it is still worth trying an H1 antihistamine. Several readers, whose kids were "allergy free", showed improvement with an antihistamine.
In summertime NAC and sulforaphane would also appear not to work in my son. I no longer test new things in spring/summer for this reason.
The other things that might be effective are anti-inflammatory therapies, but it is very hard to find the one that is effective.
Some people use NSAIDs like Ibuprofen; a more suitable one for longer term use may be Celebrex.
Some people use pioglitazone/Actos a PPAR gamma agonist used for diabetics.
In my son there are at least 2 problems. One is allergy-triggered and the other is not. For the first problem the solution is the Verapamil/Azelastine/Quercetin combination, for the second problem (not allergy related) the solution is the PPAR gamma agonist, which I use Sytrinol/Tangeretin.
Thank you.
DeleteCelebrex is only for adults. How do you calculate de dose?
i have seen 200mg capsule presentation
Olga
I only ever used Ibuprofen and at the regular child dose, but this is only ok for short term use. It appears that Celebrex can be used longer term and it is also an NSAID. I would first see if Ibuprofen has any effect. Both are used in autism in the US.
Deletepeter, have you looked into a low oxalate diet for Monty? The issues with oxalates resonate with the thinking behind channelopathies. It might be that a diet can serve to support or disrupt ION channels. Maybe is part of a combined diet, supps and generics approach to channel support.
ReplyDeleteNo, I have not really looked at diet, because it would seem likely that for diet to be part of the problem there should be at least some GI problems. Monty has a varied diet and no GI issues.
DeleteThere is research showing that oxalate is high in many people with autism, but there is no research indicating that this causes them a problem. It would seem logical that they should be more prone to kidney stones, but they are not.
Ion channels are known to cause all kinds of medical problems and they are well researched. So you know which genes are responsible which channel. They you can even identify a genetic dysfunction causing its ion channel to misbehave. So this approach is scientifically valid, although highly complex.
Diet clearly does play a role in some people's autism. I think that in some very mild cases, diet may be the only issue.
I am now at the stage where I look at the changes in Monty's autism, so I can see what any flare up is caused by. His diet remains constant, but his autism varies, so there is much more to it than diet.
I think that "disabling" autism is a severe condition and should be treated medically, if at all possible. Because of the bizarre attitude of most doctors, most parents do not have this opportunity, so they focus on diets and supplements.
Hi Peter,
ReplyDeleteI just spoke with my son's doctor and he (on his own) brought up the subject of Bumetanide and Baclofen as potential drugs to trial. I was really surprised because he is very conservative and wasn't willing to try the low dose of Klonopin. He said that he would like to try a very low dose of Abilify first before prescribing Bumetanide or Baclofen, but when I refused due to our past experience with the ATypical class of drugs (Risperadol and Seroquel)he relented on Baclofen. He wanted to try it before Bumetanide because he wouldn't need to do monthly labs to monitor electrolytes. I am thrilled that these two drugs are on his radar and that we now have options.
He is recommending 10mg (split up 5 in the am and 5 in the pm). Question: Do you think it is ok to continue the NAC and BioGaia Gastrus while on this? I respect your opinion and just don't want to do too many things at once. Thanks so much! Christine
Baclofen is good to trial; it seems to help the majority with Asperger's. If it is a more like classic autism I think it is less likely to help but certainly worth a try. I see no reason not to take NAC and BioGaia at the same time.
DeleteBumetanide is not such a bother since the majority do not have a problem with electrolytes, you just need to know is your son in the 20% that lose a lot of potassium. My son is in the 80% and so we do not need to keep checking potassium.
It is classic autism -- not Aspergers. If we have no success with Baclofen and I am able to get him to trial Bumetanide, perhaps he will take blood for a few months and then if there is no issue with electrolytes, we can assume he doesn't have a problem with potassium loss. Thanks! Christine
DeleteHi Peter,
ReplyDeleteAs I had mentioned above, my son has started a trial of Baclofen -- 5mg AM and 5mg PM. Because he is sensitive to meds, I decided to just start with 5mg for a few days to see how he did and then on day 4 split the dose as instructed. He did fine on the 5mg. On day 4 when I went to give the 2nd dose of 5mg, I accidentally gave him a whole 10mg pill. Call it mental exhaustion -- I have no idea why. The next morning I had a dilemma: do I give the 5mg AM dose and get back on schedule or would that be too much. I decided to give it to him and then the 2nd dose in the PM. He was a mess! He couldn't sleep. His verbal OCD was as bad as ever (repeating his schedule over and over). The NAC which helps with this wasn't working and he was very emotional (crying and then laughing). My husband and I were just about to go to sleep when he came into our room and said "a shower please". We realized quite quickly that he had terrible diarrhea in bed. In years past this had been an almost daily occurrence but had not been a problem for about two years. Can you tell me what you know about meds and how they affect the GI. Any specific information on Baclofen that you know of. I know they often call the stomach the "2nd brain" so it makes sense that chemical changes in the brain from meds can affect the GI. Any insight is much appreciated! Thanks, Christine
Christine, some people do find baclofen causes diarrhea.
Deletehttp://www.ehealthme.com/ds/baclofen/diarrhea/
It might be a coincidence and it might just be a short term issue.
I did try baclofen on myself and did not like it. It gave me mild chest pains. For my son there was no big effect, good or bad.
The people with Asperger's seem to get only good effects.
I would suggest you ask your doctor to move on to trial bumetanide, if baclofen does not help.
Christine and Peter: Christine, did you keep your son on baclofen? If so, how is he doing? Peter, why is it that baclofen is more effective with Asperger's? I was reading baclofen can be effective for treating nerve pain and fibromyalgia as well as anxiety - thinking this might be good for my son (who does not have asperger's but severe ASD) as a double benefit for him . I think at times he does have fibro like fatigue and of course anxiety. He also has intermittent pain episodes from a nerve tumor. Would be wonderful if baclofen can help
DeleteHi Tanya,
DeleteI didn't end up keeping my son on Baclofen because I didn't see any results. My son has classic Autism (not Aspergers). No effect on anxiety unfortunately. From what I have read, it seems that it is ARBACLOFEN that really worked for the kids with Fragile X. Once they were unable to get it (after the study ended) some of them decided to try BACLOFEN and said that they didn't have the same results.
As you know, every kid is different, so by all means talk to your son's doctor and see if you can trial it. Best of luck!! --Christine
Really appreciate your reply Christine! Right now we are trying low dose mirtazapine for anxiety and read that it also is used t treat chronic pain - so we shall see.... Baclofen if the plan B. thanks again for sharing!
DeleteTanya, why Baclofen helps so many with Asperger's and not Autism is a good question. The GABAb dysfunction must be less present in autism, or perhaps where it is present but the dosage is too low. Arbaclofen, the more potent version, was originally be trialed for Fragile X.
DeleteAt moderate doses Baclofen is well tolerated, which is good news for people with Asperger's.