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Sunday, 17 January 2016

Autism PolyPill vs Personalized Medicine and the KD/MAD diet




The idea behind personalized medicine is the realization that humans are all slightly different and that some of the diseases they suffer, like autism, are also all slightly different.  In order to treat them optimally, you would need to use drugs and dosages customized to each person.





Here below are three slides used to illustrate Personalized Medicine in cancer care.  Instead of treating “cancer”, four sub-types are identified and then treated using four different drugs.  Each person only receiving the effective drug.













Autism is not cancer, but understanding cancer gives you a much better concept of what can underlie a highly complex disease like autism.  You need to consider multiple hits as in cancer, which is very similar to Russian Roulette.

The thing that does not seem to exist in cancer is the "double tap", when in a minority of cases, a moderate case sudden changes to a severe case.  This is caused by a new factor coming into play, or an existing factor that had been dormant. In cancer, metastasis is a progression of the existing condition, not something unrelated.  

In the above case there were just for four types of cancer and all you have to so is to find the molecular biomarker for each one.  Then you treat each person with the appropriate drug and avoid side effects from the wrong drugs.

Autism is much more complex because it has "layers" and these may change over time. You have to treat the outer layer first.  This explains why some effective autism treatments appear to "stop working".  Something else has started to work and now forms the outer layer.  This could be related to mast cells, mitochondrial dysfunction or probably a whole host of other factors.

The autism equivalent graphic above, would have people in multiple colours as if dressed.  Just as people change the colour of their clothes, some of the colours of each figure might vary over time and this is what really complicates things.

People with oxidative stress might be represented by having blue socks, reductive stress red socks and "no" stress black socks. There would be lots of blue socks and very few of red or black socks.

NAC for those with blue socks.




PolyPill

So my idea of a PolyPill arose from the idea that when a non-verbal three year old with some odd behaviors goes to his doctor, he might not come home empty handed, and not with those wholly inappropriate psychiatric drugs.  The PolyPill might contain some ingredients that were not necessary, but it would show that a single pill could produce marked improvements in the majority of cases.  All without any complicated and expensive genetic or metabolic testing.

Since I only treat one person, my PolyPill is really a perfect example of personalized medicine.  As time passes, it becomes even more tailor-made.

Monty’s big brother did recently ask why don’t you actually make the PolyPill?  Good question. I did look into this in some detail and even gave a presentation to the European drug regulator (EMA).  There are enormous barriers, few of which relate to developing the drug itself.

If I was James Simons (of the Simons Foundation) that is exactly what I would do, make a PolyPill that could help hundreds of thousands of people.  But unless I receive a call from them, I’ll be sticking with a personalized medicine called Monty’s PolyPill.

The huge advantage of Personalized Medicine is that it minimizes the number of drugs and quasi-drugs that you give.  Let's not pretend that nutraceuticals and OTC supplements are not drugs. This is a concern raised on this blog, just how many ingredients can you (safely) have?  

It certainly can be a bother dispensing them.  Your typical multivitamin contains 14+ ingredients, who would give their child 14 pills at breakfast?  Almost nobody.  But a single little multivitamin pill is just fine. Do they even need all 14?  Unlikely.



So, how many drugs can a PolyPill have?

That was Agnieszka's point in a recent comment.  Things do interact and this does include supplements as well as drugs.  It can be time consuming preparing all these ingredients, not to mention having to swallow them.

This is why someone took Dr Kelley's mitochondrial therapy and packaged it up and sell it as a single product, Mitospectra.




DAN! and Diets over Time

Another vaguely related issue is what happens to autism therapies over time.

It is clear that while allergies may moderate over time and hormonal changes have secondary effects, the core dysfunctions in autism are likely to be permanent.  You can treat them, but you probably cannot cure them.  None of my therapies seem to be disease changing.

So what happens to the thousands of kids, mainly in the US, who follow DAN therapies and diets?  This was raised recently on a popular autism blog and the conclusion was that, after a few years, the great majority of people give up.

This is rather sad.  It shows that the majority of those therapies had no significant effect on the majority of people that tried them, otherwise they would not have given up.

An example being the blog author, with one of those children who had a "second tap", that shifted him to the very severe kind of autism.  This became a new "outer layer", in Peter-speak.  What if that second tap was due to mitochondrial dysfunction (as appears to be relatively common)?  If that was the case, it is not surprising that the gluten free diet did not help, nor  HBOT etc.  Surprisingly, there actually is a diet that might have helped.  No, not the GAPS diet, but the Ketogenic Diet (KD); more a medical therapy than a diet, so well worth reading about.

I was surprised how much evidence there is that indicates that the Ketogenic Diet (and hence likely also the Modified Atkins Diet, MAD) MIGHT  help those with mitochondrial disease. There is no reason to think unrelated diets would do any good whatsoever.

In some cases the Ketogenic Diet can have disease changing effects, meaning you do not need to stay on it for life.  Many people transfer to the MAD.

So if you have a case of severe autism, resulting from a second tap, or a late regression, and nothing covered in this blog seems to help, test for mitochondrial disease.  

If Dr Kelley's therapies reverse the decline, but progress is painfully slow thereafter, it could be worth trying the KD or MAD.








16 comments:

  1. Hi peter, we have been reading your blog for less than a month now. We already tried NAC with sucess and then tried sulforaphane with only a little success. We bought b complex (with folate), Miyarisan probiotics, bio30, potassium and cocoavia. We are still waiting to start trials with them. She is already taking cod liver oil.We will also try bumex next month or so. How to you combine them? Our daughter doesn't swallow pills.

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    1. You can crush pills and mix with liquid. Some people use a fruit smoothie or apply sauce.

      Some pills have little taste but some substances taste pretty bad (eg broccoli).

      My son has been drinking one potion, or the other, for three years. So I can just add something new and does not mind.

      I use 5ml of high flavanol cocoa powder, rather than cocoavia, it just goes in with his potassium, broccoli powder and half a fluimucil (helps things bind together and provides NAC) and then 5 seconds with a hand held frappe mixer. I serve with straw (masks the taste) and drinks it 10 seconds. When he was younger there was bumetanide in there as well.

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    2. My son won't do pills either. He also is not a fan of apple sauce or smoothies.

      Sulfur based stuff like Broccoli extract goes well with cheesy stuff such as Mac and Cheese. The mediciny tasting stuff (sour taste) goes better with sugary drinks, but if your child is picky enough you need to put some extra sweetener in to make it palatable as fruit taste is generally a mix of sweet and sour.

      NAC is hard because it really throws off the taste of a sweet drink and with sweeteners whether they be sugar or sucralose (what I use) you can't overpower bad tastes unless you are willing to dilute what you want to go down in an extreme way, and then you have issues getting your child to drink a large amount of liquid on a regular basis (if the child is non-verbal or generally uncooperative with anything, then this is not practical).

      B-Complex is water soluble, but many supplements are fat soluble. If you are going to try and mix oils and fat soluble vitamins with everything else into one giant supplement drink, you are going to need an emulsifier such as soy lecithin such as if you were going to mix fish oil with orange juice (can be tolerable through a straw, but every kid is different).

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    3. My son accepts almost anything if I mix with strawberry jam.
      Its very sweet and the consistency doesn't change much no matter what I put in it.
      I mix 1 generous spoon of jam with the supplements then apply to his waffles or bread/toast.

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    4. Hi peter, thanks for your quick reply. The cocoavia bottle says " not for children". Each pill contains only 375mg of flavanol which is not much. What do you think?

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    5. The trials for memory improvement in adults used 900mg of flavanols. For improved cardiac health it is suggested to use 200+ mg. I use 5ml of high flavanol cocoa (ACTICOA). I do not think they ever thought kids would need such a product. Bumetanide is not approved for kids, since they never envisaged a kid needing a diuretic. So you are experimenting.

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    6. 5ml of ACTICOA equals 2.5g and is claimed to contain at least 200mg of cocoa flavanols.

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  2. Well in the United States at least, as long as you don't include actual regulated drugs in a "polypill", you can just bundle everything together as a "supplement" or "food". That won't work for Bumetanide obviously. Sadly, the way medicine works in the United States is that unless a drug does exactly what it is supposed to do with a huge success rate, then it is deemed a failure. This is why drug manufacturers nowadays instead go for treating specific metabolic changes rather than actually developing drugs or treatments to treat a disease itself. For example, just look at statins and the zillions of different drugs for that category. Statins are given to lower cholesterol, but they make no claims about lowering overall mortality from cardiovascular disease. All claims made are indirect in that if you lower cholesterol then the logic goes that less people die of cardiovascular disease, side effects be damned. Another example, are SSRI's where the logic is that if you raise serotonin signaling in the brain, then people will stop being depressed. Unfortunately, when you look at SSRI's in treating depression as a disease the numbers are quite grim relative to other treatments and therapies, some of which happen to be free (exercise, diet, sleep).

    I think a PolyPill can be done, but you would first have to find a partner doctor willing to give you legitimacy and authority via him/her putting on their white coat, then you have to get your doctor partner to contact a research group at a university or institute to trial your idea after of course the doctor discusses privately that there is already a lot of success in what he/she is proposing as research these days is almost always positive research because negative research ruins ones career in science (research that does not demonstrably prove a particular hypothesis doesn't get published or even made public which is a huge problem in science). Then if that is successful, then you have to partner with a big pharma company to go through the massive red tape with the FDA and likewise agencies around the world.

    It can be done, but obviously is impossible on your own and will eventually require capital raising skills from yourself or else someone else involved in the operation.

    A movie that might give you an idea of what one might have to go through would be Extraordinary Measures starring Brendan Fraser:

    http://www.imdb.com/title/tt1244659/?ref_=nm_flmg_act_12

    In this case there was no competition and lot less inertia and noise (unlike with autism and pushing treatment ideas around), plus being an executive at a major corporation (as was the John Crowley character played by Brendan Fraser) helps with contacts and moneymaking) helps a lot too.

    I would check it out if you have not seen it yourself already. Its a good movie any parent with disabled children would appreciate.

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    1. There are many other barriers, including the fact that re-purposing existing drugs means there is little upside for any financial investor and that many interests do not even want to treat autism pharmacologically.

      So unless Jim (with all his non profit seeking mega resources) gets in touch, I will continue as I am.

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    2. Well it really is the regulatory agencies. Marijuana is legal in many USA states but non-addictive medicine is not for off-label use unless you can find a very liberal doctor (and why would any doctor do anything off-label unless he was getting a kickback as off-label treatments open yourself up to litigation). They ban Picamilon but do nothing to discourage alcohol consumption in the manner done with cigarettes because for some reason the myth that even moderate ethanol consumption is good for you keeps getting perpetuated by the media.

      Yues it is frustrating to say the least, but as a counterpoint, a very successful drug these days is Suboxone which is actually a combination of two drugs (Naloxone and Buprenorphine that I believe are both off patent), yet Suboxone itself is still quite pricey. If you get a formulation (your polypill) that works and substantially reduces autism symptoms with a large enough percentage of people with classical autism, then you can probably find investors, provided you have built up your other contacts first to establish credibility (like I mentioned in the previous posting).

      The bigger problem here is there still is no real societal consensus on how you define a positive outcome from drug treatment for autism. You can medicate many severely autistic people into zombies, but that is not what I would call a good outcome, but apparently it is good enough for risperidone as heavy meds are the go to solution for anyone who is institutionalized. A good outcome by my standards would be a measure of how independent the person is and whether they can contribute to society in any small way. This means IQ gains and that kind of solution is likely something that could be more broadly applied to a whole whose of neurological disorders. Nootropics unfortunately are rather taboo to most people because most people see it as cheating like in the manner of using steroids in sporting competitions, but this is the route any autism drug combo is going to have to go down eventually if it is going to be more than just a band-aid.

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  3. Thought you might be interested in some stuff I dug up while researching something completely different.

    The first is a link to a study done on bee retinas:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2229498/

    What they were studying is how ammonia uses a CCC (cation-chloride cotransporter) to preferentially enter the cell over potassium. What they found is that to prevent ammonia entry into the cells, you have to have a relatively high amount of potassium (i.e. the potassium and ammonia compete with each other). Too much ammonia buildup can dysregulate Ph cellular homeostasis and obviously cause problems. And to prevent this buildup, the drug they used was Bumetanide. Now I didn't even know ammonia could use CCC's to enter cells, but obviously if there is not high enough potassium relative to ammonia (or chloride) and there are too many CCC's floating around, then you could deduce you are going to have more than just excess chloride problems. This is all very dense stuff so my analysis could be a little off here, but that is the gist of what I read. Oh and this is about glial cells (not neurons), but obviously drugs like Bumetanide could have a secondary (hypothetical I must stress) benefit to reducing glial stress and attenuating autism symptoms or even reversing them. In a review I recently read on use of Bumetanide for autism, one speculation is that nobody yet knows whether higher dosages than the 0.5mg twice per day dosage of Bumetanide in the Lemmonier study would improve symptoms. I also suppose that the potassium wasting effects of Bumetanide are related to NKCC1 and NKCC2 being blocked and thereby preventing cellular uptage of potassium (thereby letting it flow directly into urine). This also suggests that excess ammonia in the body could perhaps do the same thing as Bumetanide in terms of lowering potassium peripherally. This could all be a redundant observation, but I found it interesting nevertheless even though this paper is about bees and the last paragraph covers how the findings may or may not have applicability to mammals.

    Last but not least, excess ammonia and glutamate happen to be one of the more common findings in amino acid profile studies for those afflicted with autism, so considering you have given an entire weekend of work yourself to just discussing potassium on your blog as well as many postings on chloride-cation cotransporters, I thought you would be very interested in this paper if you have not already read it yourself.

    Another paper I found is more or less a followup to the other one but it addresses mouse and rat astrocytes:

    http://ajpcell.physiology.org/content/274/4/C883.long

    Here they speculate that the swelling of astrocytes in hyperammonemia is due to excess ammonia flooding the steady state of NH3 and NH4+ via NKCC1/NKCC2 and this condition is rescued partially by Bumetanide and also more partially by barium but near completely by both Bumetanide and Barium administration (Barium is considered a potassium channel blocker).

    Anyways, feel free to delete this post if it is too offtopic. Just thought this might be material you may want to look over if you have not already before.

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  4. Another topic you might want to look into are polyamines and GABA transmission which I happen to know a little bit about from research into other stuff relating to mTOR and autophagy with respect to autism.

    A paper I just read in a tadpole model of epilepsy suggested that there may be an alternative intracellular pathway for synthesizing GABA independent of using GAD via intracellular putrescine being converted into GABA in interneurons which helps protect the tadpole brain from additional seizures several hours later through a neuroprotective cascade resulting in additional GABA release from interneurons.

    http://www.nature.com/neuro/journal/v14/n4/abs/nn.2777.html

    Their hypothesis is quite complicated so it takes some careful reading, but what I found interest is that even though they looked at intracellular putrescine formation, they cited another paper where injections of putrescine into the amygdala helped prevent seizures and I know from other research that you can significantly raise the levels of polyamines via dietary measures. If you want high levels of spermidine, eat lots of wheat germ (there are some other alternatives like natto but wheat germ is the best I know of). In this case, you would want to raise putrescine levels in the body (and also the brain) and grapefruit/grapefruit juice happens to be the best food for doing that. So perhaps getting around GAD dysfunctions is possible so that you can have more selective increases in GABA, rather than bathing the entire brain exogenously via GABA mimetics or even GABA itself which in rather popular paper last year suggested that GABA supplementation does indeed cause an increase in brain GABA levels (at least in the striatum which is what they looked at via fMRI). Obviously, we don't want to make our children drunk on GABA even though it may attenuate some of the nastier behaviors in autism because too much extracellular GABA impairs mental functioning just as benzos do through long-term use.

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  5. I have written before and found your blog and polypill to be very useful. The broccoli sprout powder works well for us for mood and the 1mg split daily bumetanide seems to be a huge piece of the cognitive puzzle. We also use .2mg Clonidine and 20mg Melatonin at night. We are doing D3 5000 IU in summer and 10,000 in winter and just started 200mg Azithromycin every 3 days and 15mg Prednisolone every other day. Wondering what dose you used for the Diamox as my boy is 9. I always appreciate your well reasoned and researched responses. Thank you

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  6. Veronica, I am using 125 mg of Diamox once a day. It does appear to have the desired bumetanide-like effect. Increasing bumetanide itself seems to have no further effect, but this is as expected, there is a plateau.

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  7. I will propose this to our dr. and see if we can obtain. I often read your blog, its one of my weekly touchstones. Thank you for the science and the hope.

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