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Friday, 19 August 2016

PAK inhibitors and potentially treating some Autism using Grandpa’s Medicine Cabinet





I wrote several posts about why PAK1 inhibitors should be beneficial in some autism and indeed some schizophrenia.

We also saw that PAK1-blocking drugs could be potentially useful for the treatment of neurofibromatosis type 2, in addition to RAS-induced cancers and neurofibromatosis type 1.

One problem with drugs developed for cancer is that, even if they finally get approved, they tend to be ultra-expensive.  Production volumes are low because even if they “work” they do not prolong life for so long and cancer has numerous sub-types.

Cheap drugs are ones used to treat common chronic conditions like high blood pressure, high cholesterol and indeed treatment of male lower urinary tract symptoms (LUTS), like benign prostatic hyperplasia (BPH).

A small number of readers of this blog have confirmed the beneficial effect of PAK inhibitors in their specific sub-types of autism.  The problem is that there are no potent PAK1 inhibitors suitable for long term use that are readily available.

The anti-parasite drug Ivermectin is an extremely cheap PAK1 inhibitor, but cannot be used long term, due to its other effects.

Propolis containing CAPE (Caffeic Acid Phenethyl Ester) is a natural PAK1 inhibitor, but may not be sufficiently potent as is reported by people with neurofibromatosis.

You would think somebody would just synthesize CAPE (Caffeic Acid Phenethyl Ester) artificially and then higher doses could be achieved.


PAK Inhibitors and Treatment of Prostate Enlargement

I was rather surprised that research has recently been published suggesting that PAK inhibitors could be used to treat the prostate enlargement, common in most older men. 



Abstract

Prostate smooth muscle tone and hyperplastic growth are involved in the pathophysiology and treatment of male lower urinary tract symptoms (LUTS). Available drugs are characterized by limited efficacy. Patients’ adherence is particularly low to combination therapies of 5α-reductase inhibitors and α1-adrenoceptor antagonists, which are supposed to target contraction and growth simultaneously. Consequently, molecular etiology of benign prostatic hyperplasia (BPH) and new compounds interfering with smooth muscle contraction or growth in the prostate are of high interest. Here, we studied effects of p21-activated kinase (PAK) inhibitors (FRAX486, IPA3) in hyperplastic human prostate tissues, and in stromal cells (WPMY-1). In hyperplastic prostate tissues, PAK1, -2, -4, and -6 may be constitutively expressed in catecholaminergic neurons, while PAK1 was detected in smooth muscle and WPMY-1 cells. Neurogenic contractions of prostate strips by electric field stimulation were significantly inhibited by high concentrations of FRAX486 (30 μM) or IPA3 (300 μM), while noradrenaline- and phenylephrine-induced contractions were not affected. FRAX486 (30 μM) inhibited endothelin-1- and -2-induced contractions. In WPMY-1 cells, FRAX486 or IPA3 (24 h) induced concentration-dependent (1–10 μM) degeneration of actin filaments. This was paralleled by attenuation of proliferation rate, being observed from 1 to 10 μM FRAX486 or IPA3. Cytotoxicity of FRAX486 and IPA3 in WPMY-1 cells was time- and concentration-dependent. Stimulation of WPMY-1 cells with endothelin-1 or dihydrotestosterone, but not noradrenaline induced PAK phosphorylation, indicating PAK activation by endothelin-1. Thus, PAK inhibitors may inhibit neurogenic and endothelin-induced smooth muscle contractions in the hyperplastic human prostate, and growth of stromal cells. Targeting prostate smooth muscle contraction and stromal growth at once by a single compound is principally possible, at least under experimental conditions.


It looks like a PAK inhibitor could potentially solve both the key problems in BPH and so replace the current therapies.



Existing Drugs for LUTS/BPH

Undoubtedly someone is going to wonder whether existing drugs for LUTS/BPH might improve autism.  This is actually possible, but totally unrelated to PAK1 inhibition and RASopathies.

Existing drugs are in two classes, 5α-reductase inhibitors and α1-adrenoceptor antagonists.


α-adrenoceptor antagonists

Alpha blockers relax certain muscles and help small blood vessels remain open. They work by keeping the hormone norepinephrine (noradrenaline) from tightening the muscles in the walls of smaller arteries and veins, which causes the vessels to remain open and relaxed. This improves blood flow and lowers blood pressure.
Because alpha blockers also relax other muscles throughout the body, these medications can help improve urine flow in older men with prostate problems.

Selective α1-adrenergic receptor antagonists are often used in BPH because it is the α1-adrenergic receptor that is present in the prostate.

 α 2-adrenergic receptors are present elsewhere in the body

Alpha-2 blockers are used to treat anxiety and post-traumatic stress disorder (PTSD). They decrease sympathetic outflow from the central nervous system. Post-traumatic stress disorder is an anxiety disorder that is theorized to be related to a hyperactive sympathetic nervous system.

Alpha-2 receptor agonists for the treatment of post-traumatic stress disorder



So a nonselective alpha blocker, like one given to an older man with high blood pressure and BPH, might well have an effect on some kinds of anxiety.

You would think that a selective alpha 2 blocker might be interesting, how about Idazoxan?

Idazoxan is a drug which is used in research. It acts as both a selective α2 adrenergic receptor antagonist, and an antagonist for the imidazoline receptor. Idazoxan has been under investigation as an antidepressant, but it did not reach the market as such. More recently, it is under investigation as an adjunctive treatment in schizophrenia. Due to its alpha-2 receptor antagonism it is capable of enhancing therapeutic effects of antipsychotics, possibly by enhancing dopamine neurotransmission in the prefrontal cortex of the brain, a brain area thought to be involved in the pathogenesis of schizophrenia.


Mirtazapine is a cheap generic drug used at high doses for depression.  It happens to be a selective alpha 2 blocker, but it has numerous other effects as well.  One reader of this blog does respond very well to Mirtazapine.


So realistically in Grandpa’s medicine cabinet there might a selective alpha 1 agonist or a non-selective alpha agonist, it is the latter type that might have an effect on some kinds of autism.


5α-reductase inhibitors

The pharmacology of 5α-reductase inhibition involves the binding of NADPH to the enzyme followed by the substrate. Specific substrates include testosterone, progesterone, androstenedione, epitestosterone, cortisol, aldosterone, and deoxycorticosterone.

Beyond being a catalyst in testosterone reduction, 5α-reductase isoforms I and II reduce progesterone to 5α-dihydroprogesterone (5α-DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC).

In vitro and animal models suggest subsequent 3α-reduction of DHT, 5α-DHP and DHDOC lead to neurosteroid metabolites with effect on cerebral function.

These neurosteroids, which include allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 5α-androstanediol, act as potent positive allosteric modulators of GABAA receptors, and have anticonvulsant, antidepressant, anxiolytic, prosexual, and anticonvulsant effects.

Inhibition of 5α-reductase results in decreased conversion of testosterone to DHT.

This, in turn, results in slight elevations in testosterone and estradiol levels. 

In BPH, DHT acts as a potent cellular androgen and promotes prostate growth; therefore, it inhibits and alleviates symptoms of BPH. In alopecia, male and female-pattern baldness is an effect of androgenic receptor activation, so reducing levels of DHT also reduces hair loss.

A new look at the 5alpha-reductase inhibitor finasteride


Finasteride is the first 5alpha-reductase inhibitor that received clinical approval for the treatment of human benign prostatic hyperplasia (BPH) and androgenetic alopecia (male pattern hair loss). These clinical applications are based on the ability of finasteride to inhibit the Type II isoform of the 5alpha-reductase enzyme, which is the predominant form in human prostate and hair follicles, and the concomitant reduction of testosterone to dihydrotestosterone (DHT). In addition to catalyzing the rate-limiting step in the reduction of testosterone, both isoforms of the 5alpha-reductase enzyme are responsible for the reduction of progesterone and deoxycorticosterone to dihydroprogesterone (DHP) and dihydrodeoxycorticosterone (DHDOC), respectively. Recent preclinical data indicate that the subsequent 3alpha-reduction of DHT, DHP and DHDOC produces steroid metabolites with rapid non-genomic effects on brain function and behavior, primarily via an enhancement of gamma-aminobutyric acid (GABA)ergic inhibitory neurotransmission. Consistent with their ability to enhance the action of GABA at GABA(A) receptors, these steroid derivatives (termed neuroactive steroids) possess anticonvulsant, antidepressant and anxiolytic effects in addition to altering aspects of sexual- and alcohol-related behaviors. Thus, finasteride, which inhibits both isoforms of 5alpha-reductase in rodents, has been used as a tool to manipulate neuroactive steroid levels and determine the impact on behavior. Results of some preclinical studies and clinical observations with finasteride are described in this review article. The data suggest that endogenous neuroactive steroid levels may be inversely related to symptoms of premenstrual and postpartum dysphoric disorder, catamenial epilepsy, depression, and alcohol withdrawal.


This would suggest that a 5α-reductase inhibitor, like finasteride, that might be among Grandpa’s tablets might very well have an effect on someone with GABAa dysfunction, this includes very many people with autism, schizophrenia and Down Syndrome.

Whether the effect will be good or bad is hard to say, and may well depend on whether other drugs that target GABA or NMDA receptors are being used. Due to their other effects, 5α-reductase inhibitors are usually only used in adults.

Merck developed a lower dose form of finasteride, called Prospecia to treat baldness, usually in men.  It is 20% the normal potency used for BPH.


Side effects

The current BPH drugs cause side effects in some people.  PAK1 inhibitors may also have some side effects.


Conclusion

Going back in the days of living with your extended family might make treating many people’s autism much simpler.  It looks like many older people’s drugs can be repurposed for some types of autism (ion channel modifying diuretics, calcium channel blockers, statins, even potentially intranasal insulin in some).  Because older people’s drugs are so widely used they are well understood and inexpensive.  

Clearly the research on PAK inhibitors for LUTS/BPH is at an early stage, but there is a huge potential market.   A widely available PAK1 inhibitor might be a big help to some people with autism, neurofibromatosis, other RASopathies, not just Grandpa’s prostate.

In addition to FRAX486 and IPA3, why doesn’t someone try synthetic CAPE, i.e. without the bees, as a PAK inhibitor?

Bioactivity and chemical synthesis of caffeic acid phenethyl ester and its derivatives.



There is far more chance of a PAK1 inhibitor coming to market for LUTS/BPH, or certain cancers than for autism.  That is a fact of life.

As for 5α-reductase inhibitors, like finasteride, we know from Hardan’s study on Pregnenolone at Stanford that this hormone can have a positive effect and we know that various natural steroid metabolites will modulate GABA subunits.  So it is quite likely that finasteride is going have a behavioral effect.  Perhaps Hardan would like to trial finasteride 5mg and 1mg (Prospecia) in some adults with autism. I suspect it will make some people “worse” and others somewhat “better”; so please do not report the “average” response, highlight the nature of the positive responders.






39 comments:

  1. Just to add that in a recent study, the same PAK1 inhibitors showed great effect in the mouse model of prostate cancer.

    UGA researchers find potential treatment for prostate cancer
    http://news.uga.edu/releases/article/potential-treatment-for-prostate-cancer-0316/

    So using PAK1 inhibitors for BPH should also be chemoprotective. So potentially a "cure-all" drug for Grandpa's urologist.

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  2. Hi Peter, you are probably familiar with this and might have mentioned it before in other posts, but might be worth bringing up again:

    "... Our results suggest that (in mast cells) Pak1 is involved in receptor-mediated calcium influx from the extracellular environment...

    ... Precisely how Pak1 is involved in calcium mobilization is unclear, but our data indicate that Pak1 is required for events occurring between the release of calcium from intracellular stores and the influx of extracellular
    calcium."

    https://scholarworks.iupui.edu/bitstream/handle/1805/4162/Allen2009_p21-activated.pdf?sequence=1&isAllowed=y


    I don't know anything about neurofibr but remember that extracellular calcium levels seem to play an important role BPH and/or risk of prostate cancer.

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    Replies
    1. Thanks Nat, calcium has remarable roles in humans. Use of calcium channel blockers may be good for those with mast cell activation, and good for those at risk of type 2 diabetes, but it is bad for those with BPH. The science is far from complete.

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  3. Yohimbine is an A1A adrenoreceptor antagonist. On the other hand, Agmatine is an A1A agonist and an imidazoline receptor agonist. A paper I read a while ago suggested doing both at the same time would help normalize the hyperactivity effects of morphine withdrawal (I made a post a while back on this site explaining in depth the reasoning behind this). I stopped this treatment because it would work great for mood and lucidity for a week and then things would go in the opposite direction, likely from some homeostatic receptor response (which combining the two substances in theory would get around). Maybe there is a proper way to cycle it or a different ratio/dosage that is optimal (I used the ratio in the paper using rats and scaled it up from there). It was one of the longer shots in terms of interventions I have employed.

    As far as 5 alpha reductase inhibitors are concerned, I try and stay away from interventions that have strong effects on hormones because while there are extensive studies on finasteride and similar compounds on adult men, there is as best I know no study on children to date. Of course, anything from sunshine to food can have a developmental impact on a child that may be different than what happens in an adult, but steroids and androgens in particular have a checkered past with children. For example, my father had terrible childhood asthma and the steroids they used back when he was a child were quite primitive compared to what they use now and they likely had some developmental side effects on him over the years.

    I do agree that trialing these drugs on adults sounds like a safe area of exploration, just the only problem is all of the research dollars on autism in human beings seem to be going towards studying children, rather than adults these days when trialing these drugs in adult populations should probably be the first step taken, if for any other reason than establishing safety measures for child studies.

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  4. Sorry, I think I accidentally said or inferred that agmatine is an A1A agonist. I meant that it is an A2A agonist, while yohimbine is both an A1A and A2A antagonist.

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  5. I finally got around to reading this paper which I think you might be interested in reading after having it in my queue for well over a month:

    http://www.sciencedirect.com/science/article/pii/S0304416516301520

    Basically, it discusses a model for neurotransmitter balance with respect to working memory in schizophrenia. The idea being an old one in that if you increase the production of a particular neurotransmitter in one part of the brain, it has downstream effects on the levels of other neurotransmitters in other parts of the brain. It is just food for thought with respect to considering what the effects might be for multiple instances of the kind of autism interventions discussed here on your blog.

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  6. So sytrinol is a pak1 inhibitor.. And my son did quite well with it for a week or so... He is non verbal and he's babbling went through the roof... But after a week it stopped working... Anyone have any ideas as to why? And how I can reignite the efficacy ? Thanks

    ReplyDelete
    Replies
    1. Audrey, sytinol is a PPAR gamma agonist. Many people report it helps for a short while, some find the effect continues. You could use a more potent PPAR gamma agonist (used to treat type 2 diabetes) or find what is causing it to "stop working". There may well be some kind of feedback loop at work. It did occur to me that people using larger doses of the L.reuteri bacteria/probiotic, that in effect dampens the immune system, might want to retry some previously discarded interventions, like sytrinol.

      Did you try the Biogaia (L.reuteri) probiotic?

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    2. Thanks Peter. I ordered it but have been nervous to try as my son's GI issues have been struggling recently and it says it may contain traces of Milk Protein... he has such a hard time with Milk... has anyone found adverse effects with the Biogaia? So are you saying... try the biogaia for a while, then try sytrinol again and it may work better/longer this time around?

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    3. Audrey, one reader did check with the producer about the milk content and concluded that it should not be an issue. In people who respond (seems >50%) the effect is really fast, so you only need a couple of days at most to see if it helps.

      If it helps, then this really does tell you something useful about your son's condition. By modulating his immune response this may have numerous benefits and might help with the feedback loop/tolerance issue that causes some interventions to stop working. Just an idea, I have no proof.

      First establish if he is a responder. Start with a modest dosage. In some people the regular dose shows effect and a higher doses improves the effect. Some people like Alli's son take a very large dose. Some people have reported negative reactions, but they just need to stop taking it.

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  7. Saw palmetto as a natural alternative for BPH?

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    Replies
    1. It works for some and is widely used in countries with German-based medicine. I think there are multiple causes of BPH and some are not so benign, and that in those cases the PH is the precursor to PCa. I think lycopene is the clever natural alternative for (B)PH that will lead to PCa (prostate cancer).

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  8. Here is a topic I believe you have talked about before on your blog if I am not mistaken (SK Ion Channels). What this paper showed is that methylation activity in neurons changes the intrinsic membrane excitability of neurons as opposed to merely enhancing post synaptic excitability via synaptic modifications. Methylation interventions are one of the older and more controversial interventions in autism as to whether supplementing with B12, TMG, and methylfolate helps, relative to HDAC inhibitors like sodium butyrate that suppress some forms of epigenetic modification.

    http://stke.sciencemag.org/content/9/442/ra83

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  9. Here is some very interesting new research on calcium channel blockers, and in particular Verapamil and how it works at the atomic level.

    https://www.sciencedaily.com/releases/2016/08/160824135052.htm

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  10. To those dosing their kids with butenamide: is sleep usually affected at first? We are on day 3 of 1mg/daily Miccil (MX butenamide) for my 35lb toddler and he has been falling asleep around 3 or 4 for the past two days. Has not done this in at least 6 months, and believe me I'm not complaining! He needs this extra sleep and hasn't been getting it, but I want to be cautious in case this is a weird reaction. Waking and bedtimes are still the same. Is this the GABA already becoming inhibitory after just a few days and/or perhaps a sign that this is not his problem? And yes, I'm keeping up lots of fluids and making sure he has a whole banana with breakfast every day. Takes his pill ground up in orange juice with grenadine to mask flavor.
    Would be grateful for any and all thoughts on this~
    Thank you :)
    MKate

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    Replies
    1. In our case there was no effect on sleep.

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    2. Hi,

      I had been discussing effective therapies, both behavioural as well as pharmacological with my therapist and homeopath and they opined that

      1. Rate and magnitude of improvement attributed to the intervention should be significantly greater than natural growth processes in a growing child.

      2. Progress after prolonged period of stagnation, a levelling or plateauing out of development, following an intervention is an indication

      3. If it is effective in adolescents and adults, and severely autistic individuals, it's definitely worth a trial.


      I had been reading subjective parental observations like getting extra hugs, lifting of fog, extra words. During the same periods as these comments were made, mostly I think in response to biogaia, my son displayed exactly the same behaviour, more language, affection, awareness and even a budding ability to draw. I was wondering is it something to do with planetary influence..so many kids across the globe some on probiotics, others on nac and fascinatingly some on nothing at all, are behaving so nicely.

      On other words, I feel all of us parents desperately want treatments to work because this gives is a sense of control over something which seems so depressingly unfathomable..and it's about our kids. And parents can also intuitively differentiate when a treatmemt is actually effective and when it's just hoping the treatment will actually start working if we keep on counting the sporadic instances of nice gains.





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    3. I also did not experienced sleep issues on Bumetanide; when I started I used 2 x 0,5 mg daily for 7 yo/~ 20 kg. Is your son alert and energetic as usual when he is awake on Bumetanide?

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    4. Hi Mkate,
      Generally speaking, a toddler should get around twelve hours of sleep daily..if his earlier daily quota was much less than this, it might be he is catching up on his sleep. If he is sleeping excessively, it could be just be a phase and probably nothing to worry about. But if you are feeling it's something totally uncharacteristic of him, no harm in calling up his paed.

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    5. Well I generally dose Bumetanide twice a day (depends on what gets in the way whether it be school, therapy, or whatever). However, if he gets Bumetanide anytime past 4-5 pm it tends to delay his sleep. The reason for this (my best guess based on research I have read) is that there are a group of cells in the superchiasmatic nucleus (SCN) of the hypothalamus which acts as a clock for the body which are sensitive to chloride levels within the neurons where chloride levels rise throughout the day all the way up to sleep time. So hypothetically, Bumetanide too late in the day could interfere with this process, thereby pushing back the circadian clock just as blue light, caffeine, and other environmental stimulants that artificially modify the functionality of the SCN. I do twice a day because Bumetanide has a half life of about 5 or so hours. Who really knows what the optimum dosage and regimen should be since Bumetanide is not a mainstream therapy for autism at the moment, so research studies exploring optimum dosage just don't exist yet. Maybe sometime in the next few years those studies will be done, but right now there is the Ben-Ari/Lemmonier work to go on and that is about it.

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    6. Hi Tyler,
      If I not mistaken, Mkate is not concerned about change in circadian clock and altered sleep pattern..her child seems to be sleeping extra hours at noon although time of going to bed at night and getting up in mornings is the same as before. Can you throw light on what could be responsible for this if at all it is related to bumetanide.


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    7. Well there are two issues here. One is general GABAergic dysfunction due to immaturely developed interneurons that have not made the developmental shift from a baseline depolarized state (high chloride) to a hyperpolarized state (low chloride). This is the hypothesis put forth by Ben-Ari which he posits is due to problems with infants being exposed to maternal oxytocin at birth which acts as a trigger to cause this developmental change in interneurons from being depolarized to hyperpolarized and this hypothesis has evidence to it via studies he has done on mice. This is a hypothesis I agree enough with to go through the trouble of doing Bumetanide treatment (and it is a lot of trouble but I do believe it has helped my son quite a bit cognitively).

      The second issue is the what I brought up with specialized cells in the SCN which act kind of like an hourglass with respect to rising chloride levels throughout the day. So to answer the question, any normalization of chloride homeostasis so that proper inhibition occurs throughout the brain is going to probably have a general improvement on reducing hyperexcitability throughout the brain, which should definitely improve sleep, just as reducing stimulation that dumps a lot of dopamine is also going to help improve sleep as dopamine tends to be stimulatory most of the time (it is sort of like a booster for glutamate).

      To make a long story short, it sounds like mkate's has nothing to worry about with regard to the extra Z's (some research has shown that young children basically don't learn anything except what they immediately just learned right before they took a nap or went to sleep) and in fact it is likely a very good thing. I myself would prefer 9 hours a night of sleep (back in the good old days), but with the autism parent lifestyle now I personally get maybe 5 hours a night on average and 6 hours a night if it has been a good week. Unless the kid is sleeping 16 hours a day or something extreme like that, I would just be grateful for the peace and quiet and be glad your child is sleeping at all (because many kids with moderate to severe autism almost never get a good night's sleep and neither do their parents).

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    8. Hi Tyler,

      Now this lowering of overall hyperexcitability resulting in more sleep does seem like a plausible explanation, although this has not been observed by other parents, and this effect in itself adds one more feather to bumetanide's cap. As for 9 hours sleep, me too, 9 or more. God, have mercy on thy beings!

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    9. Bumetanide is not going to work for all forms of autism, since there appear to be many different things going wrong with regards to hyperexcitability and autism as I am sure you well know is far from homogeneous. Plus, since you may have multiple vectors for causing hyperactivity, unless you deal with all of them, you are not going to solve the problem, though you might have slightly improved symptoms from one intervention to another. The brain and body typically are pretty stubborn about maintaining homeostasis, but obviously in autism some of these biological systems (neurological, immune, etc.) are perturbed in such a way that they have very complex effects.

      I do know with my son that there has been a significant improvement in sleep quality with Bumetanide, however, if he got his second dose too late in the day then there could be some insomnia issues and this seemed very consistent so that is why if something gets in the way of him getting his second dose in the afternoon, then we just skip it because it does more harm than good if it is keeping him up till 3AM.

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    10. Hi Tyler,

      So bumetanide could cause shifts in circadian rhythm. Apart from that, what other serious troubles have you faced..you mentioned somewhere that bumetanide is lot of trouble but its worth the cognition enhancing effects.

      And deviating from the topic what are your views on right brain left brain issues which you seem to have lot of insight about. I went through Melville's disconnected kids and although some ideas seem to make sense, they seem too advanced to be executed on my son at present. What do you think of mendability excercises? Although getting even half an hour of structured and consistent activity done at home seems like mega commitment to me..what with the sheer physical exhaustion of dropping and picking my four and a half year old to school, then to his therapy center and then back to home where the greatest drama unfolds. Probably I am not cutout to be the exceptional parent that you and other autistic parents seem to be and therefore just want to put any new concerted efforts only on those interventions which can make significant differences and not generalised improvements which are brought about in my son by every little activity, right from holding him, to walking, to running. And I am having serious doubts about the benefit of sensory integration excercise, at least in the mindless manner it is carried out and at least on my son.

      Would be grateful for any suggestion on any of my queries as after about two years of following the experts and investing lot of time and money i am sceptical and tired.

      Delete
    11. Sorry for the typo in the above query..it's mellilo, R. Mellilo of the disconnected and reconnected kids fame and not Melville.

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    12. First off, Brain Balance may work for some people, but not because it is based on any mainstream science. That is just my opinion. Prior to educating myself more on these matters, I have gone through the whole gamut of evaluating the options and while there unfortunately is no silver bullet for treating autism, there are unfortunately legions of so-called "experts" claiming cures, not to mention tons of attention seeking parents claiming they cured their child with one or two interventions when in fact it was more likely their child was misdiagnosed in the first place, assuming the symptoms are actually gone. There is still no clear consensus among medical professionals for an objective way of diagnosing autism (e.g. blood test, brain scan, combinations thereof) so if your child is typical and is having a bad day when they are evaluated, they might be misdiagnosed, and sometimes if a child is borderline autistic and they have a good day when evaluated, then they might be denied the services they need.

      Also, with respect to sensory integration therapy and "Brain Balance" there is no real right brain and left brain balance in an individual as asymmetry is based on many factors including handedness. I am left-handed myself which means it is likely my brain is more symmetrical than yours if you are right-handed. This asymmetry is especially prevalent when it comes to the language areas of the brain which typically in right-handers is mostly in the left hemisphere whereas in left-handers, language processing is usually more evenly distributed among the hemispheres or sometimes you have right hemisphere language dominance. You can even live with only one hemisphere of your brain as one girl with severe epilepsy had literally half her brain removed and leads a mostly normal life to this day.

      Secondly, with respect to Bumetanide the circadian shifting is just a hypothesis of mine and nothing more than that. I just personally noticed that getting it too close to bedtime consistently kept my son up and of course being that it is a diuretic, it would also increase the likelihood he would wet the bed. The trouble with Bumetanide is that there are no real "autism doctors" in the United States who would prescribe it. They might prescribe medication I would not give my child under the worst circumstances because of the nasty long-term side effects whereas Bumetanide has been used for a very long time with only minor side effects like potassium wasting which I remedy with supplemental potassium gluconate you can buy in bulk powder form. This means I have to get the Bumetanide via non-orthodox methods which is frustrating when you know 10 times more about this stuff now than your own pediatrician who may take several hour seminar on autism once a year at best, that is unless they send you to a specialist who does not treat autism as a serious medical issue, yet the pediatrician is the one who writes prescriptions for anything regardless of whether they have any domain expertise or not. I am grateful I can at least get Bumetanide through other methods, thanks to the advice of Peter especially.

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    13. My kids of course do speech therapy and occupational therapy on top of other interventions employed, but speech and OT will only get you so far if their ability to learn in the first place is seriously compromised by autism's side effects and the intellectual disability that often accompanies the disorder.

      Last but not least, don't beat yourself about being not "cut out to be the exceptional parent that you and other autistic parents seem to be", because we are all in the same boat if we are still doing our best. I have certain privileges that allow me to devote the amount of time I can to this journey that most parents don't and a background that at least has given me a jump start in understanding some of this stuff. We all know the pervasive helpless feeling that autism brings into our lives and the frustration that comes along with the lack of urgency out there in treating the middle-ground as I call it as most of the money is spent on figuring out ways to diagnose autism in the womb (under the premise the child would be aborted) on the one hand, while on the other hand much of the rest of the money is spent trying to figure out ways to best manage those with autism live comfortable and disabled lives, rather than actually try and give these people the agency to be cognitively in control of themselves and have all the basic experiences of life everyone else seems to take for granted these days.

      I ran into a woman at the grocery store 3 weeks ago who I noticed had an autistic child with her and I asked her about her son. She said it was not her son, rather she was a foster parent and explained to me how so many people these days will sign their autistic children over as a ward of the state and abuse the foster system as they are allowed "weekend" visits by the biological parents while the foster parent has to deal with the same stuff we all have to deal with, except they are getting paid to deal with it. If you are not one of those people who pass the buck onto someone else, well in my book you are just as exceptional a parent of a child with autism as the rest of us.

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    14. Hello Tyler,

      Thanks for your response although you did not exactly answer my questions..or probsbly I missed the subtext.

      As far as intellectual disability is concerned, there seems to be an emerging understanding nowadays that a majority of individuals assessed as being autistic, might not be mentally underdeveloped..just differently devrloped. Problems with assessment of intellect arise not only due to lack of interest on part of the test subject but also an autistic individuals inability to understsnd what is expected of them. Well..if we can grant male gender a benefit of doubt as to their deficits on account of different language that each gender speaks, we can definitely extend that generosity to the autistic population.

      The therapist who runs the remedial center I take my son to opines that if a child has good memory, and if he can identify his basic needs..feeling hot, cold, thirsty, hungry, toilet needs and recreational needs and be able to satisfy those needs through whatever means he employs, he is unlikely to be intellectuslly disabled.

      Wishing the kids, autistic or otherwise, a life full of all basic experiences and then some more..

      Regards


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    15. Hello Taylor

      Thank for the extensive explanation . It seems the first half of your reply could not be put up earlier.

      So basically we are all on our own..with our internet.

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    16. Thank you everyone for replying. His sleep has stayed at just that mid afternoon nap, which is pretty normal. He wasn't getting enough before, maybe only 8 hours a day... definitely a big GABA excitatory example in a child, especially with his activity level. Much more "with it" lately, speech is improving, starting to want us to teach him to read, everything is starting to improve drastically. Can't wait to speak to our Dr. about trying clonazepam.
      Again, thank you all so much. I look forward to reading the rest of the comments asap and learning more.
      MKate

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    17. Tyler--May I ask about your bumetanide? Just curious if it's similar to mine, ie country of origin ;)
      Thanks~
      MKate

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    18. Donald Trump just went to go visit the country where you get Miccil from.

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    19. Hehe, yes, ahh...fun times that we live in *sarcasm*. But yes, I know Miccil is mx , that is what we use. I was just wondering if others like Tyler were able to obtain rx, or other brands of butenamide, that's all. I've used a few medications myself from mx with varying results, which makes me a tiny bit wary, especially with what I let my son consume. Thank you though ;)
      MKate

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    20. For those collecting case histories or results of butenamide usage, I've also noted some improvements in my son's muscular function. He has mild hypotonia in his legs but in the last few days has started to jump more, has more desire to run around and wrestle. Also his voice is more pronounced and sounds deeper, which would perhaps indicate the muscles used for sound production, ie diaphragm, etc are being positively affected. Again, these are just a few of my observations but when reading about GABA, it makes sense that butenamide is the obvious cause of the improvement.
      My thanks as always~
      MKate

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  11. Another paper released in the last week which discusses microglia contact to dendrites being necessary for spine formation.

    http://www.nature.com/articles/ncomms12540

    This is relevant to autism (as discussed in the paper in the discussion section) in that "activated microglia" seem to be associated with many forms of autism as well as the finding of hyperconnectivity via excess dendritic spines and a lack of synapse pruning that goes alone with that.

    Also discussed are Interleukin-10's role in this process (relevant to Biogaia Gastrus), as well as BDNF.

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  12. Peter, last night my son, although he went out with friends and had a good time, back home he had a meltdown. Whenever he has a meltdown he needs something to calm down, but anxiolytics don't help.
    I read a paper on Bumetanide which says that many anxiolytics act by increasing the effect on GABA, which normally inhibits the neurons. When the cells contain high levels of chloride however, GABA effects are reversed. The anxiolytic molecules have an excitatory effect, aggravating the disorder rather than alleviating it. Bumetanide showed a benefit in mitigrating this effect.
    Does this mean that if he is a responder and takes anxiolytics in case of a meltdown, it will work for him?
    I know it's too early for chloride levels to have fallen and that I also have to try it.

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  13. Thank you for that paper on calcium channels Tyler, very interesting.

    I have also found fascinating the finding that some types of calcium channel blockers are protective from Parkinson's disease:
    http://www.medscape.com/viewarticle/716103


    Fascinating because high rates of parkinsonism/Parkinson's are found in adults with autism!
    https://jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-015-9125-6

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  14. Speaking of Bumetanide and chloride levels in this thread, this research just came out (on tadpoles no less) which shows that endocannabinoids can inhibit NKCC1 activity in retinal ganglion cells, thereby helping to boost sensitivity in those cells to low light conditions. Granted, this finding is just one type of brain cell and in tadpoles, nevertheless it is interesting research in contemplating how many indirect vectors there may be in modulating chloride levels in neurons, besides the direct route with drugs like Bumetanide or other more selective NKCC1 and KCC2 drugs potentially developed in the future.

    https://elifesciences.org/content/5/e15932/article-info

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