UA-45667900-1
Showing posts with label Picamilon. Show all posts
Showing posts with label Picamilon. Show all posts

Thursday 21 January 2016

2016 To-do List

I expect many readers of this blog have a list of things to trial in 2016; I certainly do.

Monty’s older brother, codenamed Ted, did say to me recently, “I thought you said you’d be all finished with this, in a couple of years”; that was indeed the intention.  


A medicine cabinet to be proud of, but not mine


It has now been three years.  I never really intended to go so deeply into the science, and I never expected there to be so many “obvious” things un/under-investigated by researchers.

Most people diagnosed these days with “autism” are fortunate to be relatively mildly affected.  Parents of those kids likely find this blog rather shocking; how can so many pills be needed and still you want more?

Some other people also diagnosed with autism, face really big challenges, not limited to:-
  
     ·        Unable to talk
·        Unable to walk
·        Unable to eat (must use G tube)
·        Unable to be toilet trained
·        Unable to read
·        Unable to write
·        Have seizures 

So when asked by a teacher at school, if Monty, now aged 12, has severe autism I responded in the negative.  He does not tick any of the above boxes.

If you have more than “mild autism” it seems that there are likely many dysfunctions and the more you treat, the better the result.  A quest without an end.


School

Ted hates his relatives discussing his school grades and I agree with him that they are entirely his business.  We all know that typical kids vary in how smart they are and how motivated they are.  NT kids tend to get the grades they deserve.

I do break these rules with Monty, but that is because I really want to show that when a person has numerous neurological dysfunctions, as those found in classic autism, if you treat them with science (not with bleach and other nonsense), you can end up in a different, better place. 99.99999% of the world do not know this; perhaps 500 people do know.

Improving IQ will improve the person’s ability to understand and compensate for the dysfunctions that have not been treated.  

Grading academic performance at school is something we all understand and along with its limitations.  We have all been there, so let's use it.

Kids with classic autism do not get the grades they potentially deserve.  Most can be made smarter and it is easy to measure.

Before coming to my to-do list, I did receive another question about what exactly is the effect of bumetanide. 

When I collected Monty from school the other day, his assistant was proudly holding up the latest “quick fire” math test, where speed is seemingly even more important than the right answer.

So Monty, the only one with autism, came first and by a long way. 3 minutes and 35 seconds, with the runner up taking 3:56.  He got 90% correct, but that is enough to keep first place.   The previous test before Christmas he got 100%, but finished 7th out of 16 on speed.  It must be the turkey.

The questions are very simple, since you have to be very fast; but until the age of 9, and the introduction of Bumetanide, the class teacher would never have dreamt of having Monty compete at all.  Coming a distant last in everything would be disheartening, for the teacher. Monty would not have even noticed, let alone cared.

People with Classic Autism, or what Knut termed SDA (strict definition autism), are usually hopeless academically; but with Bumetanide, it does not have to be that way. 

Many people with classic autism leave school 18 years old, still at the level of single digit addition and subtraction, or perhaps up to 20.

If you reach the academic level of Grade 2 (Year 3 in the UK system), that of a typical 7 or 8 year old, by the time you “graduate” high school, you are doing above average.









So Ted is not alone in being able to get good grades.  The PolyPill is indeed worth all the bother.



To-do list


I did have to go through by supply cupboard to see what I had not got round to testing and that I still think has some potential merit.  Some things did get thrown out.

Some old ideas are worth revisiting.

·        Biotin (high dose)
This did seem to have a marginal positive effect and is both cheap and harmless. 

·        Pregnenolone (very low dose)
This also appeared to have some positive effect and should affect GABA subunit expression. High doses have been used in a Stanford clinical trial. We saw in earlier posts that allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor, meaning that a tiny dose can have the same effect as a large dose.
 I like low doses.  

Old ideas worth developing:-

·        Miyairi 588 bacteria, but at higher doses

This is the bacteria used as a probiotic in Japan for humans, since the 1940s.  It is also added to animal feed to avoid inflammatory disease and so produce healthier animals.

The science showed that it should be helpful to raise Butyrate levels.  It can be achieved directly via supplementation, with sodium butyrate, and indirectly by adding a butyrate-producing bacteria, such as Clostridium Butyricum or Miyari 588.

I have been using a tiny dose of Miyari 588 for months.  It achieves what it is sold for in Japan, in that it reduces gas, which is the only obvious negative side effect of Monty’s Polypill, other than diuresis.

The positive side effect of the Polypill is near perfect asthma control.  Asthma is an auto-immune/inflammatory disease, highly comorbid with autism. 

The effect of Miyari 588 is reversible because this bacteria cannot survive long in the intestines, which is why you have to take it every day.  It crowds out some of the other bacteria in the intestines, but they will soon grow back.


New ideas already in this blog:-

·        Diamox

I did suggest on several occasions that it might be possible to get a “Bumetanide plus” effect by adding Diamox.

Diamox (Acetazolamide) is another diuretic and it is a carbonic anhydrase inhibitor


Acetazolamide is a carbonic anhydrase inhibitor, hence causing the accumulation of carbonic acid Carbonic anhydrase is an enzyme found in red blood cells that catalyses the following reaction:



hence lowering blood pH, by means of the following reaction that carbonic acid undergoes:


The mechanism of diuresis involves the proximal tubule of the kidney. The enzyme carbonic anhydrase is found here, allowing the reabsorption of bicarbonate, sodium, and chloride. By inhibiting this enzyme, these ions are excreted, along with excess water, lowering blood pressure, intracranial pressure, and intraocular pressure. By excreting bicarbonate, the blood becomes acidic, causing compensatory hyperventilation, increasing levels of oxygen and decreasing levels of carbon dioxide in the blood

This change in bicarbonate will also affect the AE3 and NDAE exchangers.

As you will see in the figure below the regulation of bicarbonate HCO3- and pH is directly connected to chloride Cl- homeostasis.  This means that via AE3 and NDAE you can affect intracellular chloride levels by change the level of HCO3-

In turns this means that Diamox (Acetazolamide) really should have an effect on the level of intracellular chloride.

This in turn suggested to me that Diamox could augment the effect that bumetanide has on NKCC1.

 In the case that Bumetanide can lower intracellular chloride, but not to the optimal level to correct the GABA dysfunction, Diamox might be able to lower chloride levels a little further so further shifting GABA to inhibitory.










http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1317631/

Neuronal activity results in significant pH shifts in neurons, glia, and interstitial space. Several transport mechanisms are involved in the fine-tuning and regulation of extra- and intracellular pH. The sodium-independent electroneutral anion exchangers (AEs) exchange intracellular bicarbonate for extracellular chloride and thereby lower the intracellular pH. Recently, a significant association was found with the variant Ala867Asp of the anion exchanger AE3, which is predominantly expressed in brain and heart, in a large cohort of patients with idiopathic generalized epilepsy. To analyze a possible involvement of AE3 dysfunction in the pathogenesis of seizures, we generated an AE3-knockout mouse model by targeted disruption of Slc4a3. AE3-knockout mice were apparently healthy, and neither displayed gross histological and behavioral abnormalities nor spontaneous seizures or spike wave complexes in electrocorticograms. 



After only a couple of days of Diamox, it is pretty clear that there is indeed a “bumetanide plus” effect.  So the same changes that were noted when starting bumetanide appear again.

A promising start to 2016.



·        Ponstan

This is the NSAID that is also suggested to be useful to affect the ion channels expressed by the genes ANO 2/4/7 & KCNMA1.  We saw in this post

http://epiphanyasd.blogspot.com/2015/12/autism-treatments-proposed-by-clinical.html

where Knut highlighted that Fenamates act as CaCC inhibitors and also stimulate BKCa channel activity.  Ponstan is a Fenamate.



·        Vitamin A

This was Maja’s discovery, that in some people vitamin A will stimulate oxytocin, via upregulation of CD38.


·        Zinc

Zinc should affect GABA, particularly in immature neurons.  Zinc homeostasis is disturbed in some autism and perhaps, in some people, a small dose of zinc may actually have a positive effect.  Simple to check.

Clioquinol, the drug that shifts zinc to the “right” place, is not without risks.


·        Picamilon

Once the GABA switch has been repaired, it may be time for a little extra GABA.  GABA should not be able to cross the blood brain barrier (BBB), but in the form of Picamilion, it does cross the BBB.


·        Inositol

This it naturally produced in the body from glucose and used to be known as vitamin B8.  In some people Inositol reduces OCD and stereotypy.  Simple to check.


·        Montelukast

This is an asthma drug, considered very safe in children, that Dr Kelley (formerly of Johns Hopkins and likely the cleverest autism clinician)  uses in children with AMD, as a short term therapy, when they are sick and, very interestingly, before immunizations.  This is to avoid further mitochondrial damage.  Montelukast is a leukotriene receptor antagonist (LTRA) used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies.

Dr Kelley also uses Ibuprofen as a short term therapy to counter the effects of increased cytokine production.  Montelukast is more potent and has different side effects, meaning it might be a better choice than ibuprofen for some people.

Ibuprofen may be OTC, but, more than very occasional use, can cause side effects in many people.  These side effects are caused by NSAIDs also being COX-2 inhibitors, which leads to stomach and intestinal adverse reactions.

Since I have determined that in the case of autism I deal with, the surge in cytokines like IL6 causes behavioral regression, Montelukast might be a good alternative to Ibuprofen to treat some types of autism flare.  

So a new addition to the autism flare-up toolkit, I hope.

  

Ideas not yet in this blog:-

·        Curcumin

Curcumin, and particularly some of the substances within it, have been shown to have very interesting autism-relevant effects, particularly in vitro (in test tubes).  Whether taking curcumin orally, in reasonable doses, produces any of these effects in humans is a big question.  Many such substances like luteolin and resveratrol fail to meet expectations in humans, due to poor bioavailability.

There are various ways to improve the bioavailability of curcumin, so it seems worth investigating.



·        5-loxin

Frankincense has been used for 5,000 years.  More recently, two thousand years ago, three wise men did bring gifts of gold, frankincense, and myrrh.

Frankincense is an aromatic resin obtained from trees of the genus Boswellia.  Boswellia is used for inflammatory conditions like arthritis in a similar way to curcumin.

There are six boswellic acids, one is most active. This fraction is called AKBA. 5-Loxin is a boswellia supplement claiming to deliver a high standardized level of AKBA.

5-Loxin does seem to help some people with arthritis, but does it have any benefit for the pro-inflammatory aspects found in some autism?  I am not expecting much, but you never know.

  
Ideas suggested to me by others, that look interesting:-


·        Mint/Menthol

This is Natasa’s discovery and there is evidence to show that Menthol does indeed affect GABAA receptors.



These results suggest that menthol positively modulates both synaptic and extrasynaptic populations of GABAA receptors in native PAG neurons. The development of agents that potentiate GABAA-mediated tonic currents and phasic IPSCs in a manner similar to menthol could provide a basis for novel GABAA-related pharmacotherapies.

  
·        NIAGEN / Nicotinamide Riboside

This was highlighted by Tyler and is another potential therapy for oxidative stress.  Not as cheap as peppermint, but definitely interesting, perhaps particularly for those with autism and mitochondrial dysfunction.

Also note that there are odd recurring links between some autism and obesity. This is not the first anti-obesity therapy that potentially has some benefit for autism.



Summary
As NAD+ is a rate-limiting cosubstrate for the sirtuin enzymes, its modulation is emerging as a valuable tool to regulate sirtuin function and, consequently, oxidative metabolism. In line with this premise, decreased activity of PARP-1 or CD38—both NAD+ consumers—increases NAD+ bioavailability, resulting in SIRT1 activation and protection against metabolic disease. Here we evaluated whether similar effects could be achieved by increasing the supply of nicotinamide riboside (NR), a recently described natural NAD+ precursor with the ability to increase NAD+ levels, Sir2-dependent gene silencing, and replicative life span in yeast. We show that NR supplementation in mammalian cells and mouse tissues increases NAD+ levels and activates SIRT1 and SIRT3, culminating in enhanced oxidative metabolism and protection against high-fat diet-induced metabolic abnormalities. Consequently, our results indicate that the natural vitamin NR could be used as a nutritional supplement to ameliorate metabolic and age-related disorders characterized by defective mitochondrial function.
  



Low-grade chronic inflammation (metaflammation) is a major contributing factor for the onset and development of metabolic diseases, such as type 2 diabetes, obesity, and cardiovascular disease. Nicotinamide riboside (NR), which is present in milk and beer, is a functional vitamin B3 having advantageous effects on metabolic regulation. However, the anti-inflammatory capacity of NR is unknown. This study evaluated whether NR modulates hepatic nucleotide binding and oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. Male, 8-week-old KK/HlJ mice were allocated to the control or NR group. NR (100 mg/kg/day) or vehicle (phosphate-buffered saline) was administrated by an osmotic pump for 7 days. Glucose control, lipid profiles, NLRP3 inflammasome, and inflammation markers were analyzed, and structural and histological analyses were conducted. NR treatment did not affect body weight gain, food intake, and liver function. Glucose control based on the oral glucose tolerance test and levels of serum insulin and adiponectin was improved by NR treatment. Among tested lipid profiles, NR lowered the total cholesterol concentration in the liver. Histological and structural analysis by hematoxylin and eosin staining and transmission electron microscopy, respectively, showed that NR rescued the disrupted cellular integrity of the mitochondria and nucleus in the livers of obese and diabetic KK mice. In addition, NR treatment significantly improved hepatic proinflammatory markers, including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1. These ameliorations were accompanied by significant shifts of NLRP3 inflammasome components (NLRP3, ASC, and caspase1). These results demonstrate that NR attenuates hepatic metaflammation by modulating the NLRP3 inflammasome

  

  

  

An apparently crazy idea of my own, but actually serious:-


·        Propolis tincture, without the propolis

The BIO 30 Propolis from New Zealand is a (mild) PAK1 inhibitor.  One reader is convinced of its cognitive enhancing effects in autism .  I also think it had an effect, but in our case not as potent as that reader.  Now I am wondering what was it that produced this effect. 

Most propolis is made as a tincture with ethanol.  Propolis is not soluble in water.  They typically use 70% ethanol to make propolis tincture.  “Non-alcoholic” tinctures use glycol.

In the last post we saw ethanol has pronounced effects on several GABAA receptor subunits, mainly delta but also alpha, including possibly down regulating alpha 5.

So was it the propolis, or the ethanol that has the effect?

Propolis tincture is either made with ethanol (grain alcohol) or if it is “alcohol free” they use propylene glycolPropylene glycol actually is a food ingredient but it is also used to de-ice aircraft in winter.  Ethylene glycol is the antifreeze in your car and you would not want to drink that.

Compared to ethanol, glycol can dissolve less propolis, 

A quick check of school chemistry reminds us that if it is an –ol , it’s an alcohol.

·        Alcohols have at least one hydroxyl group
·        Diols have two hydroxyl groups

Propylene glycol is  C3H8Oand as you can see below it has two hydroxyl groups (the – OH), so it is both a diol and an alcohol. 






So your Propolis tincture can be ethanol-free, but it cannot be alcohol-free.  Someone might point that out to the supplement makers.

It also should be noted that propylene glycol has known effects on GABA very similar to ethanol.


  
This suggests that the users of ethanol-free BIO30 may also be seeing responses unrelated to propolis.

Propylene glycol even has an E-number, it is E1520.  It is cheap and they even sell it on Amazon.

Food grade ethanol is normally not sold to the public.

In lay terms, ethanol and alcohol are interchangeable, so one corner of the supermarket contains food grade ethanol, with some impurities.

Japanese research suggests that these impurities are much more potent than ethanol in modulating GABA receptors.  It is the fragrant compounds that accumulate over the years on wooden barrels that cause this effect.

The twenty drops of propolis suggested to me by the Japanese PAK1 researcher/doctor contained about 1ml of ethanol.  It seems that to get an effect on GABA similar to this amount of ethanol would require a much smaller amount to well-aged Japanese whiskey.

So if someone over 18 responds well to twenty drops of BIO 30 propolis, it would helpful if they could compare the effect with 1ml of Propylene glycol (E1520), 1ml of ethanol, if they find it, and with a few drops of well-aged whiskey.








Wednesday 23 December 2015

“More GABA” for Autism and Epilepsy? Not so Simple

Today’s post was prompted by Tyler highlighting a very recent paper from MIT and Harvard, with some interesting research on GABA in autism.  It also provides the occasion to include an interesting epilepsy therapy, which I encountered a while back.  This fits with my suggestion that the onset of much epilepsy in autism could be prevented.

In the MIT/Harvard study, they were looking into the excitatory/ inhibitory (E/I) imbalance found in ASD and schizophrenia. They used a non-invasive optical method to measure E/I imbalance and this did get some media coverage.  However, I am not sure this could be a diagnostic tool in very young children with classic autism, as was suggested; most such children would not cooperate.  It is not just a problem of being non-verbal, as was suggested in the media.

Indeed, due to the nature of the experiment, the researchers involved older subjects, with milder autism and none had MR/ID (IQ<70).  Being a trial done in the US, of the 20 autistic subjects, 11  were being treated with psychiatric medications: antidepressants (n = 8), antipsychotics (n = 2), antiepileptics (n = 4), and anxiolytics (n = 2).

The easy to read version is from the MIT website:-


Study finds altered brain chemistry in people with autism



The full version is here:-




They used something called Binocular Rivalry  as a proxy for  E/I imbalance.

During binocular rivalry, two images, one presented to each eye, vie for perceptual dominance as neuronal populations that are selective for each eye’s input suppress each other in alternation [16, 17]. The strength of perceptual suppression during rivalry is thought to depend on the balance of inhibitory and excitatory cortical dynamics [12–15] and may serve as a non-invasive perceptual marker of the putative perturbation in inhibitory signaling thought to characterize the autistic brain.

We therefore measured the dynamics of binocular rivalry in individuals with and without a diagnosis of autism (41 individuals, 20 with autism). As predicted, individuals with autism demonstrated a slower rate of binocular rivalry (switches per trial: controls = 8.68, autism = 4.19; F(1,37) = 16.52, hp 2 = 0.311, p = 0.001; Figure 1A), which was marked by reduced periods of perceptual suppression (proportion of each trial spent viewing a dominant percept, (dominant percept durations)/(dominant + mixed percept durations): controls = 0.69; autism = 0.55; F(1,36) = 7.27, hp 2 = 0.172, p = 0.011; Figure 1B). The strength of perceptual suppression inversely predicted clinical measures of autistic symptomatology (Autism Diagnostic Observation Schedule [ADOS]: Rs = 0.39, p = 0.027; Figure 1) and showed high test-retest reliability in a control experiment (R = 0.94, p < 0.001; see Supplemental Experimental Procedures and also [18]). These results replicate our previous findings in an independent sample of autistic individuals [11] and confirm rivalry disruptions as a robust behavioral marker of autism.


To test whether altered binocular rivalry dynamics in autism are linked to the reduced action of inhibitory (g-aminobutyric acid [GABA]) or excitatory (glutamate [Glx]) neurotransmitters in the brain, we measured the concentration of these neurotransmitters in visual cortex using magnetic resonance spectroscopy (MRS).


GABA and glutamate are predicted to contribute to different aspects of binocular rivalry dynamics: mutual inhibition between (GABA) and recurrent excitation within (glutamate) populations of neurons coding for the two oscillating percepts [14].

. Critically, reducing either mutual inhibition or recurrent excitation is predicted to reduce the strength of perceptual suppression during rivalry in one implementation of this model [14], mirroring the dynamics we observed in autism. We therefore considered each neurotransmitter separately to test whether inhibitory or excitatory signaling was selectively disrupted in the autistic brain.

As predicted by models of binocular rivalry, GABA concentrations in visual cortex strongly predicted rivalry dynamics in controls, where more GABA corresponded to longer periods of perceptual suppression (Rs = 0.62, p = 0.002; Figure 2B). However, this relationship was strikingly absent in individuals with autism (Rs = 0.02, p = 0.473; Figure 2B). The difference between the two correlations was significant (hp 2 = 0.167, p = 0.013; Figure 2C), indicating a reduced impact of GABA on perceptual suppression in the autistic brain.


GABA was working backwards

Importantly, this finding was specific to GABA: glutamate strongly predicted the dynamics of binocular rivalry in autism (Rs = 0.60, p = 0.004; Figure 2B), to the same degree as that found in controls.


Glumate is working just fine.

These findings suggest that alterations in the GABAergic signaling pathway may characterize autistic neurobiology. Consistent with prior evidence from animal and post-mortem studies, such dysfunction may arise from perturbations in key components of the GABAergic pathway beyond GABA levels, such as receptors [3–9] and inhibitory neuronal density

Together with the pivotal roles of GABA in canonical cortical computations [39] and neurodevelopment [40], these findings point to the GABAergic signaling pathway as a prime suspect in the neurobiology of this pervasive developmental disorder [41]




This study reconfirms what regular readers of this blog already knew.



Epilepsy

I thought it was positive that the MIT researchers suggested that the high level of epilepsy in autism and this E/I imbalance really must be connected.

I have been suggesting for some time that by correcting this E/I imbalance in children with autism, it is likely that the onset of epilepsy could be avoided (in some cases).

I did suggest this to one well known researcher who thought the idea of preventing the onset of epilepsy was not something that the medical community would accept as a concept.

I also raised the novel epilepsy therapy, below, to the same researcher who thought it also would never be considered.

The therapy was to use both bumetanide and potassium bromide to switch GABA back to inhibitory and then give a little boost using a GABA agonist.   

There are many types of epilepsy and some do not respond well to current treatments.  It would seem plausible that the autism-associated type of epilepsy might constitute a specific sub-type.









Potassium Bromide was the original epilepsy therapy over a hundred years ago.  It is still used in Germany as a therapy.  Reports from a century ago suggest it has the same effect in autism as Bumetanide. (we saw this in my post on autism history). 

As you can see on Wikipedia there is a wide range of GABA agonists, but the only ones that would help in epilepsy and autism would be the ones that can cross the blood brain barrier.

GABAA receptor Agonists

·         Bamaluzole
·         GABA
·         Gabamide
·         GABOB
·         Gaboxadol
·         Ibotenic acid
·         Isoguvacine
·         Isonipecotic acid
·         Muscimol
·         Phenibut
·         Picamilon
·         Progabide
·         Quisqualamine
·         SL 75102
·         Thiomuscimol


In an earlier post, we looked at the possible use of small doses of AEDs (anti-epileptic drugs).  One reader found that tiny dose of Valproate (known to raise GABA) had a positive effect when combines with Bumetanide.

In a recent comment one reader showed the same result by combing picamilon with bumetanide.

Both Picamilon and Valproate are having the effect proposed by the epilepsy researchers.

Potassium Bromide does have known side effects, but the idea of further boosting the effect of Bumetanide is interesting.  I have suggested before that this should also be possible using Diamox (Acetazolamide).  Diamox does not affect NKCC1 or EGABA,  it affects the  Cl-/HCO3-exchanger AE3  to further affect Cl- levels.  

I did suggest this a long time ago in my posts on the GABAa receptor.  I am not the only one to realize this.

NKCC1 and AE3 Appear to Accumulate Chloride in Embryonic Motoneurons

   

Picamilon is well researched Russian drug, sold in other countries as a supplement.  It is a modified version of GABA that includes niacin; together it can cross the blood brain barrier (BBB).



So I think a better version of what the epilepsy researchers suggest might be:-

                           Bumetanide  +  Diamox  +  a touch of Picamilon



What would be the effect in autism?