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Thursday, 30 November 2017

Macrolide Antibiotics for Some Autism? Or better still, Azithromycin analogue CSY0073, or just Nystatin?




Magical Poland


Today’s post is about yet another reason why some people with autism might have a positive behavioral response while on antibiotics. Today it is the turn of macrolide-type antibiotics, which have proven immunomodulatory effects.

To get the immunomodulatory benefits, without worsening antibiotic resistance, a neat solution called CSY0073 is coming. Nystatin is another possibility.
One of the best papers happens to come from a pair of researchers from Lodz (Łódź, pronounced “Wudge”) in Poland. This blog has many Polish readers. 

I was recently helping my son, Monty aged 14 with ASD, with his geography presentation on Poland.  I used to travel quite a lot to Poland and I am familiar with its turbulent history. So today’s picture above is actually from Monty’s PowerPoint presentation on Poland. As musical backing, we added one of Chopin’s Polonaises, since Monty is the piano man and Chopin was born in Poland. Polonaise (Polonez) is the name of a type of Polish dance and yes, Monty did dance to the music for his classmates.
The Germans and the Russians have changed the make-up of Poland profoundly and someone has produced the animated map above to illustrate this (it should play automatically). Lodz used to be a textile city with a population one third Jewish, who were later exterminated.  Lviv (Lwów), another large and once Polish city, also had a large Jewish population which the Germans exterminated. Then the Soviets gave the then Lwów (Lviv) to Ukraine and deported the Polish population.  The Soviets gave the German city of Breslau to Poland and it became Wrocław; most Germans were deported and many Poles from Lviv were relocated there.
Gdansk (Danzig) changed hands as well and, as Monty informed his class, they even had their own currency. Few outside Poland will recall Gdansk was home to Lech Wałęsa and his Solidarity Movement.  Monty’s elder brother knows about Solidarity and Katyn (see below) and we agreed Lech will for sure not be on Vladimir Putin’s Christmas list. 


A very charismatic older Pole in Warsaw once told me “the Russians were our brothers, your friends you can chose”. Having also been to Russia many times in the early 1990s, just after the collapse of the Soviet Union, I should point out there are plenty of nice Russians too. An old Russian former naval commander in St Petersburg  once told me how his father always kept a packed bag by the front door at home, in case the NKVD (Stalin’s secret police) came knocking at the door in the middle of the night. Half a million Russians were taken during Stalin’s purges 1936-8. In 1940 the same NKVD perpetrated the Katyn massacre, when 22,000 Polish army officers, policemen and “intellectuals” were killed.  In a sad twist of fate in 2010 a Tupolev plane carrying the Polish president, senior politicians, senior army officers and other leading Poles to a commemoration of the Katyn massacre crashed in very bad weather trying to land at Smolensk.  The cockpit voice recorder showed that the crew were too intimidated by the President to divert the plane and be late for the ceremony, so they all died.  History repeated itself.
The Poles and Russians do share traumatic histories and many like drinking too much vodka. As Monty’s classmates learned, “vodka" is one diminutive form of the Slavic word voda (water). They like diminutives and you can even make your own.  The Russians have a diminutive of vodka, водочка (vodochka).
Back to science …

Macrolide Antibiotics 

Macrolide antibiotics are widely used across the world, the most popular ones are:-

As readers will know, you normally take an antibiotic short term to treat a bacterial infection.
It was discovered that this class of antibiotic also has immunomodulatory and anti-inflammatory properties.  They became used long-term to treat conditions like cystic fibrosis, COPD (Chronic Oppressive Pulmonary Disease) and sometimes even asthma.
The problem is so-called “population antimicrobial resistance” associated with chronic macrolide use, which means these antibiotics can stop working for everyone else.
The good news is that not all macrolides have antibiotic properties and analogues (slightly different version) of both azithromycin and erythromycin are being developed to give the immunomodulatory and anti-inflammatory properties, without risking antimicrobial resistance.
Of course what will happen is that the new drugs will be far more expensive than the old ones and so the old ones will continue to be used. Such is the world.
So first we will review the science showing these special properties of Azithromycin, which can apparently work wonders for some people with autism plus allergy, although the research below talks about other inflammatory diseases.
Here is the paper from Poland:-

 Macrolides are a group of antibiotics whose activity is ascribable to the presence of the macrolide ring, to which one or more deoxy sugars may be attached. Two properties are inherent in this group of antibiotics, the immunomodulatory and the anti-inflammatory actions, ensuring great efficacy in a wide spectrum of infections. Macrolides demonstrate several immunomodulatory activities both in vitro and in vivo. They can down-regulate prolonged inflammation, increase mucus clearance, prevent the formation of bacterial biofilm and either enhance or reduce activation of the immune system. According to given properties and exceptional effects on bacterial phatogens, the macrolide antimicrobial agents have been found to serve a unique role in the management of chronic airway disorders, including diffuse pan bronchiolitis, cystic fibrosis and chronic obstructive pulmonary disease. Use of macrolides can result in clinical improvement in patients with severe, chronic inflammatory airway diseases, improving their spirometry indicators, gas exchange and overall quality of life. 
Anti-inflammatory and immunomodulatory effects Macrolides have a direct antimicrobial effect but more importantly, also modulate many components of the immune response. Because of this anti-inflammatory or immune modulating effect, macrolide antibiotics have been widely used as a maintenance treatment for various chronic inflammatory airway diseases [1]. Interest in the immunomodulatory effects of macrolides began with showing that in patients with bronchial asthma, requiring glucocorticoids administration, application of macrolide antibiotics allowed for reducing steroids dose [6]. This phenomenon is known as ‘sparing effect’.




After more than 30 years, macrolides still hold a vital place in our therapeutic armamentarium. They possess immunomodulatory and anti-inflammatory actions extending their antibacterial activity. Indeed, they are able to suppress the “cytokine storm” of inflammation and confer an additional clinical benefit through their immunomodulatory properties. The majority of cells, involved in both the innate and adaptive immune responses, are influenced when macrolide antibiotics are administered.
Suppressing a cytokine storm is not easy. Atorvastatin can also do this.


Azithromycin as an immunomodulator

In addition to their antimicrobial properties, there are in vitro and animal data on the immunomodulatory or anti-inflammatory effects of macrolides.1 Effects in humans were initially reported in the treatment of diffuse panbronchiolitis, in which macrolides are associated with improved lung function and prognosis based largely on non-controlled trial data and retrospective studies.1 In cystic fibrosis, treatment for six months is associated with improved respiratory function and reduced respiratory exacerbations.11 Azithromycin produced a small increase in lung function (mean 8.8%) at seven months in patients treated for bronchiolitis obliterans syndrome after lung transplant,12 but was no different compared to placebo for bronchiolitis obliterans syndrome after haematopoetic stem cell transplant.13

Azithromycin and other macrolides have also been proposed for use in sepsis and epidemic respiratory viral infections to prevent cytokine storm.1 It has been used for various respiratory and non-respiratory inflammatory conditions. However, this use has been controversial due to limited direct clinical evidence for many conditions, and concerns about increased antimicrobial resistance.1,14 New non-antibiotic macrolides may provide immunomodulatory benefits without contributing to antimicrobial resistance.14


Risks of population antimicrobial resistance associated with chronic macrolide use for inflammatory airway diseases.


Macrolide antibiotics have established efficacy in the management of cystic fibrosis and diffuse panbronchiolitis-uncommon lung diseases with substantial morbidity and the potential for rapid progression to death. Emerging evidence suggests benefits of maintenance macrolide treatment in more indolent respiratory diseases including chronic obstructive pulmonary disease and non-cystic fibrosis bronchiectasis. In view of the greater patient population affected by these disorders (and potential for macrolide use to spread to disorders such as chronic cough), widespread use of macrolides, particularly azithromycin, has the potential to substantially influence antimicrobial resistance rates of a range of respiratory microbes. In this Personal View, I explore theories around population (rather than patient) macrolide resistance, appraise evidence linking macrolide use with development of resistance, and highlight the risks posed by injudicious broadening of their use, particularly of azithromycin. These risks are weighed against the potential benefits of macrolides in less aggressive inflammatory airway disorders. A far-sighted approach to maintenance macrolide use in non-cystic fibrosis inflammatory airway diseases is needed, which minimises risks of adversely affecting community macrolide resistance: combining preferential use of erythromycin and restriction of macrolide use to those patients at greatest risk represents an appropriately cautious management approach.  

Changes in macrolide resistance rates since the introduction of long-acting macrolides Although erythromycin has been used since the 1950s, rates of macrolide resistance among respiratory pathogens were consistently low worldwide until the late 1980s. Since then, macrolide resistance rates have risen sharply, coincident with the introduction of long acting macrolides, particularly azithromycin (see later) but also clarithromycin.







  Conclusions The development of novel, non-antibiotic macrolides with anti-inflammatory properties, including EM703107 and CSY0073, holds great promise for delivering the benefits of macrolide treatment without the associated risks of antimicrobial resistance in the future. Until then, use of long-term macrolide antibiotics to treat respiratory disorders must be prudent. The benefits shown with maintenance macrolides so far have been modest in COPD and non-cystic fibrosis bronchiectasis, and their use should be limited to patients with more difficult (and otherwise optimally managed) disease. For non-cystic fibrosis inflammatory airways diseases, combining the preferential use of erythromycin along with restriction of macrolide use to only those likely to derive the greatest benefit represents a clinically appropriate, and ecologically responsible, management approach.



CONCLUSIONS AND IMPLICATIONS:


Unlike azithromycin, CSY0073 had no antibacterial effects but it did have a similar anti-inflammatory profile to that of azithromycin. Hence, CSY0073 may have potential as a long-term treatment for patients with chronic lung diseases.
  

Tuebingen, Germany: – German-based pharmaceutical discovery company Synovo GmbH today announced that the European Medicines Agency (EMA) has granted its anti-inflammatory drug with orphan (rare disease) status as a treatment for Cystic Fibrosis. Synovo refers to its candidate as CSY0073.
CSY0073 has been adjudged to provide an alternative to anti-inflammatory therapies that are also anti-bacterial, thus potentially contributing to a reduction in selection for antibiotic resistance. The drug is a novel compound that reduces inflammation and prevents recruitment of excess immune cells to diseased tissues. It is a non-antibacterial analog of the well-known antibiotic azithromycin, that is extensively used in many diseases of the lungs including Cystic Fibrosis.
  

Conclusion
We saw in earlier posts why beta lactam antibiotics might benefit some people with autism.
We came across the GLT-1 (EAAT2) transporter, the principal transporter that clears the excitatory neurotransmitter glutamate from the extracellular space at synapses in the central nervous system. Glutamate clearance is necessary for proper synaptic activation and to prevent neuronal damage from excessive activation of glutamate receptors. EAAT2 is responsible for over 90% of glutamate reuptake within the brain. Beta lactam antibiotics, like penicillin, upregulate EAAT2/GLT-1 and so reduce glutamate.
I suggested that people with autism who improve on penicillin types antibiotics should get a similar effect from riluzole, which is now a generic drug.
People whose autism benefits while on macrolide antibiotics are benefitting from its immunomodulatory effects.
People with severe allergy and autism are likely to respond to long term moderate dose of macrolides. 
The problem of long term use of any antibiotic is that it contributes to the decline in its effectiveness for everyone else.
Some DAN-type doctors apparently do apparently give one year prescriptions for beta lactams.   I think these people likely should be on riluzole.
Some mainstream doctors prescribe moderate dose macrolide antibiotics long term to treat people with “over-active” immune responses. It appears many people with cystic fibrosis are treated long term with macrolide antibiotics.
I am informed that some people with autism and “over-active” immune responses respond very well behaviorally to long term use of macrolide antibiotics.
The best solution in the long run is for people to use non-antibiotic macrolides like CSY0073, from Synovo. If it turns to be very expensive, people will just use azithromycin.
In the meantime note there are other non-antibiotic macrolides sitting in the pharmacy. 
·        Nystatin is a non-antibiotic macrolide. As we know, DAN-type doctors widely prescribe Nystatin to treat “candida overgrowth” in autism. It is also a potassium channel (Kv1.3) blocker. 
·        The drugs  tacrolimus, pimecrolimus, and sirolimus, which are used as immunomodulators, are also non-antibiotic macrolides.

There look to be many interesting possibilities for those with autism and allergy/mast cell activation/ulcerative colitis/asthma etc. 
I wonder if the people with autism and allergy who respond to long-term Azithromycin use would see the same benefit from Nystatin?

Long term use of antibiotics will disrupt the gut microbiome, i.e. kill the good bacteria.  People should be aware of this and that in minimizing one problem, they may create another one. The non-antibiotic options are clearly best. If you have cystic fibrosis the advantages of an antibiotic clearly outweigh the disadvantages. 







63 comments:

  1. Hi Peter, Ian waiting for bumetanide,would be better to try it first than azith? Iam afraid of bouth drug interactions.
    Valentina

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    1. Valentina, Bumetanide needs 2+ weeks to show any effect. I would first do azithromycin; if it helps, you should see a benefit in a few days.

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  2. One problem with regular use of antibiotic medication is that you are going to kill off the good bacteria too. A healthy gut is supposed have all sorts of things populated it in. My son was on both prophalaxic macrolide and beta lactim(sp) treatments for Sydenham's Chorea /Pandas for a long time and the doctor would talk about the other benefits you mention too. With everything it is balance, but the only risk is not resistance but changing your gut eco system too.

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    1. Yes, this is why I highlighted the non-antibiotic options. So riluzole instead of beta lactam and non-antibiotic macrolide instead of antibiotic macrolide.
      I am surprised anyone would prescribe two antibiotic drugs for long term use.

      I should have directly mentioned losing the good bacteria.

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    2. I just wanted to reinforce other risks which I know you have mentioned before -- and fortunately other substitutes. My son was never on both at the same time, but the protocol for my son with major flaring of Sydenhams chorea was to go on lower dose antibiotics (at Stanford). We moved to monthly strep checks instead. He also goes on Aleve if his inflam markers are high. Your others options look very interesting to explore. My son had significant OCD and tics (which he hadn't had before getting Chorea) and now is in high school and generally OCD and tic free.

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  3. It was not necessary you mention losing the good bacteria, that's obvious, do you think that using miyari along with azith is ok? It is the only probiotic i have at home, but can get Bacilor. Valentina

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  4. The Wikipedia entry "Macrolide" notes under "Side effects" that "A 2008 British Medical Journal article highlights that the combination of some macrolides and statins (used for lowering cholesterol) is not advisable and can lead to debilitating myopathy". The BMJ reference is Sathasivam, S; Lecky, B (November 2008)."Statin induced myopathy", British Medical Journal, 337: a2286. doi:10.1136/bmj.a2286. PMID 18988647.

    I don't have access to the BMJ so can't tell if the Wikipedia entry accurately reflects the article's contents; nor can I work out what the "some macrolides" are. I thought I would raise this concern as a precaution for those people using statins & considering investigating macrolides. For future comment from Peter & others! Ciao for now, Alexandria

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    1. Alexandria, well spotted. As always is the case, anybody using any drug, supplement or herbal remedy needs to know what they are doing. You doctor needs to know all the pills you take and it is best to also do the homework yourself.

      The point here is that some drugs, like statins, are metabolized by the cytochrome P450 pathway. Certain substances like grapefruit also affect cytochrome P450, so your doctor/pharmacist will tell people on statins not to eat grapefruit.

      The interaction via P450 can be good or bad, because it may increase or reduce the concentration of your drug. If it is critical for your drug to be at a specific concentration, drug interactions can be dangerous.

      Your paper is warning doctors that the drugs listed below in the excerpt from your paper will increase the concentration of the statin and therefore increase the chance of side effects like myopathy. In reality if you really need to be on such drugs you would lower the dose of the statin.

      On the other hand some drug interactions are very useful. If you want to boost a beta lactam antibiotic to kill a tough bacteria you add a drug called probenecid, which increases the concentration of antibiotic in your blood.

      Your paper:-

      Factors that may increase the risk of statin induced myopathy

      Advanced age (>80 years old)
      Female sex
      Low body mass index
      Multisystem diseases (for example, diabetes mellitus)
      Diseases affecting kidney or liver function Hypothyroidism (untreated)
      Drug interactions, especially with drugs that are inhibitors or substrates of the cytochrome P450 pathway (for example, fibrates, nicotinic acid, calcium channel blockers, ciclosporin, amiodarone, thiazolidinediones, macrolide antibiotics, azole antifungals, protease inhibitors, warfarin)
      Vigorous exercise

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  5. Peter, yesterday was his first dose 250 mg azith, within an our he started to show a tic with his head,turning back from one side to the other,as if someone was chasing him,OCD behaviour in general,the response was fast and acute but not for the better. Today, day off, he didn´t show that tic. What is this showing me?
    Valentina

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    1. We had similar symptoms after Fluconozole. We initially thought that it is a drug reaction. But they completely went away when we gave fluconozole with ibuprofen. Worth trying Azithromycin with ibuprofen. We now suspect hat drug excipients cause some MCAD reactions which leads to neuro-inflammation and which leads to these symptoms.
      We had different but severe neuropsychtric reactions when we initially started daily prophylactic azithromycin. These reactions went away after doctors reduced the dosage to Mon-Wed-Fri doasage only

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    2. Peter and Rahul, regarding what has to do with medicines that attack virus and bacteria, my son dosen´t stand even the lowest doses.Now I was giving him between 200 and 300 mg of acyclovir, because his infection was viral, not bacterial, or may be both because one is consecuence of the other,he began to show more tics, pulling his T shirt and aggressive bahavior. If it is a process ot getting worse to improve later, Iam not prepared to bear it. Clearly he is a viral kid.Today I will get L Lysine and will keep the natural way.Peter, regarding bumetanide, it is a shame that this happened in the middle of the trial, all was excellent until I gave him acyclovir.The same happened with azith.I have a chance of getting bumetanide from Spain, fordiuran, but I don´t know wich brand is better in terms of tablet ingredients.
      Valentina

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    3. Valentina, I don't think it matters Spanish vs Mexican Bumetanide.

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  6. Valentina, I think you should stop your trial. There are different types of "immune variation" in autism, this has been shown Paul Ashwood at UC Davies. I recall your son also had a negative reaction to the biogaia probiotic, that also has immuno-modulatory effects.

    I think this tells you that your son's type of immune variation is not the same as that of the some of the other people who read this blog. So what works for them does not help.

    There are many different pro-inflammatory and anti-inflammatory cytokines. You can measure them and establish your exact profile, this is what Ashwood did.

    Once you know which cytokines are elevated/reduced you might determine what might help. Most people are just guessing. I am assuming in my case IL-6 is elevated and IL-10 is reduced.

    I would now move back to your bumetanide trial.

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    1. Ok Peter, the best would be to see an immunologist, I could ask my mother´s husband who is the best. How can be meassured pro an antiinflammatory citokines? IL6 is surely high.From what I have read and understood, my son´s profile is very close to Tanya and Petra´s sons, I think that Petra had a good experience with bumetanide.My son did excellent with omega 3 and citrulline. Valentina

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    2. Valentina, it is a blood test like this one:

      https://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/75139

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    3. Peter, now that you mention elevated IL-6 and reduced IL-10, I see that this inflammatory pathway is also implicated in periodontitis.

      IL6 and IL10 are genetic susceptibility factors of periodontal disease.
      https://www.ncbi.nlm.nih.gov/pubmed/23814583
      Vitamin D receptor relevance is investigated in this paper as well.

      There are interrelationships between periodontitis and diabets role in inflammation.

      https://www.ncbi.nlm.nih.gov/pubmed/11887455

      One promising way to reduce IL-6 would be sideritis aqueous extracts.

      Effects of Sideritis euboea (Lamiaceae) aqueous extract on IL-6, OPG and RANKL secretion by osteoblasts.
      https://www.ncbi.nlm.nih.gov/pubmed/22224290

      I remember some posts in your blog connecting autism and bone health but don't know if they share similar inflammatory pathways(IL-6, IL-10 etc.).
      This paper says that sideritis could help with bone mineral density.

      Protective effect of Sideritis euboea extract on bone mineral density and strength of ovariectomized rats.
      https://www.ncbi.nlm.nih.gov/pubmed/21505372

      Personally I think it's worth investigating this herb's antiinflammatory properties.
      Wikipedia says:
      Significant research has been done on ironwort confirming its popular use to prevent colds, flu, and allergies. Most of this research has taken place in universities in the Netherlands and in Greece, Turkey, Republic of Macedonia, Bulgaria, and Albania, where the plant is indigenous.[14], I could interpret this as if it implies that researchers have conflict of interest.

      I haven't found any paper about sideritis and reduced IL-10.
      Thank you for deleting my previous comments with personal information.

      Delete
  7. A new paper came out which discusses the use of an old drug approved for use in China and Japan, but not in the United States or EU called Fasudil:

    https://en.wikipedia.org/wiki/Fasudil

    Fasudil is a Rho-Kinase inhibitor which has been a topic discussed here on this blog before.

    Press Release:

    https://www.sciencedaily.com/releases/2017/11/171130122753.htm

    Paper:

    https://www.nature.com/articles/s41467-017-01915-4

    In the paper, the researchers were able to in effect erase habitual behaviors in mice so that the mice were able to learn new adaptive behaviors. One of the most frustrating things with my son is his cognitive rigidity so that if he learns something the wrong way the first time, it is next to impossible for him to unlearn what he has learned. This drug seems to reduce spine density (which in many autism studies excessive numbers and density of dendritic spines seems to be a hallmark condition) via increasing synaptic pruning. Of course the researchers note that excessively pruning synapses is a bad idea, but in the case of autism, especially during childhood, there seems to be an excess of spines which seems to impeded learning and cognitive flexibility.

    Here is a paper I just dug up which uses Fasudil to reverse deficits in a mouse model of intellectual disability due to brain ventricular enlargement (typical of large heads):

    https://www.ncbi.nlm.nih.gov/pubmed/27146843

    As far as good Fasudil alternatives, and in particular natural/supplement options, there don't appear to be many. I did find this paper suggesting isoflavone as a natural Rho-Kinase Inhibitor (ROCK):

    http://jpet.aspetjournals.org/content/326/3/991

    Since this drug is approved and used in China, there might be indirect ways of sourcing this for therapy since it is unlikely it would ever be approved by the FDA due to patents expiring and therefore it being commercially useless in the United States and likely Europe as well.

    For anyone who has a child with a macrocephaly subtype of autism (large head), this drug looks like it could potentially make a big difference in boosting IQ.

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  8. Peter, I have in my hands 10 packs of bumetanide!don't know where to start.I must get potassium.
    Valentina

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    1. In the USA you can't have potassium tablets greater than 100mg by law which makes them quite useless. The reason is that lawmakers thought people would commit suicide with potassium since it is used for lethal injections. Yes it is that silly.

      Nevertheless, you can legally buy potassium gluconate in powder form which gets around this stupid law. The brand I get is NOW Foods. It has a sweet taste so it is also easy to mix in drinks.

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  9. Peter and all, thought you might find this interesting. I am not surprised:

    "Antibiotics may reduce the ability of immune cells to kill bacteria"

    https://www.sciencedaily.com/releases/2017/11/171130141100.htm

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  10. Petra, you were right: my son's vit D was just tested low - the doctor has him on a once a week dose of 50,000 IU for 8 weeks.

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  11. Hi everyone,

    Just wanted to post an update on how my daughter has been doing on the following change in regimen:

    - Significantly reduced Casein
    - Significantly reduced Gluten
    - Use a digestive enzyme when she is having casein / gluten
    - Antibiotic to kill bad bugs (oral Vancomycin)
    - Anti-fungal to kill candida (oral Nystatin - still ongoing)
    - probiotics
    - Sac Boulardii (good yeast)

    OK, so it's been about 3 weeks since we started all of the above, and maintained everything else, as my daughter's OAT testing and gluteomorphin / Caseomorphin tests detected (I) bad bacteria (ii) bad yeast (iii) high gluteomorphin (iv) high caseomorphin

    And the verdict is ... It's really something! It's not a "cure" by any means, but my wife and I have seen some clear signals that at least one aspect of our new therapy is making a difference in each of the 3 areas we are concerned with (i.e. speech, cognitive, behaviours).

    I would say that the impact on speech and cognitive is noticeable but mild. But we're talking a short period of time, and if it continues at this pace for a while, we'll be happy campers. My daughter's speech is more complex, and the ideas she is expressing are more complex. Not a huge improvement but improvement at a better pace than historic experience.

    I have to say, my wife literally just called me downstairs to see something, and what a great example of how my daughter has improved in the last 3 weeks. On her ipad, there was a cartoon of a little girl in a bath tub that she could colour. Instead, she (by herself) wrote "The Tub" on the picture (using her fingers as paintbrushes). She is hyperlexic, so knows how to spell and read, but over the last 3 weeks, she has been writing words with markers which is new.

    The actual example I wanted to share relates to behaviours. My daughter uses bath letters on the bathtub wall when she has a bath (places the alphabet in order by herself), but when a single letter falls, she panics and asks us to fix it. About a week ago, 5 letters fell together, and she just looked at it, shrugged, and kept doing something else. For her, this is extremely unusual. Her BT and ST have noted big positive changes in behavior.

    I'll keep everyone posted, but the above-noted regimen is really showing some positive changes for us that are clearly outside of normal growth trajectory.

    AJ

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    1. Hi AJ,

      Thats great to hear, I hope the effect will get stronger as time passes.

      For me personally fixing gut issues, was one part of the solution, but not a full fix.

      All the best

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    2. Hi Aspie,

      Thanks for the kind words! I'm very curious to see if we can continue the improvement after my daughter finishes her dose of Nystatin in a week.

      One other thing I'm looking to do is to find a better way to make the bitter flavor of a few options I want to try but can't less problematic. These include Berberine, and even Reishi. I've been reading up on Reishi and see some interesting things, including Rho Kinase (ROCK) inhibition (Tyler has posted about this) and gut health.

      I'm going to see what my local compounding pharmacy can offer. There is also a product called YummyMeds - does anyone have any experience with their product?

      Have a great day!

      AJ

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  12. Peter, which source of potassium is better, chloride or citrate?, I read that potassium chloride is for hypokalemia and citrate for kidney stones, or can be any form? Can I give it any time of the day? Valentina

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    1. Valentina, I use citrate and give it at the same time as the bumetanide. Some potassium supplements cause GI irritation, so give with lots of water. The dietary potassium (eg banana) is absorbed slowly whereas the supplement is absorbed fast.

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    2. A chelated potassium is probably best for absorption. Potassium Gluconate is good if you can get it. The kind you get should not matter that much.

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    3. Peter and Tyler,I got a potassium chloride called K Retard,in capsules that contain microgranules of prolongued release. It says: each capsule contains 500 mg = 6,7 mmol K = 6.7 meq K. I don´t know what it means, Iam sure that each capsule can´t contanin 500mg of elemental potassium. I did a convertion and was 26.13 mg/dl. Still, don´t know what it means, but 3 daily capsules are recommended in leaflet. I will order now potassium gluconate and can get it by december 15. Valentina

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    4. Valentina, a large banana contains about 800mg of potassium. An adult is supposed to require about 3,000mg a day of potassium, but most do not get it.

      You should not take a large dose of potassium supplement all in one go, because it gets absorbed quickly. I think it is best to add dietary potassium that is gradually absorbed and a supplement at the same time you take the bumetanide. I used to give 250mg with 1mg of bumetanide, now I give 2mg of bumetanide and so I give 500mg of potassium. Via diet I give plenty of potassium as fruits. If a child does not eat fruit, you would need more as a supplement.

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    5. Indeed, too much potassium can even be very dangerous including heart problems and heart failure, always take potassium with food, this is very important.

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    6. Ok, thanks for the tips, I will have to figure out which is the real amount per capsule, maybe calling the lab, until I can get the potassium I will use definetly, if Iam lucky and have an opportunity with bumetanide.Today was the first day and coincided that he played games with many dialogues and imaginary characters.
      Valentina

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    7. Valentina, you may check Table 1 in this very useful paper on HypoKPP:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2374768/table/T1/

      Seems like your capsules contain 6,7*39.1=~260 mg elemental potassium. It is helpful to use mEqK+ when using different potassium formulas.

      I would not worry about potassium overdose when using loop diuretic provided good kidney function and within reasonable dose range of course. Hypokalemia is more probable.




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    8. Agnieszka,thanks for the excellent link, I confirmed the dose, it seems that my capsules of potassium chloride contain the right amount,a little bit more than 200mg.It is a good potassium supplement. Valentina

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    9. Valentina, you're welcome.

      I've done my homework with potassium as without some tricks on the way I wouldn't be able to use bumetanide in my son who is prone to hypokalemia.

      Do you still use valproate in your son? Together with bumetanide?

      Delete
    10. Agnieszka! you read my mind, I was going to write Peter about valproate, if I should suspend it or not. He is taking 250 mg, a very low dose, but may be I can´t give it to him with bumetanide, or is not necessary any more.
      Also wanted to ask you or Peter if I can give him the bumetanide at lunchtime, with food and the potassium. For me is better this way.He is very calm and plays a lot since he takes bumetanide, its only 3 days, no way a bad reaction. May be is the beginning of something. Valentina

      Delete
    11. Reading drug interactions over time, they are really scary. Do I have to suspend it now or lower the dose to 125 mg, one capsule,and stop it in a few days? Or can I suspend it now? Valentina

      Delete
  13. Peter, very interesting post (and intro).

    My first encounter with azithromycin use in autism was on your blog, in Veronica’s comment:
    https://epiphanyasd.blogspot.com/2016/01/autism-polypill-vs-personalized.html?showComment=1454002218132#c1174719452435701283

    I would be happy to hear from Veronica whether she still uses azithromycin in addition to Bumetanide and other drugs mentioned. It’s been almost 2 years.

    I will try Nystatin as the risk is minimal, but would you really expect neuroprotective or any systemic effect from the drug which is not absorbed if used orally?

    ReplyDelete
    Replies
    1. Agnieszka, pro-inflammatory signaling has been proved to pass via the vagus nerve to the brain. Intranasal insulin (and other drugs) pass via nerves to the brain, not via the nasal membrane. So perhaps nystatin can have an effect on the brain, it would be very interesting to know.

      Delete
  14. Just quick question to Peter are you still using kb-r dibro be mono for your child and as this contains potassium bromide can be considered also source of potassium as well as bromide cheer Paul

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    Replies
    1. Paul, yes this is another benefit of KBr, which I do still use.

      Delete
  15. Hello Peter,

    I would like to share that a fortnight ago my son (who has annoyingly been getting sick every second week now with cold and cough with high fever) caught a nasty gi infection...the child kept on rushing to the toilet every fifteen minutes for three days while I observed adding in Bacillus clausi as a probiotic, following our pediatrician s advice. Finally, he relented and prescribed cefixime as a five days course. Three to four days into the antibiotic, and my son started sleeping a sleep that made me want to hug god and my paedtrician and my son. Smiling and loving as he slipped into slumber, every noon and night for about ten days and a huge language boost. Lots of demanding unclear blabbering with the right intonations and attempts at speaking and repeating and attention seeking and pure joy to have around..even his therapist noticed this. Now, slowly, the sleep pattern is returning to pre antibiotic days though language improvements are still lingering on.

    Do not know if its the beta lactam effect or the probiotic or a combination. Will give cefixime another shot after a month or two to confirm. Riluzole is too expensive to try.

    ReplyDelete
    Replies
    1. In some countries there is generic Riluzole. The effective dose of Riluzole might be much less than one tablet. Its main use is to treat motor neuron disease and that is a severe condition. In Europe it costs about EUR1 per tablet.

      Delete
    2. Peter,

      Here in India we get riluzole under the brand name rilutor 50 mg, priced at INR 200...a little under 3 EUR. Few tablets will not be a problem monetarily...procuring, deciding the dose and trial period plus possible side effects given my sons response to most drugs...too many unknowns and could not find parental trials or experiences with riluzole for autism. It would be wiser to first confirm glutamate issues with tried and tested taxim o forte (cefixime) and if we get a similar boost again, then to investigate further, dont you think.

      Delete
    3. Kritika, Riluzole was trialed for OCD.

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560666/

      It has a very specific function and its effect will depend on whether you have excess glutamate or not. In me, it made me feel a bit lethargic and that was it. I suppose in some people who appear hyperactive, or just feel on edge, it might help them.

      It is possible that beta lactams may have further additional effects other than on glutamate, that we have not considered.

      Delete
  16. I am curious why specifically Riluzole? There are much cheaper alternatives to block NMDA receptors or block glutamate release:
    To block NMDAR:
    - Namenda / memantine
    - Ketamine
    - Neramexane
    - Amantadine
    - Acamprosate
    - Gabapentine
    - Pregabalin (Lyrica)
    - Minocycline (will reduce microglia activation as well)
    - Huperzine A
    - Cat's Claw
    - Agmatine
    - Dextromethorphan (in cough medicine)

    To block glutamate release:
    - Lamotrigine (very similar to Riluzole)
    - Polygala tenuifolia
    - Berberine
    - Gastrodin

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    Replies
    1. Oh, specifically riuzole as Peter had mentioned that it might be worth trying in case ones child responds favourably to beta lactam antibiotics. Beta lactam antibiotics affect glutamate through a specific process I think..clearing it from nerve synapses faster through a particular transporter thus preventing glutamate accumulation, hence neurotoxicity and excitotoxicity. Beta lactams also have been reported to help ameliorate seizures. Cephalosporins, like cefixime, have in particular found to be effective in certain autisms and I have read a few parental experiences similar to mine. I am aware that it could all be a coincidence or simply antimicrobial action of cefixime heliping with acute gut infection/chronic infections.

      Delete
    2. Anonymous,

      I do think trialling dextromethorphan should be a good idea...as it is, my son keeps on coming down with colds and coughs. As my son doesnt do very well on most antiallergic medication (erratic sleep), I would know if dextromethorphan is doing something more. I will do this very soon.

      Thanks.

      Delete
    3. DXM is dangerous in my opinion daily, there is bromium attached to it, dont know why, guess it has to do with better absorption or anything.

      Ive used it 2-3 times in the past... works amazing honestly, especially the 'afterglow', but requires mild ineberation to get an afterglow (feelings of reborn/refreshed/erasing of bad memories of the past).

      NMDA antagonists are unique and have rapid onset antidepressant effects, this is one of the reasons why there has been research in using ketamine for depression.

      My personal experience with it feels like:
      temporary NMDA antagonism = compensatory NMDA receptor expression during the after glow.

      Now, most will think more nmda receptors will give neurotoxicity and all that, but as someone with aspergers myself it feels as if there is by default hanging too much NMDA hanging around in my brain without having enough receptors for it to attach to!, I think this is the main problem.

      Alcohol is also an NMDA antagonist in high doses and a hangover gives me a feeling of reborn/empathy aswell, that feeling of youthfullness... like experiencing things for the very first time. It feels very novel yet nostalgic at the same time and it improves my flow of thoughts and seems to fix prepulse inhibition for me.

      Im getting memantine soon and will update on that.

      Delete
    4. Aspie,

      I would trial DXM more as a test for identifying issues than a continuous therapy.

      Excuse me, but I think the particular pleasant sensations you describe following alcohol intake is not unique or specific to your being on the specteum. I am a teetotaller but I have observed how individuals, particulatly men, start behaving so idiotically after a drink or two. Most Indian men will suddenly break out into broken English. Creepy!

      Delete
    5. Kritika I have a hard time deciphering your last post :),
      you realise I was talking about the hangover being therapeutical to me? (it brings back my social 'wanting' system back online). 99.99% of the population hate hangovers.

      NMDA 'hyperfunction' is associated with alcohol withdrawal, including in the amygdala, and I think that it is this that brings back emotional intensity for me.

      Anyhow NMDA hyperactivity is a strong word.
      After the receptors get antagonized by alcohol, there is most likely a compensatory receptor upregulation that builds up, once a hangover sets in, the nmda antagonism goes offline and there is a temporary state of supersensitivity of some receptors including those of NMDA thereby improving their function.

      Delete
    6. Aspie,

      I got it this time. I mixed up everybody's glow of intoxification with your afterglow of a hangover. Sorry!

      Delete
  17. To get back to DXM, I found that the combination of wellbutrin and dxm is being researched for treatment resistant depression and alzheimer, see below:

    https://en.wikipedia.org/wiki/Bupropion/dextromethorphan

    "Bupropion/dextromethorphan (developmental code name AXS-05) is a combination formulation of bupropion (Wellbutrin), a norepinephrine reuptake inhibitor (NRI) and nicotinic acetylcholine receptor (nAChR) antagonist, and dextromethorphan (DXM), a sigma-1 receptor agonist, NMDA receptor antagonist, and serotonin-norepinephrine reuptake inhibitor (SNRI), which is under development by Axsome Therapeutics for the treatment of treatment-resistant major depressive disorder (MDD) and agitation in Alzheimer's disease.[1] Via inhibition of CYP2D6, similarly to quinidine, bupropion slows the metabolism of DXM and thereby increases its levels. As of 2017, the combination is in phase III clinical trials for the aforementioned indications.[1]"

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  18. Hmmm... Bromine in DXM HBr, chloride in Memantine, both are sanitizing chemicals, both are essential, take your pick

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  19. and Riluzole contains Flourine ...

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  20. Aspie, a new study claims the painkiller paracetamol may have the ability to ease both physical and emotional pain.
    Have you noticed any behavioural/emotional response to paracetamol yourself? Thank you

    ReplyDelete
    Replies
    1. Hi Petra, I might try it, my bouts of crying have dramatically increased (also time of the year), oddly enough im somewhat delighted I can freely cry more now than I did in the last few years, after all crying is a relieve of stress, if you cannot cry you cannot let go of the past.

      Also Ive noticed that my ability crying and emotional hypersensitivity strongly correlates with self acceptance of who I am (in other words, im no longer scared what others think about me and therefor tears flow easily when emotions come to the surface, a blissing and a curse at once, yet far better than the feeling of apathy!).

      You see, to me it feels as if crying is therapeutical, it is necesarry for processing of sadness, if you cannot let the tears and stress out, the mind will get stuck in a loop, this I often noticed with other people aswell who do not have aspergers but have low emotional capacity.

      I think the problem with aspergers is not the lack of empathy (I feel as if it was always an excess of), but more or less a build in protection system to prevent my brain from frying itself due to the stress, reflecting in anhedonia and apathy.

      To get back to your question: yes I have tried paracetamol, It also seems to greatly reduce my headaches aswell as help my daily routine, but as you know glutathione is low in autism and paracetamol is known to deplete it, so be aware of that.

      Delete
    2. Hi Aspie,
      https://epiphanyasd.blogspot.gr/2015/09/is-reductive-stress-common-feature-of.html
      Paracetamol is mentioned here as a biomarker for reductive stress.
      Moreover: Acetaminophen also reduced the unpleasantness of noise blasts delivered to the participant, which mediated acetaminophen's effects on empathy.
      This comes from the following paper:https://academic.oup.com/scan/article/11/9/.../2224135

      Delete
    3. Hi Petra,

      Thank you so much for trying to help me out, I have read about paracetamol in the past allready and the papers that I have read on it were mixed, some reports of both positive and negative emotions being blunted, where in other reports its mainly the negative emotions that get blunted.

      Im somewhat 'scared' to use it for the glutathione lowering effect, many of the supplements that I have had success with target glutathione (as you know glutathion, glutamate, gaba and glutamine are all linked, they use the same buildingblock: glutamine). I feel as NRF2 inducers/glutathione precursors suchs as NAC/sulforaphane, help get rid of the extra glutamate in the brain by somehow shifting the glutamate as a fuel for detoxification (glutathione).

      Delete
  21. Hey everyone,

    Here are two recent papers of particular interest that I've been looking over, and wanted to share as I think they are quite relevant:

    Deficiency of a brain-specific chemokine-like molecule, SAM3, induces cardinal phenotypes of autism spectrum disorders in mice

    http://www.nature.com/articles/s41598-017-16769-5

    The autism protein Ube3A/E6AP remodels neuronal dendritic arborization via caspase-dependent microtubule destabilization

    http://www.jneurosci.org/content/early/2017/12/04/JNEUROSCI.1511-17.2017

    I'll post my thoughts on them when I get the chance, but wanted to share. If anyone wants to share insights in the meantime, kindly do so.

    AJ

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  22. Peter, Iam concerned about valproate for its strong interactions with bumetanide,wrote you yesterday, should i suspend valproate now? because i could lower the dose to 125mg and suspend in a few days. Valentina

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    Replies
    1. Valentina, best to ask Agnieszka, she is the doctor. The lower the dose the weaker any interaction will be. I have no expertise in this area

      Delete
    2. Valentina,

      I usually use this drug interaction checker:
      https://reference.medscape.com/drug-interactionchecker
      It does not warn against bumetanide use together with valproic acid.

      I did not use them together long term. For a few weeks I used bumetanide with low dose valproate without any problems. I quit as this solution did not prevent migraines in my son and this was (and is) my most important goal.

      In my son bumetanide alone was not enough to keep his EEG clear from sleep epileptiform discharges.

      Delete

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