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Wednesday, 1 November 2017

OAT3 inhibitors for Bumetanide - Probenecid, but also Aspirin, Chlorogenic acid (Coffee), Epicatechin (Cocoa, Cinnamon) and more.


Today’s post is about OAT3, highlighted by the green lines.
The interventions reduce renal excretion and raise plasma
concentration rather than directly improving transport across the BBB

Today’s post is a collaboration. Our reader Ling pointed out research trying to boost the bioavailability of bumetanide using something clever called an OAT3 inhibitor.  This would reduce the rate at which the body excretes bumetanide and thus potentially improve its therapeutic effect.
Petra, our reader from Greece, pointed out that in her son Bumetanide seemed to work better when taken with Greek coffee and that that Greek Grandpas like to take their diuretics with a steaming Greek coffee.
Most people, me included, automatically think caffeine when someone mentions coffee.
So I assumed that caffeine might be an OAT3 inhibitor and I did make some experiments on that basis. There is no research data to support caffeine as an OAT3 inhibitor.
Recently I was again looking for other potential Bumetanide boosters.  The obvious one is called Probenecid.  Probenecid is used to treat gout because it lowers uric acid.
Aspirin has some odd effects; low dose aspirin will raise uric acid, but high dose aspirin will lower it. Aspirin is an OAT3 inhibitor.
OATs are a very niche subject, to add to the confusion sometimes you are better looking for SLC22A8, the gene that encodes the transporter. 
There was an earlier post on this subject, which showed that many NSAIDs inhibit OAT3, including Knut’s favourite Ponstan. They are not so well suited to continued use.

At the end of my little investigation I figured it out; there are many OAT3 inhibitors available, including some in your kitchen.  


Key points on OAT3 (Organic Anion Transporter 3)
If you want to increase the peak concentration and indeed the half-life of a drug that is excreted from the body by OAT3 (organic anion transporter 3), an OAT inhibitor is what you need.
The drug Probenecid is by far the best known OAT3 inhibitor and it is very potent. It has long been to boost the performance of penicillin type antibiotics to treat tough bacterial infections.
Probenecid, if available, may very well be the ideal bumetanide booster.
For adults a simple option is Greek/Turkish coffee. I see little downside as long as you can handle the caffeine. The Greeks live a long time and drink plenty of coffee.
For those who do not like caffeine you can go to active components within the coffee, which seem to be the chlorogenic acids (1,3- and 1,5-dicaffeoylquinic acid). They are sold as a weight loss supplement, the long established version is the French-made Svetol, but there are now others. They still contain 2- 3% caffeine.
Epicatechin, found in cinnamon, dark chocolate and high flavanol cocoa is another OAT3 inhibitor. Cocoavia, made by Mars, is used by some readers of this blog. Cocoa flavanols do clever things with nitric oxide (NO) and have been shown to improve mild cognitive impairment (MCI) and heart health by improving blood vessel elasticity.
Catechins are flavanols belonging to a family of closely related compounds, such as epicatechin, epigallocatechin, epicatechin gallate (EGC), and epigallocatechin gallate (EGCG). They are all slightly different. Catechin itself is not an OAT3 inhibitor; EGCG may or may not be.
Low dose aspirin is likely the cheapest OAT3 inhibitor. It also increases peripheral circulation, which could benefit some. Low dose aspirin has the downside of a small bleeding risk, mainly in old people, and there is a risk of Reye’s syndrome if given during/after a viral infection.
I think for adults a Greek coffee may be the best. For people who have a profound benefit from Bumetanide, I think they should look into Probenecid.
Personally I think Svetol is worth a try.
Coffee that has been extensively processed (just as we saw with cocoa) may not have the same chlorogenic acid content as the more gritty coffee used in the Balkans. Coffee consumption is actually associated with many neurological benefits, reducing the incidence of Parkinson’s and Alzheimer’s; the common mistake in research is the assumption that the effect must be from caffeine.











  
The health effects of decaffeinated Coffee
My eureka moment in this post was reading about gout and coffee and then decaffeinated coffee. 




So then it was a question of finding what in coffee could be the OAT3 inhibitor. At which point I found a very insightful paper that tells you everything, once you realise that:

Coffee = chlorogenic acids  = 1,3- and 1,5-dicaffeoylquinic acid


Five compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acids (15 : 1) and (17 : 1), and epicatechin, significantly inhibited hOAT3 transport under similar conditions

3.2. Inhibition of hOAT3 by Natural Anionic Compounds and Flavonoids

Human OAT3 expressing cells showed about 4-fold greater accumulation of ES as compared to background control cells ( versus  pmol mg 10  , resp.). Similar to hOAT1, hOAT3-mediated ES uptake was completely (>96% inhibition) blocked by probenecid (Figure 4). Five of the compounds, 1,3- and 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acids (15 : 1) and (17 : 1), significantly inhibited hOAT3-mediated transport at 50-fold excess (Figure 4). 1,3-Dicaffeoylquinic acid and ginkgolic acid (17 : 1) exhibited 41% inhibition, while 30–35% reduction of hOAT3-mediated ES uptake was observed for 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acid (15 : 1). Catechin, 18β-glycyrrhetinic acid, and ursolic acid failed to produce significant inhibition. Based on the level of inhibition observed, values for all of these compounds would be greater than 50 μM, much higher than clinically relevant concentrations (Table 1). Therefore, further dose-response studies were not performed.










Lay off the Lycopene?
Lycopene does the opposite of what we want. Too much lycopene may lower the effectiveness of a drug that is excreted via OAT3. 

2.29. Lycopene

Lycopene is a carotenoid pigment found in tomato [94]. Lycopene from dietary sources has been shown to reduce the risk of some chronic diseases including cancer and cardiovascular disorders [95]. The administration of lycopene significantly normalized the kidney function and antioxidant status of CSP-treated animals. Furthermore, lycopene also increased the expression of the organic anion and cation transporters (OAT and OCT, resp.) including OAT1, OAT3, OCT1, and OCT2 in the renal tissues [9698]. In addition, lycopene also decreased the renal efflux transporters (multidrug resistance-associated protein [MRP]-2 and MRP4) levels and induced Nrf2 activation, which activated the antioxidant defense system [99]. Furthermore, lycopene protected against CSP-induced renal injury by modulating proapoptotic Bax and antiapoptotic Bcl-2 expressions and enhancing heat shock protein (HSP) expression [97].

https://www.hindawi.com/journals/omcl/2016/4320374/                                                                                                                  

Aspirin
I actually started out this post by looking at what dose of aspirin might be effective in inhibiting OAT3.  We do know that Aspirin is indeed an OAT3 inhibitor.  


I did find the answer, but along the way you do end up having to look at uric acid. 
Uric acid is taken up by OAT1 and OAT3 from the blood and reabsorbed into renal tubular cells via URAT1 Uric acid is taken up by OAT1 and OAT3 from the blood and reabsorbed into renal tubular cells via URAT1Uric acid is taken up by OAT1 and OAT3 from the blood and reabsorbed into renal tubular cells via URAT1. 
Uricosuric drugs increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. 
In general, uricosuric drugs act on as urate transporter 1 (URAT1). URAT1 is the central mediator in the transport of uric acid from the kidney into the blood.  By their mechanism of action, some uricosurics (such as  probenecid) increase the blood plasma concentration of certain other drugs and their metabolic products  – this is their effect on OAT3.
Probenecid is a medication that increases uric acid excretion in the urine.
Atorvastatin is a so-called secondary uricosuric. High dose aspirin should also be called a secondary uricosuric.
Antiuricosuric drugs raise serum uric acid levels and lower urine uric acid levels. These drugs include all diuretics and low dose aspirin. 
Low dose aspirin inhibits OAT1 and OAT3 which reduces urate secretion, but high dose aspirin inhibits URAT1 and reduces urate re absorption. This is sometimes known as the biphasic effect.
So low dose aspirin will increase plasma uric acid, but high dose aspirin has the same effect as Probenecid, it lowers plasma uric acid levels.
So Aspirin and Probenecid both affect URAT1 and OAT3. 






At what dose is Aspirin an OAT3 inhibitor?
If we just want aspirin to inhibit OAT3 and not inhibit URAT1, what dose is effective? Fortunately this has been answered in the research. The typical low dose of aspirin (75mg) used preventatively in older people is OAT3 inhibiting, it raises plasma uric acid.  





Salicylate

Salicylic acid and its derivatives are the most prescribed analgesic, antipyretic, and anti-inflammatory agents. Salicylates have a “paradoxical effect” on the handling of uric acid by the kidney. The action of salicylates on uric acid excretion depends on the dose of salicylates. At doses of less than 2.5 g/day, salicylates cause the retention of uric acid by blocking the tubular secretion of uric acid, while at dose of higher than 3 g/day, they cause increased urinary excretion of uric acid [70]. Mini-dose aspirin, even at a dosage of 75 mg/day, caused a decrease in uric acid excretion and raised serum uric acid level [71]. It has been suggested that the “paradoxical effect” of salicylate can be explained by two modes of salicylate interaction with URAT1: (1) acting as an exchange substrate to facilitate uric acid reabsorption, and (2) acting as an inhibitor for uric acid reabsorption [72]. Low dose of salicylate interact with OAT1/OAT3, the uric acid secreters [73].

Low dose aspirin leads to decreased renal excretion of uric acid and raised serum uric acid levels, which can cause a gout attack in those predisposed to this condition.
High doses of aspirin lower serum uric acid concentration.

Reye’s Syndrome
In children aspirin is very rarely used because of the risk of Reye’s syndrome. Reye’s syndrome causes severe liver and brain damage. It is a type of severe mitochondrial failure that can occur after a viral infection like flu or chickenpox, but it almost only occurs when aspirin has been prescribed. Nobody knows for sure the exact mechanism of the disease.
So do not give aspirin to children with a viral infection.  We already know to avoid paracetamol/acetaminophen (Tylenol in the US) in babies/children and people with autism. Paracetamol/acetaminophen depletes the body’s key antioxidant GSH. 
If someone overdoses on Paracetamol/acetaminophen you give them a high dose of NAC to prevent death. 


Conclusion
Given how long it takes to develop new drugs, I think that improving the pharmokinetics of bumetanide is a pretty obvious thing to do. 
Diamox is an OAT3 inhibitor and our reader Agnieszka found it beneficial only when administered along with Bumetanide.
Strong coffee is an OAT3 inhibitor and this was found to enhance bumetanide by Petra’s son with Asperger’s.
Cinnamon which contains epicatechin, another OAT3 inhibitor, did seem to be helpful in Monty who also takes bumetanide.
I suspect Diamox may be the most potent OAT3 inhibitor of those three
The interesting OAT3 inhibitors seem to be:-

·        Probenecid

·        Low dose aspirin

·        Epicatechin (cocoa, cinnamon ..)

·        Chlorogenic acids (coffee and decaffeinated green coffee extracts) 

Cinnamon, high flavanol cocoa and indeed coffee (minus the caffeine) have numerous health benefits.
Note that Catechin has no effect on OAT3. EGCG was not tested but in other studies has been shown it does affect.



The logical next step would be to improve bumetanide transport across the blood brain barrier.










72 comments:

  1. I posted on this blog a while ago new research that showed adenosine a2a receptors being the lock for opening up the blood brain barrier. Caffeine obviously comes to mind in modulating this action as the other drugs I found with regard to a2a receptors were for experimental purposes only or else drugs I had never heard of before.

    ReplyDelete
    Replies
    1. Tyler, the following paper explores just how complicated the process is of bumetanide crossing the BBB.

      Multiple blood-brain barrier transport mechanisms limit bumetanide accumulation, and therapeutic potential, in the mammalian brain.
      https://www.ncbi.nlm.nih.gov/pubmed/28192112

      The full text goes into great detail. In the end they think it is better to use a lipophilic prodrug called BUM5.

      I think just improving the duration bumetanide stays in plasma at a high level may be enough. I found multiple low doses of bumetanide has no effect, much better one big one. The diuretic effect of bumetanide has a plateau, so more bumetanide does not mean more diuresis after this point. So I think 2mg of bumetanide plus an OAT3 inhibitor may result in much more bumetanide crossing the BBB than just 2mg of bumetanide.

      Delete
    2. Well short of taking blood samples and testing for Bumetanide, perhaps another way of seeing if the OAT3 inhibitor idea helps would be to first carefully regulate how many servings of fluids your child gets in a day at regular intervals over a or series of days on just Bumetanide and then meticulously document how many times he went to the bathroom as Bumetanide not just increases urine volume output, but it increases frequency of urination too. Give one Bumetanide in the beginning of the day and use that as the baseline.

      Then do the same thing but use whatever OAT3 inhibitor you plan on using and record the same data. If Bumetanide is staying in his system longer, then its diuretic effects should be extended as well.

      Ideally blood draws and stuff like that would be better, but just recording bathroom visits would be a more practical way I think to see if you are getting the results you want.

      Delete
    3. Tyler, it gets more complicated. Loop diuretics have a maximum effective dose, beyond which there is no further diuresis. The maximum effective dosage of bumetanide is quite low, suggested in the paper below to be just 1mg.

      http://cursoenarm.net/UPTODATE/contents/mobipreview.htm?35/31/36350?source=see_link

      In my son when I increased his dosage from 1mg to 2mg there was no noticeable additional diuresis.

      This drug is so old, and well used, there is a vast amount of of data on it.

      Delete
    4. This is I/V not oral bumetanide, but the same idea will apply.

      http://www.globalrph.com/bumex_dilution.htm

      In 56 infants aged 4 days to 6 months, bumetanide doses ranging from 0.005 mg/kg to 0.1 mg/kg were studied for pharmacodynamic effect. Peak bumetanide excretion rates increased linearly with increasing doses of drug. Maximal diuretic effect was observed at a bumetanide excretion rate of about 7 mcg/kg/hr, corresponding to doses of 0.035 to 0.040 mg/kg. Higher doses produced a higher bumetanide excretion rate but no increase in diuretic effect. Urine flow rate peaked during the first hour after drug administration in 80% of patients and by 3 hours in all patients.

      Delete
    5. Well in that case you could start with 0.5mg and test from there and see if the OAT3 inhibitors will yield the same kind of results you get from a 1mg dose. This is trivializing things obviously, but it is a start.

      Delete
  2. Peter,

    What would be the difference between adding an OAT3 inhibitor and just increasing bumetanide dose? Do you think that improving the duration bumetanide stays in plasma at high level will not result in longer time of diuretic effect? What about hypokalemia?

    I cannot use more than 2 x 1 mg because of dehydration in my son. Handling the diuretic effect of high doses is an issue also.

    On the other hand, so far it seems there are no better interventions across a range of his "autism" related issues than those targeting chloride neuronal regulation. I can see this once again after a month on slightly increased dose of potassium bromide.

    ReplyDelete
    Replies
    1. Agnieszka, I think all options should be considered. There is likely a plasma concentration at which bumetanide starts to cross the BBB. At higher concentrations bumetanide can cross, but what is better, a short time a very high concentration or a longer time but at a moderately high concentration? We can only guess. My hope is that by using the correct OAT3 inhibitor I can extend the time during which bumetanide crosses the BBB and so that it builds up a more meaningful concentration within the BBB.

      I did also think why not just use more bumetanide. That would give a big spike in plasma concentration, but the short half-life remains. More bumetanide will be different to bumetanide + OAT3 inhibitor.

      It would be helpful if there was research on the diuretic effect of an OAT3 inhibitor. This would then help with understanding hypokalemia.

      In my son 2mg of bumetanide causes similar diuresis to 1mg. I do not know where the plateau level is, but I think it may vary greatly from person to person. I did use 2mg AM and 1mg PM, but never 3mg all in the morning.

      I expect that the chlorogenic acid supplement will only have a moderate effect on OAT3 and so just give a moderate boost, like Petra's Greek coffee; but that is all I want, I do not want a dramatic effect.

      Delete
    2. Well if increasing the concentration of Bumetanide in the brain is a goal, perhaps increasing blood flow directly to the brain via the mammalian dive reflex could help things:

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

      http://www.sciencedirect.com/science/article/pii/S0361923003000650

      Also, here is a new paper showing trigeminal nerve stimulation as a therapy for traumatic brain injury. What is relevant here is at the bottom of the abstract:

      https://www.nature.com/articles/s41598-017-07219-3

      "Furthermore, rats in TNS-treatment group showed significantly reduced brain edema, blood-brain barrier disruption, lesion volume, and brain cortical levels of TNF-α and IL-6. These data provide strong early evidence that TNS could be an effective neuroprotective strategy"

      The mammalian dive reflex works in a similar manner trigeminal nerve stimulation (the nerves on the face).

      The only thing here which I am sure you will notice is that IL-6 which is generally bad for autism, also makes the blood brain barrier more permeable (which is generally bad all around if this happens chronically).

      Also, in general hypoxia will make the blood brain barrier more permeable. I don't know if this applies to breath holding with the face submerged in cold water (the way to maximally drive the mammalian dive reflex), but this practice does not seem to do any long-term damage as many people in the world practice apnea (David Blaine for instance) with no apparent long-term health problems that I am aware of.

      In practical terms of employing this, you would probably want an ice cold wet towel you place on the face as your child is told to hold their breath.

      I have done static apnea with my face submerged in cold water myself in the past and from experience it will supercharge your brain (or at least that is how it feels) for the rest of the day. I rarely do it anymore because I have no privacy in my life anymore, but at my peak I could do over 4 minutes (world record is like 7 minutes without the aid of inhaling pure oxygen). People also cheat like hell with drugs like EPO now, so I think the record now is well north of 7 minutes, but if you want to selectively dump a lot of blood into the brain, the mammalian dive reflex can be a great tool.

      Last but not least, HIF-1 will make the blood brain barrier more permeable (HIF-1 is upregulated from hypoxia). However, mild and acute hypoxia does not seem to cause any problems as any stress to the BBB is quickly repaired and may even have a hormetic effect similar to what altitude training can do for some athletes, whereas cell death is the result of severe and chronic hypoxia.

      http://online.liebertpub.com/doi/abs/10.1089/ham.2012.1052

      Now, none of this will keep Bumetanide in the body any longer, but it could potentially increase the amount that makes it to the brain (as well as other stuff you don't want as well, but only temporarily).

      Delete
    3. Tyler, I really think your research into TNS is worth the effort, because interventions with chemical compounds have obvious limits.

      On the other hand, I can see why some people (like myself in the beginning) move away from this blog when they see some of the very creative solutions we discuss. We have the TSO intestinal worms (Peters favourite!), fecal transplant and IR saunas. And now - holding your breath!

      Not meaning to be disrespectful at all, this just made me smile. :) Thank you for unintentionally lifting my mood!

      /Ling

      Delete
    4. Well other than the Simons Foundation which mostly focuses on genetics studies (which is important), I would not expect much to get done from the formal research side into autism going forward as science is all screwed up politically right now here in the United States and organizations like Autism Speaks have lost a lot of support compared to just 5 years ago both because of missteps by the organization, as well as the myriad of autism organizations that seem more concerned with playing politics with each other, rather than getting along and investing their scarce resources wisely. Autism Speaks is also more focused on helping people with autism with practical solutions and not so much the hard science anymore if you follow their new mission statement.

      Really, you get the feeling a lot of people in the autism research space are giving up due to lack of funding and obviously if you read Peter's blog, you realize there is indeed a lot of autism related research going on in the world, just it is not directly autism related much of the time as it covers the more politically relevant and better funded research for neurodegenerative diseases like Alzheimer's disease that have people who are directly affected and vote for what is most relevant to them. Most people with autism cannot advocate for themselves and therefore funding for autism research will always play second fiddle to just about everything else, aside from the temporary bump in funding when autism rates seemed like they were on a never ending increase (the famed 1 out of 68 number).

      Also with respect to the political issues, here in the states you have a situation where universities have expunged pretty much all people who believe in religion or else have conservative values and as a result they find themselves surprised when half the country or more won't support research funding in general under the premise you should not fund your opposition. It also does not help that other than wealthy families, college education is becoming more a luxury good that signals family status that much of the rest of society is beginning to resent. Why would you support institutions, including research institutions, your children or grandchildren are more or less locked out of.

      The other problem of course is like most European governments, the United States has massive debt and demographic challenges that were addressed in the short-term via immigration (both legal and illegal), but in the long run the chickens are coming home to roost as older generations keep stealing from the younger generations via the welfare state, and that includes austerity towards research which generally benefits society in the future and not the present. Younger people cannot afford to get married and raise children, which only exacerbates the problem as the birth rate continues to crater. You can't have increasing research budgets with a shrinking economy due to a shrinking population so I am a little pessimistic on this front.

      In the meantime, we have to throw enough stuff at the wall to see if it sticks and pay close attention to the research that still is getting funded and go from there. Obviously there are better more formal ways for this to be achieved, but there are too many artificial factors holding things back in the formal research space to just twiddle our thumbs as parents and hope somebody else solves the problems our children face on a daily basis.

      Delete
  3. Hi everyone,

    Check out this new paper - it provides additional backing for R-Baclofen for use in specific genetic cause of ASD:

    R-Baclofen Reverses Cognitive Deficits and Improves Social Interactions in Two Lines of 16p11.2 Deletion Mice


    http://www.nature.com/npp/journal/vaop/naam/abs/npp2017236a.html

    AJ

    ReplyDelete
  4. Hi everyone,

    Hot off the presses:

    Potential new treatment of ASD for kids with a KCTD13 deletion:

    https://medicalxpress.com/news/2017-11-autism-treatments-brain.html

    Looks very promising - just found this so haven't had time yet to look for a natural way to inhibit RhoA protein. If anyone finds a way of targeting in the meantime (before I get a chance to), kindly share!

    AJ

    ReplyDelete
    Replies
    1. Isoflavone Attenuates Vascular Contraction through Inhibition of the RhoA/Rho-Kinase Signaling Pathway
      http://jpet.aspetjournals.org/content/326/3/991

      AJ, it looks like you would need Genistein or Daidzein, which a found in soy and in supplements.

      There is a more potent synthetic version called Genistein Aglycone (GAG), which does clever things in trials that Genistein fails to do, due to low bioavailability.

      Delete
    2. Hi Peter,

      Thanks very much for your response!

      I've found a few interesting options other than Genistein and Daidzein (which I'm always a bit hesitant to use due to impact on hormones) and they are:

      Taurine
      https://www.ncbi.nlm.nih.gov/m/pubmed/28718066/?i=175&from=rhoa
      https://www.ncbi.nlm.nih.gov/m/pubmed/28412885/?i=330&from=rhoa

      Astaxanthin
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537536/

      I already use Astaxanthin, and just started Taurine, so hopefully will see if the addition of Taurine makes a noticeable difference.

      Aj

      Delete
    3. AJ, taurine has so many different effects it is impossible to know which one might be helping. It is very widely used by people using supplements for autism.

      Delete
    4. Is Taurine a Biomarker in Autistic Spectrum Disorder?
      https://www.ncbi.nlm.nih.gov/pubmed/28849439
      21 out of 66 children with ASD had low taurine concentrations (<106 μM). Since taurine has anti-oxidant activity, children with ASD with low taurine concentrations will be examined for abnormal mitochondrial function. Our data imply that taurine may be a valid biomarker in a subgroup of ASD

      Delete
    5. Thanks Peter! I've started Taurine, and will let the community know if I see any noticeable impact.

      AJ

      Delete
    6. Good findings AJ!
      Let us know your results with Taurin.

      /Ling

      Delete
  5. Hi, I am a new reader and just overwhelmed at the minute. My 8-yr-old son seemed to be developing typically until age 14 months when his development just froze. He remains a toddler to this day. He had a couple of words that emerged around age 3 then disappeared. He has an abnormal EEG and chronic urticaria. Very very hyper and head banging has recently started. I've been trying to toilet train him since age 3. Just exhausted. Stumbled upon this blog but don't know where to start. We did have a lumbar puncture in Jan 2013 that showed mildly elevated neopterin and biopterin levels but otherwise "normal". Probably needs to be redone.


    Please help. What sort of autism
    "sub type" is this ? I was told he is profoundly "MR". Please help. I am willing to work hard but I just need to know where to start. Thanks for any advise you can give me.

    ReplyDelete
    Replies
    1. Gail, what you can do depends a lot on where you live, If you live in the US you have far more options. What country do you live in?

      There are hundreds of different biological dysfunctions that can lead to behaviours that get called autism. Some of these dysfunctions are treatable and then "autism" becomes less severe and cognitive function (IQ) rises.

      Abnormal EEG and chronic urticaria are both common in autism and both are treatable. Histamine issues are very common and when treated with mast cell stabilizers etc, behaviour improves.

      In about 40% of cases kids respond well to a drug called bumetanide. This is an old drug in the process of being approved as an autism drug. In kids with MR it can increase their intelligence.

      So, step one is which country do you live.

      Delete
    2. Hi Gail!
      Jump on board - this blog might be a lifechanger for you as it has been for many of us. We've all been overwhelmed at some point, but the good news is that autism interventions are abundant.
      You are having a hard time at the moment, and I think you should focus on improving the current situation. Head banging is more severe than toilet training, and if this is histamine related other interventions won't do the trick until you have addressed it.
      Do you suspect any allergies (food or pollen)? Then mast cell stabilizers would help. Verapamil seems to be the best for aggression and SIBs, but it is a prescription medicine. It might be easier to get your doctor to prescribe it for urticaria than for autism. Other alternatives would be quercetin (easy to find, buy and try) or certain allergy medicines (chromolyn sodium, ketotifen, montelukast are some of the ones mentioned here).

      Peter has also pointed out that loss of milk teeth have a similar effect, so see if you can rule out that to.

      Hope this helps!

      /Ling

      Delete
    3. Hi Peter and Ling,

      I am in California but have a very bad insurance (HMO) which has refused to pay for anything. I am on a limited income and unable to afford anything beyond a few hundred dollars a month. He developed hives when I was trying to titrate up the Lamotrigine he was on from 100 mg to 200 mg. He is currently on 200 mg of Topomax but will have a 24 hour EEG next month. I am concerned about the head banging and the toileting. If I can help him become more independent with self help skills that would be a great start !!! He hasn't lost any milk teeth recently. Should I start with mast cell stabilizers first ? I suspect auto immunity but all tests have come back negative so far. What am I missing ?

      Delete
    4. In terms of low hanging fruit in addressing SIB, I would start with NAC first. Oxidative stress will tend to disproportionately compromise the amygdala and hippocampus first and both are involved in SIB. N-Acetyl-Cysteine also happens to be relatively cheap if you can get your son to do pills. Otherwise, you will need to get the more expensive effervescent variety called PharmaNAC. NAC is not a silver bullet, but probably the easiest and cheapest intervention in dealing with aggression and SIB.

      Delete
    5. Gail, you either try and figure it all out by yourself, or go and consult someone who understands at least part of autism. The most capable clinician/researcher in the US seems to be Dr Richard Frye at Arkansas Children's hospital.

      http://www.archildrens.org/find-a-doctor/find-a-doctor?id=259

      Even he does not know it all, but he is a very good place to start. I am told there is a long wait to get seen.

      In my son, his histamine-related SIB responds immediately to verapamil, which is a calcium channel blocker. Many people respond well to chromolyn sodium, a mast cell stabilizer.

      Histidine and quercetin are both OTC and they also help stabilize mast cells.

      Cognition can be improved substantially in some of the people who respond to bumetanide. It allows this subtype of severe autism to commence learning.

      Some readers in California get bumetanide and verapamil from their local doctor. Others buy online, or take a drive to Mexico.

      I would start with NAC 3 or 4 times a day.

      The drugs and supplements I use are inexpensive and so my monthly cost is less than a hundred USD. This is tiny compared to our costs for a 1:1 assistant at school.

      In the US you have extremely expensive drugs but very cheap supplements. The drugs described in this blog are very cheap generics in the rest of the world.

      Delete
  6. Peter, according to this paper, vitamin D3 may be another possible Oat inhibitor, particularly for those treated with beta lactam antibiotics (PANDAS, streps infections, OCD?).
    Please check this out:

    www.jpharmsci.org/article/S0022...0/fulltext -

    If vitamin D3 reduces clearance of this kind of antibiotics, the least I could think of is that it could also reduce clearance of important nutrients and vitamins compromised in autism, as there are many recovery stories after supplementing vitamin D3.

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    Replies
    1. Petra, vitamin D does some very clever things that are only now beginning to be understood. For example, vitamin D binds to the vitamin D receptor (VDR), which then binds to the retinoid X receptor (RXR) and activates the expression of numerous genes. This includes remyelination, which is why people with Multiple Sclerosis must not be deficient in vitamin D.

      I think we want an OAT3 inhibitor that does not do too many other things as well.

      Incidentally what is the main benefit your son gets from bumetanide ? Are you/he willing to write about it?

      Delete
    2. Hi Petra I was just wondering how is your son doing? Did you find anything that helps with the looping thoughts?

      Delete
    3. Hi Peter, I think the link I've sent doesn't open so just google SLC22A8 and vitamin D3 and you'll find this:
      Effects of 1α,25-Dihydroxyvitamin D3, the Natural Vitamin D Receptor Ligand, on the Pharmacokinetics of Cefdinir and Cefadroxil, Organic Anion Transporter Substrates, in Rat

      As for Bumetanide experience, it's sometimes difficult to explain behavioural benefits one may have gained from medication while fighting to fix so many awful things happening at the same time. It comes to mind that humans are not mice to measure with researchers' scales and write down how much time mice spend in the cave or in the open field, their scores in swimming stress test and what happens when they meet a new mouse. Obviously, real life exceeds all these and you are left to trust your instinct when it comes to what is normal versus abnormal.
      More than a year on Bumetanide went in parallel with my son's mental maturity. It seemed like an antipsychotic drug. As you know my son has high IQ but there is no point in solving maths problems and cannot take part in real life. He had to break out of his sterile mathematical environment and decode the confusing, irrational humans. He has a complicated cognitive profile and he managed to go beyond it and work with meanings.
      In conclusion, while on Bumetamide, something like brain development occured, with side effects, but he is now able to integrate information into knowledge much better and make interesting judjements. I call this cognitive flexibility which is the most important aspect when dealing with developmental disorders.

      Delete
    4. Petra, has he now stopped taking bumetanide? Or does he still use it?

      Delete
    5. Hi Tanya, things seem good for us and really hope the same for your son.
      I can't say for sure what helps with looping thoughts. My course of action, as we discussed before, whem my son's OCD had reached to the highest point, I gave 20mg fluoxetine. Two things impressed me then, first that he responded from the first dose, which is quite uncommon, and second that his uric acid decreased by 2 points immediately. I kept fluoxetine for less than 8 weeks and when he started having side effects I gradually stopped instead of raising the dose. I had noticed that fluoxetine worked much better with fish oil and also read that fish oil inhibits 5ht2c, something that fluoxetine makes from the first dose but I don't know if this is relevant. I now only give fish oil and it seems to maintain the benefit.
      I find your idea of using oregano oil very clever. It's an excellent choice for inflammation. I use sideritis mountain tea, which in Greece everybody uses for the prevention of common cold, sore throat and many other things connected with inflammation and I think it has some similar properties to oregano. This was also a hit. Sideritis is a gaba modulator, selective estrogen receptor modulator, triple monoamine reuptake inhibitor, and reduces beta amyloid plaques in humans according to research.
      Then I added vitamin D3, 2000IU daily, hit again.
      We also have nicotine replacement therapy.
      He still has cold feet and cordyceps may help for that. I bought some but haven't used it yet.

      Delete
    6. Peter, during the long and demanding summer holidays I only gave it from times to times and then stopped to see what happens. The benefits have remained until now. I also found a more effective nicotine therapy. It's Philip Morris IQOS device which heats not burns tobacco and is supposed to be less harmful than conventional cigarettes. It takes the nicotine straight to the brain nice and clean and anyway he doesn't smoke much. I know it can be harmful but he says it works. It may be a better choice than using Ketamine or psilocybin.

      Delete
    7. Petra this is such good news! That is wonderful you saw a benefit from a relatively short course and could stop it and see the benefits last with just the fish oil . I like hearing from you and what has helped. Right now my son is not doing so well. What started out seeming like a gut flare infection type trigger now has me thinking more and more it is an emotional trigger. He is 18 now and the emotional aspect is a big piece for him. The troubling thing right now has been an increase in ritualistic type of OCD. I have never seen anything like this from him before. Treating it as if it is infection based using the anti microbials has helped his gut a bit but not touching the OCD. And NAC does nothing for it . What side effects did you see from the Prozac?

      Delete
    8. Tanya, when my son was about your son's age he also started to behave in a ritualistic type of OCD.
      In the evenings he would go up and down, then to a specific point he had marked, placed his body and face there, streching to reach a line he had drawn, to such an extend that he was sweaty all over with frozen eyes and completely helpless. This usually led to self injury and property destruction. At such moments It is hard to find something that helps, it's an emotional blockage. Maybe find something to make him cry, or soften his emotions with pictures of babies, animals, favourite music or give something sweet, salty, a drink with a straw, anything that could possibly distract him and make him emotional, I am sure you know all that..
      As for fluoxetine side effects presented with involuntary half body movements with agitation and seemed it didn't work anymore.

      Delete
    9. This comment has been removed by the author.

      Delete
  7. Hi everyone,

    I had promised to update the community on our test results for Caseomorphin and Gliadorphin (I thought the result would be for Gluteomorphin but it is for Gliadorphin).

    So the results were high, not astronomically high, but about 20% above the normal maximum range, so we are going to address it with a reduction in Casein and Gluten (eliminating casein and gluten would be very difficult) with the concurrent use of digestive enzymes.

    I'm not looking for a cure per se, just an improvement. Even a 10% in my daughter's symptoms would be worth it.

    Also, we are going to start a regimen to combat (I) Clostridia and (II) yeast / fungal issues via prescription meds + probiotics (L Reuteri which I already use, saccharomyces boulardii, and other probiotics to make sure we have a higher likelihood of success).

    Does anyone have any advice or insights? I know Caprylic Acid and Grapefruit Seed supplements are natural ways to attack the issue. Anyone use them concurrently with prescription meds?

    Anything else to consider while using antibiotics /Nystatin?

    My hope is that we can replace the bad (Clostridia and yeast / fungals) with good by killing the bad and replacing them with hardy good strains (L Reuteri, Sac Boulardii, others).

    I also use Bimuno as this is supposed to be a good prebiotic.

    Also, any supplements or foods not to take during treatment? Anything else to take (e.g. activated charcoal)?

    Any insights would be greatly appreciated. Thanks very much community!

    AJ

    ReplyDelete
    Replies
    1. Hi AJ,

      Good to hear your suspision of too much of these opioid like peptides indeed seems to be true (atleast you have a biomarker now that you can target, so in that sense it is good to know).

      Im assuming with L. Reuteri you mean the ATCC6475 strain (biogaia gastrus)? I have used this one and only had mild acute effects and required higher dosing than the 1-2 blister packs tablets a day (very pricey to do 6-8 tablets a day).
      I do strongly agree this strain holds ALOT of promise however my fear is that it is very poorly colonized and I think this is the problem :(, if there would be a prebiotic that specifically enhances the colonization of this probiotic then synergism between the 2 might colonize the strain (again this is very complex and might be impossible to achieve).

      This might be very interesting for you:
      Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring (they used reuteri)
      http://www.cell.com/cell/pdf/S0092-8674(16)30730-9.pdf

      Article shows that reuteri can restore oxytocin and dopamine transmission in the VTA and restore social interaction (ginkgo also increases dopamine in the VTA and contains a prolyl endopeptidades inhibitor)

      Species Whose Abundance Is Reduced in the Gut Microbiota of MHFD Offspring
      http://www.cell.com/action/showFullTableImage?isHtml=true&tableId=tbl1&pii=S0092867416307309

      My main success was hands down with Clostridicum Butyricum (the butyrate producing strain, I suspect this strain is good at colonizing itself, it has been used in Japan since 1940!), results: perfect stools (wiping takes longer than sitting on the toilet), elimination of constipation, elimination of bloating, gaba like calmness and openess on mood.
      Been taking anywhere from 1 of the tiny pills 3 times daily after a meal all the way up to 12 pills 3 times daily (so totalling 36 pills yes), I definatly found the positive effects to become prominent at 3x daily 6 pills after meals and higher.

      My symptoms prior to its use were:
      Bloating, gas, constipation (never had loose stools!, only caffeine/coffee would losen stools, but the stools would quickly return to baseline=stools hard as rock), poor mood (pretty sure this was due to bloating/stomach discomfort).

      I have ordered clostridicum butyricum once again as I felt that some the effects of it has been somewhat permanent for me and I want to see if I can reap more benefits from using it (read my other posts about it), it takes about a month to arrive usually to my home as it comes from japan with regular post, so I will start taking it after im done with 45 day testing period on cordyceps and inositol and will update my bloodtest at early december to see if my urea has come down even more :D.

      Ive also ordered these:
      https://nl.iherb.com/pr/p/74623
      https://nl.iherb.com/pr/p/74618

      Together these offer a good dose of DPP-IV and Lactase.

      Im planning on using clostridicum butyricum first around half december and possibly adding these 2 enzyme supplements in addition to see if there would be some synergism going on.

      Honestly I would be very carefull with giving grapefruit seed/any form of grapefruit (power cyp3a4 inhibitor and can powerfully increase blood levels of alot of medications).
      Personally I avoid any form of grapefruit like the plague.

      Delete
    2. AJ here is some more information for you showing how powerfull butyrate actually is:

      Some possibly interesting clostridicum butyricum information for you:

      Neuroprotective Effects of Clostridium butyricum against Vascular Dementia in Mice via Metabolic Butyrate
      http://downloads.hindawi.com/journals/bmri/2015/412946.pdf

      "Interestingly, in this study, after the C. butyricum treatments, there was SIGNIFICANT RISE OF BUTYRATE CONTENT IN THE FECES AND IN THE BRAINS. A rise of butyrate content in the brain may be another mechanism of C. butyricum against VaD in mice."

      Now as we know, butyrate is a HDAC-inhibitor, very strongly affect gene expression, increase oxytocin, modulate inhibitory/excitatory balance.

      Histone deacetylase inhibitors facilitate partner preference formation in female prairie voles.
      https://www.ncbi.nlm.nih.gov/pubmed/23727821

      "This was associated with a specific upregulation of oxytocin receptor (OTR, oxtr) and vasopressin V1a receptor (V1aR, avpr1a) in the nucleus accumbens (NAcc), through an increase in histone acetylation at their respective promoters"

      Histone Deacetylase Inhibition Induces Long-Lasting Changes in Maternal Behavior and Gene Expression in Female Mice
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138561/

      "We report that HDACi treatment induced long-lasting changes in maternal responsiveness."

      Sodium butyrate attenuates social behavior deficits and modifies the transcription of inhibitory/excitatory genes in the frontal cortex of an autism model.
      https://www.ncbi.nlm.nih.gov/pubmed/26577018

      "Therefore, transcriptional modulation by sodium butyrate may have beneficial effects on autism related behaviors."

      Chronic treatment with valproic acid or sodium butyrate attenuates novel object recognition deficits and hippocampal dendritic spine loss in a mouse model of autism.
      https://www.ncbi.nlm.nih.gov/pubmed/25240644

      Now something I would like to add is that apparantly sodium butyrate itself is somewhat poorly available in humans, so it would make sense to make an effort to try and permanently colonize this clostridicum butyrate strain.

      Delete
    3. AJ, I second what aspie says about grapefruit seed extract. I love oil of oregano for bacteria, also the nigella oil you are using might help - maybe at a higher dose. It might also help if you try just a brief elimination diet of the offending foods, it can bring down inflammation starve out some of the bad microbes a bit, and you won't need all of these slash and burn style antimicrobials. I remember you commented on how your daughter loves her milk and cookies. That is usually the sign for my son, when he craves something so much, it is the exact thing that is bothering him. Oh and don't forget the berberine :) That could help. But i bet if you can remove the offending foods just for a bit, and bring down inflammation, that might help with getting the bad bugs better under control. Of course, if it ever gets to a SIBO situation, then slash and burn, you must do. Just some ideas.. Good luck!

      Delete
    4. Hi Aspie and Tanya!

      Aspie - First of all, a BIG thank you for all of the great information you provided!

      With respect to the L Reuteri, the product I'm using is:

      https://bioamicus.com/product/bioamicus-reuteri-2/

      It's the same as the BioGaia, but I find that this brand ends up costing me less due to shipping.

      I looked up Clostridium butyricum based on your comments and the research you've quoted and wow, this does seem like a great option. So much so that I just ordered some, to give to my daughter during and after the slash and burn period (i.e. antibiotic / antifungal / Anti-yeast meds), in the hopes that they replace the bad bugs. To your point, there are so many positives from butyrate, and since its poorly bioavailable, having the bugs in her GI tract constantly producing it could have a good effect.

      Your point about grapefruit affecting absorption of other meds / substances is a great one. I won't use the grapefruit seed supplement for that reason.

      Again, Aspie, I genuinely appreciate your input. Based on your comments I will add a C Butyrate probiotic and will not use grapefruit seed. I think both of these will be very beneficial to us.

      Have a wonderful day my friend, and I'll keep you posted!

      Tanya - As always, I really appreciate your input. Yes, my daughter loves her milk and cookies, and also goldfish crackers, so weaning her off those will be a challenge, but one we must do. I'm actually going to try to replace her milk with a Pea / Artichoke Protein powder that is Vanilla flavored, and may do gradually so that she doesn't notice the change until what she's having at bedtime is 100% Pea protein.

      I'm also going to change her favorite cheese pizza to a gluten free crust and Daiya cheese pizza - we'll see how she reacts...

      I also appreciate the point about grapefruit - yes, it can be a dangerous product to use so I will not use that.

      Oh, I would love to use berberine ... boy does it taste awful :) I'll have to wait until she can take capsules, she would never forgive me if I put this into her juice

      Finally, I have never used oil of oregano but I just read up on it, and it sounds like a perfect complement to the antibiotics and Nystatin.

      Tanya, I really appreciate your input, and I'll keep you posted on how we do with our effort to eliminate the bad bugs, and replace them with the good bugs.

      Have a wonderful day Tanya!

      AJ

      Delete
    5. No problem AJ,

      I would however like to point out that the study uses the very specific strain L. Reuteri ATCC-PTA-6475.
      This one is only available from biogaia, they patented it, therefor it is impossible to purchase it from another company.
      It seems to me that this bioamicus website is either a fraud or they have not even read the entire study themselves and have just used a random reuteri strain
      The study clearly says they used the ATCC6475 strain!
      http://www.cell.com/cell/pdfExtended/S0092-8674(16)30730-9

      screenshot of the pdf with proof they used ATCC 6475, not just any random strain:

      https://ibb.co/j3HctG


      Nowhere on the website of bioamicus they lists that their product contains the specific atcc6475 strain of L. reuteri, they seem like a fraud to me...
      Have you contacted them about this yet AJ? If not I definatly will as it is absurd and they are misleading people!

      Delete
    6. Hi AJ,

      Yesterday my 3 digestive enzyme supplements arrived:

      Enzymedica Digest gold with ATPro
      Enzymedice Digest spectrum (the one with DPP-IV)
      Source Naturals Bromelain 2000gdu/gram

      Now I took 1 digest gold and 2 digest spectrum with breakfast and I noticed that after finishing my breakfast I did not have the typical 'food/insulin crash' that I normally somewhat get after eating (keep in mind the crash I describe has allready improved 80% or so throughout the last 2 years).

      Now, about 2 hours later I decided to take the bromelain (500mg = 1000GDU without food yes, but this is also a way to take it according to the internet and on the label), I noticed a somewhat odd feeling in my head about 10minutes after taking it and about 30mins later I definatly felt somewhat different (not necesarry in a bad way though, hard to put into words).
      I also noticed WAY more mucous and the urge to scratch my legs a dozen of times (which I normally rarely do).

      Now the odd feeling in my head I never thought about after it passed and I carried on with my day.

      Lunch:
      Again 1 digest gold and 2 digest spectrum, again no stomach discomfort at all afterwards (I was eating bread for that matter which I normally rarely do as a way to test it).

      Then at around 5pm I took another bromelain 500mg=1000GDU and a few minutes later I again get this weird feeling in my head and mild ear pressure.

      Now at 8pm ish my time I keep getting pressure around my ears and my ears are starting to hurt a little (not awefull much).

      It seems to me that it is most likely the bromelain giving me the herxheimer reaction (I had the same with olive leaf extract and I didnt made the connection at the start and ended up getting incredibly depressed weak and a strong aversion for every type of food).

      So tomorrow Im dropping out the bromelain as Im pretty sure this is giving me a die-off reaction (not sure if continueing could actually be benefical though?).
      Either way I cant really afford to get sick with my job and all...

      I found this by the way:

      Placebo-controlled randomized clinical trial on the immunomodulating activities of low- and high-dose bromelain after oral administration - new evidence on the antiinflammatory mode of action of bromelain.
      https://www.ncbi.nlm.nih.gov/pubmed/22517542

      Seems to effect the circadian immune system function? not sure what to exactly make of that but it seems like it can powerfully modulate it.

      https://selfhacked.com/blog/bromelain-benefits/

      Also it seems to be possible to be allergic to bromelain according to many websites resulting in symptoms such as headache, fever, itching, nausea, etc

      Delete
    7. Seems this is the reason I had the response I described from bromelain:

      https://jonbarron.org/article/proteolytic-enzyme-formula

      Theres a huge difference between taking bromelain with food vs in between meals!
      For those interested in this it is a good video and shows how important it is to decide to take it with or without food.

      Delete
    8. Hi Aspie,

      Good news on starting your digestive enzymes.

      Yes, keep me posted on any interesting findings.

      It's interesting you mention the die-off reaction, as that is something I am definitely going to keep my eyes on.

      By the way, I read that Coconut Oil may be helpful with Candida so I have ordered some.

      I'll keep you (and the board) posted on my efforts with prescription and non-prescription methods to beat the candida and clostridia, but check out coconut oil as that seems to have many benefits.

      Have a great day Aspie!

      AJ

      Delete
    9. No problem AJ,

      I have stopped the bromelain today and the symptoms I had yesterday are decreasing (still taking the digest gold and digest spectrum and eating bread!).

      Coconutoil i tollerate very well, never any stomach discomfort from that, only positives from that, aswell as olive oil and goat cheese (high butyric acid fat source).

      Delete
    10. Hi Aspie!
      Did you stop the olive leaf extract because of your reaction, or did you push through (if that is possible) Could it have been an effect of low blood pressure instead of herxheimer?
      Is you immune system generally on overdrive or the other way around?
      I would appreciate some advice since I am planning an olive leaf extract trial soon.

      /Ling

      Delete
    11. Hi Ling,

      I stopped it after about 3 weeks or so (keep in mind this was around 4 years ago), it made me horribly depressed, gave me general weakness, increased obsessions, anxiety, was scared to go out on the street and had the same pressure around my ears/sinusses build up just like I was having bromelain 2 days ago.

      I was taking olife leaf extract to try and help bring my thyroid levels up (t4 was in the medium range then, but t3 was kind of low and olive leaf can help do this conversion) aswell as for the blood pressure lowering effects (which taurine and NO-boosters seem to take great care off - im actually normotensive now and I used to be pre-hypertension for nearly a decade!).

      Back to bromelain: So I took 1000GDU twice daily BETWEEN MEALS (so 2000GDU total) and that gave me the same earpressure/earpain/nasal /sinus problems as olive leaf extract also started with.

      Today Ive decided to give it another go and this time WITH MEALS!, I can actually hear? my stomach working now when I took it with food and no earpain coming up yet or so but ill update it by the end of the day.

      Found this by the way:

      Dose-dependent induction of IL-6 by plant-derived proteases in vitro
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1809566/

      "The production of IFNγ and IL-10 was not altered by bromelain or papain, indicating a selective and differential immune activation. Both proteases impaired cytokine stability, cell proliferation and expression of cell surface molecules like CD14 only marginally, suggesting no impact of these mechanisms on protease-mediated cytokine release. These findings might provide the mechanistic rationale for the current use of proteases in wound healing and tissue regeneration since these processes depend on IL-6 induction."

      Seems bromelain works by enhancing il-6, now as we all know il-6 is often high in autism and myself included I believe, so this is a bit trial and error for me aswell hence being very carefull with it, I want to see how body responds to it.

      As I stated in my post 2 days ago I did noticed I felt somewhat 'different' thought not in a bad way the day I took bromelain between meals.

      It could have been that I was experiencing increased PGE2, induced by il-6.

      Seems I was right about bromelain affecting sinusses:

      https://examine.com/supplements/bromelain/
      "Bromelain may reduce complications with acute sinusitis known as a 'stuffed nose' to a greater extent than placebo.[54][55][56] One study conducted noted that 83% of persons using bromelain had reductions in nasal inflammation as compared to 52% of the placebo.[57] Bromelain appears to reduce the length it takes to alleviate sinusitis significantly, yet combining bromelain with traditional therapy for sinusitis appears to reduce the efficacy of both."

      Delete
    12. Something very interesting I have just found regarding interleukin-6, as I allready knew, balance is the key and people still do need il-6:

      Enhancing influence of intranasal interleukin-6 on slow-wave activity and memory consolidation during sleep.
      https://www.ncbi.nlm.nih.gov/pubmed/19546306

      "To test this hypothesis, we compared effects of intranasally administered IL-6 (I guess they took it intranasally because it gets into the brain easily then???) (vs. placebo) on sleep-dependent consolidation of declarative (neutral and emotional texts, 2-dimensional object location) and procedural (finger sequence tapping) memories in 17 healthy young men. IL-6 DISTINCTLY IMPROVED THE SLEEP-RELATED CONSOLIDATION OF EMOTIONAL TEXT MATERIAL (P<0.03), which benefits mostly from sleep in the second night-half, in which rapid eye movement sleep (REM) dominates the non-REM-REM sleep cycle. During this second night-half, the amount of electroencephalogram slow-wave activity (0.5-4 Hz) distinctly increased after IL-6 (P<0.01). Other types of memory were not affected. The ability of IL-6 to ENHANCE SLEEP-ASSOCIATED EMOTIONAL MEMORY CONSOLIDATION highlights an example of a functional interaction between the central nervous and immune system."

      Delete
    13. Forgot to add this Ling, yes I do believe my immunesystem is overactive.

      Delete
    14. Took 2 tablets of bromelain again yesterday, one with breakfast the the other one 30minutes before dinner, no bad negative effects yet.

      Delete
    15. Hi I also received clostridicum butyricum fro Japan awhile back, but was a bit concerned giving the tablets to my child as they contain talc. Am I just being paranoid?

      Delete
    16. Honestly they felt very easy on the stomach for me, you got to give them AFTER meals by the way unlike most other probiotics which are best absorbed on a somewhat empty stomach like 30mins before a meal.

      Delete
    17. Ive stopped the bromelain by the way, it kept giving me headache like symptoms and a stiff neck/shoulders, felt very tense.

      Luckily the effect that bromelain had on me quickly vanished also.

      Delete
    18. Aspie,

      what you describe could easily be caused by "silent reflux" (LPR), and bromelain is known to cause reflux in some people.

      Both stiff neck and headaches have been described as possible symptoms of reflux - both the classic heartburn type GERD and the 'silent' LPR reflux.

      Imo LPR could be a massive problem in autism in general, causing many periodic symptoms and behaviours.

      One thing it does not cause, most of the time, is heartburn (hence 'silent), so it is hard to pinpoint.

      Delete
    19. Hi Nat,

      Thanks for your view on it, Im not exactly sure what causes the unwanted effects in me, but bromelain is able to induce il-6.

      Another possibility for my response could be an allergic response to bromelain (this happens a fair bit apparantly).

      Im not exactly what a silent reflux is, I had just used google, but I doubt that was the problem.
      Also I used to have very low stomach acid in the past, at some point I was taking 15 pills of betaine hcl (the 650mg ones per pill!!!) before each meal for the first 2 days, then gradually dropping them and eventually now I get a 'burning' feeling if I take 2-3 before a meal (I test this with my my half remaining bottle like once per 2 weeks, to get a rough indication what my hcl levels are like).

      Delete
  8. Hi everyone,

    I was wondering for those of you whose children are on prescription drugs (bumenatide, verapamil, etc.), who prescribed them? Is it a regular pediatrician/GP or a specialist?

    ReplyDelete
    Replies
    1. Jolene, this varies greatly and depends where you live. In the US some people have a very open minded GP who will prescribe these things. In other countries like the UK no doctor will prescribe any of these things. Some people are buying them on-line without a prescription. In some Latin countries (Spain, Mexico etc) you can buy these things in the pharmacy without a prescription.

      I think some people get them from their MAPS/DAN doctor.

      Delete
  9. Speaking of aspirin and the BBB, here is another way of addressing myelination in the brain, perhaps with aspirin:

    Press Release:

    https://www.sciencedaily.com/releases/2017/11/171102124907.htm

    Paper:

    http://www.cell.com/neuron/fulltext/S0896-6273(17)30976-5?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627317309765%3Fshowall%3Dtrue

    The gist of this paper is that a protein called fibrinogen which is integral to blood clotting, will seep into the brain if the blood brain barrier is compromised. Decreasing levels of fibrinogen or at least blocking its entry into the brain may be a therapeutic method of remyelinating damaged white matter tracts in diseases like Multiple Sclerosis and some autisms.

    Fibrinogen can be acetylated with high dose asprin (650mg 2x per day), but this is probably a very risky way to beef up myelination due to the anticoagulative properties of aspirin. The other idea is to simply improve blood brain barrier function which seems to be compromised in autism for any number of reasons so that fibrinogen from the peripheral blood supply does not make it into the CNS where it promotes inflammation and retards myelination.

    ReplyDelete
  10. Excellent post Peter,

    Alot of the supplements I used and had success with either reduce urea, offer neuroprotection, increase cerebral bloodflow, increase nitric oxide and are used in vascular dementia (could it be that drugs/supplements for vascular dementia are just tweaking our impaired systems? which would be good anyway)
    It turns out after reading your post most of the supplements I have had success with are also OAT3-inhibitors.
    I have tried both GCE (green coffee extract), Chocamine (patented cocoa extract) and egb761 (patented ginkgo extract) in the past and found these were indeed helpfull (mainly coginitive enhancement)

    GCE (45% chlorogenic acid) in addition to a coffee, reduced the jitters and gets rid of the famous 'caffeine crash' for me.
    By itself it feels somewhat calming yet stimulating at the same time, it is a very healthy as Peter allready pointed out, and I wouldnt be suprised if alot of the health benefits that have been associated with coffee drinking is actually linked to compounds such as chlorogenic acid in coffee (roasting of beans pretty much destroys most of it btw).
    On top of that the mental and physical benefits regarding green coffee extract/chlorogenic acid are actually backed up by science, these include:
    * increased cortisol ->cortisone conversion (this is good, cortisol is far more active than cortisone)
    * healthy weight managment, body fat reduction, blood pressure lowering ability
    * mental wellbeing and neuroprotection

    Cognitive and neuroprotective effects of chlorogenic acid
    http://www.tandfonline.com/doi/abs/10.1179/1476830514Y.0000000146?journalCode=ynns20

    Effect of green coffee bean extract and chlorogenic acid consumption on 11βHSD activity in humans and mice
    http://www.endocrine-abstracts.org/ea/0019/ea0019p122.htm

    "In conclusion, GCBE decreased urinary cortisol and cortisone excretion in overweight subjects but CGA did not significantly inhibit 11βHSD1 activity in mice in vivo. Treatments lowered blood pressure and triglyceride levels. Further research into the mechanism(s) of these beneficial effects is required."

    Consumption of Green Coffee Reduces Blood Pressure and Body Composition by Influencing 11β-HSD1 Enzyme Activity in Healthy Individuals: A Pilot Crossover Study Using Green and Black Coffee
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123567/

    "Cortisol/cortisone ratio (indicating 11β-HSD1 activity) was reduced after Green Coffee (from 3.5 ± 1.9 to 1.7 ± 1.04, P = 0.002)."

    The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: a placebo controlled, crossover, acute trial
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534492/
    "SIGNIFICANT INCREASES IN REGIONAL PERFUSION across the brain were observed following consumption of the high flavanol drink relative to the low flavanol drink, PARTICULARLY IN THE ANTERIOR CINGULATE CORTEX and the central opercular cortex of the parietal lobe."

    According to wikipedia:
    https://en.wikipedia.org/wiki/Anterior_cingulate_cortex

    "It appears to play a role in a wide variety of autonomic functions, such as regulating blood pressure and heart rate.[citation needed]
    It is also involved in certain higher-level functions, such as reward anticipation, decision-making, ethics and morality, impulse control,[1] and emotion.[2][3]"
    Very interesting to see that the supplements I benefited from actually also turn out to be OAT3 inhibitors!!!

    Also what about doing a multidimensional approach to OAT3-inhibiting for bumetanide like a combination of a low dose of:
    ginkgo, cocoa, green coffee extract instead of a high dose of a single compound?

    ReplyDelete
  11. For those interested, this study completed in 2017 shows the effect of 172 plants extracts on OAT1 and OAT3 inhibition:

    Interactions of 172 plant extracts with human organic anion transporter 1 (SLC22A6) and 3 (SLC22A8): a study on herb-drug interactions.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446775/

    ReplyDelete
    Replies
    1. It is a long list, but in practical terms I think the standardized chlorogenic acid (green coffee) is the best OTC choice to see if produces a meaningful (probably modest) effect.

      It is clear that probenecid will have an effect. The only question is how much would produce a moderate effect.

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  12. Peter,

    With regards to one of my last replies where I stated that NO-donors/bloodthinners/micro bloodflow enhancers/medication against vascular dementia seems to be 'tweaking' our impaired system I have been digging deeper and it seems that atleast for me personally that the substances that I had success with are actually things that stop my overanalyzing.

    Now, it has come to my attention that more and more evidence is pointing towards the default mode network, atleast that is for the social response/finding the soul within/connecting with others and empathy.

    Also the type of supplements/drugs that I seem to prefer are usually the ones that seem to calm down my analytical thoughts (inositol-used in ocd, cordyceps-calming/relaxing, damiana-surrendering/calming, however not any random benzo or calming substance does the trick).
    As you can see coginition is the least of my problems and infact it seems to be the reason thats holding my brain back from experiencing joy and emotions properly, my over analyzing seems to keep my emotional centers 'offline'.
    Skullcap also seemed to help me with overanalyzing.

    https://en.wikipedia.org/wiki/Altered_state_of_consciousness
    https://en.wikipedia.org/wiki/Default_mode_network

    Can you please make a post about this subject.

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    Replies
    1. Without delving into the pseudo-scientific realm of psychology and how it may intersect with neuroscience, you need to be careful whenever you read anything about "The Default Mode Network" in some ezine or newspaper like The New York Times, because at best they simplify and trivialize things for their readers, and at worst they are super wrong.

      The "Default Mode Network" is kind of a squishy idea of what the brain seems to be doing when it is doing nothing else which historically was the first MRI network discovered from the naked eye observation of a neurologist that in many of his patients/subjects that when they were not doing an active task (which at the time was thought to be more metabolically engaging than resting), their brain was far from silent. This is now known to be false as neurons are active all the time, even when they are not directly participating in so-called network activity. The only neurons that don't engage in spontaneous activity are dead neurons. Also, it was previously thought when sleeping that the brain goes into a quiet mode where it does not do much and this is also false, especially during REM sleep. Many things happen in sleep but neurons don't just shut down or sleep themselves. Housekeeping processes may be enacted but that is like saying taking a break from watching the kids to go do the laundry is rest from parenting duties.

      So, there are a bunch of studies from the lab of a neuroscientist named Jessica Andrews-Hanna and here is one of her several papers (or rather that of her lab team) that might interest you here:

      https://www.ncbi.nlm.nih.gov/pubmed/21677128

      I have probably read just about all her papers now as it is necessary for getting the answers to for a project I have been doing for the last several years (is autism related). One major theme (and she is not the only researcher on the subject) is the "Default Mode Network" is actually several different networks that seem to pop up during different spontaneous mentalizing activities, and not just "daydreaming" as it has been popularly associated. Jessica Andrews Hannah originally segmented the DMN into three separate major DMN subnetworks, but a more recent paper I read I believe had even more than that.

      Delete
    2. Though there have been many papers looking at the DMN and autism and the idea of the posterior cingulate cortex not being able to disengage from the DMN which leads to an imbalance of internal mentating as opposed to externally responding to the world (including people), in the many studies looking at resting state differences between autism and controls, the salience network is the one that pops up the most as the salience network is thought to be involved in disengaging the default mode network and switching it over to the frontoparietal control network (also called the central executive network). The core nodes of the salience network which are the anterior insula and anterior cingulate cortex seem to be quite hyperactive in autism. There are many speculations as to why this seems to be the case, but one reason could be these regions have a type of neuron only found in humans called the Von Economo neuron which is special because it only has one big dendrite (i.e. one input), whereas most pyramidal neurons have many dendrites. It is thought by some that this type of neuron's mechanics make it suitable for boosting long-range signals to distant parts of the brain which is a networking challenge for humans with our big brains and heavy myelination.

      Emotional deficits in autism are connected to many areas of the brain, with the amygdala being chief among them and an area that is likely a better candidate for pharmatherapy than the cortical areas which are more of a mixed bag. Dopamine pathways involving social reward in the nucleus accumbens also seem to be lacking in autism.

      Nevertheless, at least for lateral cortical areas such as the tempoparietal junction (thought to be dysfunctional in autism, and especially Aspergers), you can target it with rTMS which some with autism and aspergers have claimed benefited them, though rTMS's use clinically is kind of Wild West territory at the moment.

      Last but not least, smarter people tend to be less overtly emotional as intelligence is associated with prefrontal inhibition and inhibiting emotions is a skill most people learn throughout childhood until they become an adult. Emotion is a tool to manipulate people, though unless you are gaming someone it is generally done unconsciously. There is of course a difference between inhibiting emotions and having no emotions at all, but I don't think not being a crybaby should be considered a cognitive deficit. Also, a recent study on "happiness" in the United States showed that people who are married and have extreme views (left or right) were the happiest, presumably because they felt righteous in everything they did and agreed with each other on everything which only reinforced their existing views in being righteous. Of course in my experience people who have extreme views, happy or not, are not the kind

      Delete
  13. Peter and Tyler, hope you can see my comment, do you think that the homovanillic ácid test is useful to know about muy son's dopamine imbalance? Valentina

    ReplyDelete
    Replies
    1. Valentina, I think you would need to measure HVA in your son's spinal fluid. That is what was done in the papers I reviewed here:-

      https://epiphanyasd.blogspot.com/2017/02/secondary-monoamine-neurotransmitter.html

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    2. Ok Peter,thanks,I had this doubt,so,I think what is worth doing in urine is the organic acid test,here it doesn´t include HVA and VMA.I will do it tomorrow. Nevertheless,measuring HVA in my son´s spinal fluid would be the best test I could do for him, but he couldn´t stand the procedure. Valentina

      Delete
  14. I came across an interesting paper on aging that discusses at the end how resveratrol impacts ERK signaling (inhibition):

    Press Release:

    https://www.sciencedaily.com/releases/2017/11/171107113145.htm

    Paper (Open Access):

    https://bmccellbiol.biomedcentral.com/articles/10.1186/s12860-017-0147-7

    I of course knew about resveratrols impacts on mTOR but its impacts on ERK1/2 I either did not know or totally forgot about when I first read about (not sure which). I would not say resveratrol is a popular autism supplement, but it is not exactly rare either.

    Nevertheless, the easiest to go down variety of resveratrol I have found over the years (used to drink this myself before going to pills) is this product:

    https://www.amazon.com/s/?ie=UTF8&keywords=resvinatrol+complete+liquid&tag=googhydr-20&index=aps&hvadid=177842010387&hvpos=1t1&hvnetw=g&hvrand=5701671207080364487&hvpone=&hvptwo=&hvqmt=e&hvdev=c&hvdvcmdl=&hvlocint=&hvlocphy=9014968&hvtargid=kwd-35792501072&ref=pd_sl_1ydcrmvzi2_e

    You can water it down with soda or water if the grapeish taste is too strong (it does not taste bad but for some people it might be necesary).

    Thee is some debate about how well resveratrol is absorbed orally and its half-life in the body (the half-life is quite small, but its metabolite called resveratrol sulphate in one study was suggested to be more potent than resveratrol itself), but in my opinion I think it is a good aging supplement and perhaps one not given quite enough attention for autism.

    ReplyDelete
    Replies
    1. Resveratrol and its longer acting analog Pterostilbene (from blueberries) have very confusing action. Just today there was a news about Resveratrol reversing aging and extending life primarily due to its activation of telomerase. Pterostilbene does it even more potently. But you can find an equal amount of papers reporting the inhibitory effect of Resveratrol and Pterostilbene on telomerase. The same is true regarding ERK pathway. Here is the problem: if you want longevity, you need to activate telomerase, but that causes cancer to grow. That is why novel anticancer drugs are targeting inhibition of telomerase. So, longevity vs cancer. Make your pick. There is probably a good reason why the older we get the slower our telomerase is: the body protects itself from cancer.

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    2. Telomeres and telomerase are relatively recent discoveries in science. Their function can only be discerned in the most general of ways at this point. In a study I read in the last year, overexpression of telomerase which caused longer than normal telomeres in cells genetically modified to overexpress telomerase caused the DNA in the cell, or rather the entire chromosome to become unstable when it was copied so that the DNA would literally break apart as if it were some very brittle substance if my memory serves me correctly. Obviously there is a goldilocks zone here as there seems to be with many aspects of autism that are perturbed.

      Also comparing resveratrol and pterostilbene is like comparing apples to carrots in terms of their function even though some people purport the myth that pterostilbene is just a superior for of resveratrol.

      Delete
  15. Has anybody tried injections of Cerebrolysin?

    ReplyDelete

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