Suramin - Why do Clinical Trials in Autism Struggle to be Convincing? And Oxytocin fails in a large trial.

 

Results from the PaxMedica trial of Suramin

For me, Bumetanide for Autism is now ten-year-old news, for us it has been working since 2012; the next interesting drugs in the pipeline include Suramin and Leucovorin.

It is extremely difficult to trial Suramin at home, or indeed anywhere, and this makes it ever more desirable to many parents.

Leucovorin (calcium folinate) is easy to obtain; you can even buy liquid calcium folinate from iHerb.  You can find out pretty quickly if it produces a profound benefit on your child’s type of autism.

I wish Dr Frye and Professor Ramaekers good luck with the phase 3 trial of Leucovorin.  It certainly works for our adult reader Roger, but not for my 18 year old son, Monty.  Our reader SB’s child recently joined the group of confirmed responders.

After I started writing this post, the results came in of a large (250 children) trial of intranasal oxytocin.  This trial failed to show any benefit, over the placebo, in increasing social behaviors in autistic children. As I have mentioned previously, there is an inherent problem with intranasal oxytocin, the hormone has a very short action, its half-life is 2-6 minutes. It would be much more effective to provide a sustained release of oxytocin, which can indeed be achieved via adding a specific bacterium to the gut. The other problem with intranasal delivery is that you are not supposed to inhale the drug into your lungs, it has to stay in upper part of your nose. How likely is it that parents/children use the spray correctly?  There is even a special dispenser developed for drug delivery to the brain, but did they use it?

In my trials of L. reuteri DSM 17938 it was obvious that the oxytocin improved social behaviors, but I concluded that this was not such a big deal and certainly was not a treatment priority. How would you assess the effect? Very simple, you just count how many times your child is shaking boys’ hands and kissing the girls. I don’t suppose that was the measurement that Duke University used.

Many parents do use Syntocinon nasal spray and this failed trial does not mean they are imagining the effects.  If I was them, I would try L. reuteri DSM 17938 and compare the effect and use whichever is the most beneficial.

  

Suramin 

Suramin is moving towards its Phase 3 clinical trials and, very unusually, two different companies are trying to commercialize the same drug.  One company is PaxMedica and the other is Kuzani, who are ones that cooperate with Dr Naviaux.

In the background is Bayer, the German giant, who have been making Suramin for a hundred years as a therapy for African sleeping sickness and river blindness.  We are told that making Suramin is quite difficult, it is a large molecule; but if they could make it a century ago, how difficult can it really be?  The reality appears to be that Bayer do not want to supply PaxMedica or Kuzani and so they will have to figure out how to make it.  Suramin is sold as a research chemical, but there seem to be questions about its purity. The very cheap Suramin sold on the internet is very likely to be fake.

Today we will look at the data from the South African trial carried out by PaxMedica and take a look at their patent for their intranasal formulation.

We have heard very positive anecdotal reports from the very small initial trials carried out by Professor Naviaux.  Naviaux himself is very interesting, because even though he is not an autism researcher, he is far more knowledgeable than almost all of them on the subject of autism. If you read his papers, they show a rare global understanding of the subject.  This “big picture” is what you need to understand such a heterogenous condition as autism.

In the PaxMedica trial, 44 children completed the trial, so that should be enough to tell us something insightful about whether this drug is effective.

A recurring problem in all autism trials is how well the placebo performs.  Here again in the Paxmedica data we have a very impressive blue line – the placebo.  It is just salt and water and yet it is nearly as good as the trial drug (the orange line).

 

A big part of clinical trials is the statistics used to validate them.

Although I do have a mathematical background, I believe in “seeing is believing”.  The data should be crying out to you what it means.  If it is so nuanced that it needs a statistician to prove the effect, there likely is no effect.

In the above chart we want to see a decreasing slope that would possibly level off as the drug achieved its maximum effect.

What we see are two apparently effective therapies, blue and orange. 

The problem is that blue line is just water, with a bit of salt.

 

Show me the data

What we really want to see are results of each of the 44 participants, not the average.

There are likely groups:

·        Super responders

·        Responders

·        Partial responders

·        Non-responders

 

No statistician is needed.

 

The data from the Suramin trial needs to be presented in the kind of form used in the stem cell trial below:-

Since many hundreds of different biological conditions can lead to an autism diagnosis, we really should not expect there to be any unifying therapy that works for everyone.  Indeed, we should perhaps be suspicious of any therapy claimed to work for everyone.

We always get to hear about the super-responders in anecdotal reports.

We heard great things about Memantine/Namenda, but the phase 3 trial was a failure.  We heard great things about Arbaclofen (R-Baclofen), but the phase 3 trial failed. In Romania our reader Dragos is currently seeing great benefits from the standard version of Baclofen (a mixture of R-Baclofen and S-Baclofen).

My son is a super-responder to Bumetanide, but I know that most people are not. However, when I came across the “bumetanide has stopped” working phenomena, it became clear that the situation is more complex than a single one-time evaluation. We know why bumetanide can “stop working” and how to make it “start working again”.  An increase in inflammatory cytokines from the periphery (i.e. outside the brain) further increases the expression of NKCC1 in the brain and negates the effect of bumetanide; reduce the inflammation and bumetanide will start to work again.

  

Why does the placebo always do well in autism trials?

The assessments used to measure outcome are all observational, they are not blood tests or MRI scans.  They are highly subjective.

It has been suggested that just being in an autism trial improves symptoms of autism.  The parents give more attention to the child and this then skews the results.

My way round this problem in my n=1 trials was always to tell nobody about the new trial I was making and wait for unprompted feedback.  This works really well.

 

 

Who chooses the trial goal (the primary endpoint)?

I like the fact that in the Leucovorin trial the goal is speech.  It is a very simple target and relatively easy to measure.

For Bumetanide, I did suggest to the researchers that they used change in IQ as an endpoint.  Nice and simple, start with kids with IQ<70 and then recruit those who have a negative reaction (paradoxical response) to Valium/diazepam.  Then expect an increase in measured IQ of 10 to 40 points.  Then you would have a successful phase 3 trial.    

In many previous trials that ultimately failed, some people did see a benefit, but they were different benefits.  I did get a reader telling me how great Memantine (Namenda) had been for her child, when I asked why she told me that it was the only therapy that had ever solved her child GI problems.  That certainly was never considered as a trial goal/endpoint.

In my trial of Pioglitazone, I read the research about both the mechanism of action and the observed effects listed in the phase 2 trial:

"improvement was observed in social withdrawal, repetitive behaviors, and externalizing behaviors as measured by the Aberrant Behavior Checklist (ABC), Child Yale-Brown Obsessive Compulsive Scale (CY-BOCS), and Repetitive Behavior Scale–Revised (RBS-R)."

I was targeting something entirely different.  Based on the mechanism of action, specifically the reduction of the inflammatory cytokine IL-6, I expected a reduction in summertime raging.  It worked exactly as hoped for. This is the second summer we have used it.

Our reader Sara’s initial assessment of the effect of Pioglitazone is focused on the improvement in sleeping patterns.  This is great, assuming the benefit is maintained, but it is an entirely different benefit.

 

Was the trial drug actually taken?

I suspect in the bumetanide trial, many parents did not give the trial drug every day, as per their instructions, because the diuresis was too much bother.  I know from reader comments and emails that many parents stop giving bumetanide, even though their child is a responder.  Some schools refuse to allow bumetanide because of the disruption caused by frequent toilet breaks.

Because Suramin is given once a month by infusion, there is 100% certainty that the drug or placebo was actually taken.  This is a big plus.

Was the intranasal oxytocin correctly administered in the recent trial? I doubt it.

The problem with Leucovorin is that in a minority of children is causes aggression, even if you follow Prof Ramaeker’s advice and very slowly increase the dosage.  In the phase 3 trial parents should be informed of this possibility and told to report it and be invited to withdraw from the trial.  If they just stop the therapy to halt the aggression, but their data remains included in the study, the results are invalidated.

 

Intranasal Suramin

Patents are often a good source of information and they do also tell you something about the people who wrote them.

Here below is PaxMedica's patent for intranasal suramin:-

Compositions and methods for treating central nervous system disorders

These results demonstrate that an antipurinergic agent such as suramin can be delivered intranasally to achieve plasma and brain tissue levels and that variations in the brain tissue to plasma partitioning ratio can be observed. These results demonstrate that an antipurinergic agent such as suramin can be delivered to the brain of a mammal by intranasal (IN) administration. 

The following Table 1 provides the averaged accumulated amount, in mg, of suramin that has penetrated as a function of time

But how can the accumulated level after 6 hours be less than after 5 hours?

The results of the study are also shown graphically in FIG. 1 where the cumulative amount (mg) of drug permeated was plotted versus time in hours. These data demonstrate that Formulation B containing methyl β-cyclodextrin (methyl betadex) provides significantly better penetration, versus Formulations, A , C, and D in the tissue permeation assay. Also, as is seen from a comparison of Formulations A and D, having a higher drug concentration can be advantageous to increasing permeation.

 

Formulation A - suramin hexa-sodium salt at 100 mg/mL in water (no excipients) Formulation B - suramin hexa-sodium salt at 100 mg/mL in water, with 40% methyl β-cyclodextrin (methyl betadex) Formulation C - suramin hexa-sodium salt at 100 mg/mL in water, with 40% HP (hydroxyl propyl) -cyclodextrin Formulation D - suramin hexa-sodium salt at 160 mg/mL in water (no excipients)

 

FIG. 7 shows a plot comparing the total percentage of suramin in plasma in mice when administered by intraperitoneal (IP) injection once weekly for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once per week for 4 weeks (28 days).

 

FIG. 8 shows a plot comparing the total percentage of suramin in brain tissue in mice when administered by intraperitoneal (IP) injection once weekly for 4 weeks (28 days), intranasally (IN) daily for 28 days, intranasally (IN) every other day for 28 days, and intranasally (IN) once per week for 4 weeks (28 days).

 

Does anyone think the above chart makes any sense? 

 

The mice were maintained in group cages (6 mice per cage based on treatment group) in a controlled environment (temperature: 2 1.5 ± 4.5 °C and relative humidity: 35-55%) under a standard 12-hour light/1 2-hour dark lighting cycle (lights on at 06:00). Mice were accommodated to the research facility for approximately a week. Body weights of all mice were recorded for health monitoring purposes.

The mice were divided into the following 5 test groups, with 6 mice per group.

Group 1: Intraperitoneal (IP) injection of suramin, 20 mg/kg, administered weekly to animals beginning at 9 weeks of age and continuing for four weeks (i.e. given at Age Weeks 9 , 10 , 11 and 12). The suramin was formulated in Normal saline solution.

Group 2 : Intraperitoneal (IP) injection of saline, 5 mL/g, administered weekly to animals beginning at 9 weeks of age and continuing for four weeks (i.e. given at Age Weeks 9 , 10 , 11 and 12). This was a control group.

Group 3 : Intranasal (IN) administration of a formulation, described below, of suramin, at a concentration of 100 mg/mL x 6 mL per spray, administered as one spray per nostril, one time per day, (interval of each application is around 2 minutes to ensure absorption) for 28 days (total of 56 sprays over 28 day period) beginning at 9 weeks of age (i.e. given daily during Age Weeks 9 , 10 , 11 and 12).

Group 4 : Intranasal (IN) administration of a formulation, described below, of suramin, at a concentration of 100 mg/mL x 6 mL per spray, administered as one spray per nostril, one time every other day, for 28 days (total of 28 sprays over 28 day period) beginning at 9 weeks of age (i.e. given once every other day during Age Weeks 9 , 10, 11 and 12).

Group 5 : Intranasal (IN) administration of a formulation, described below, of suramin, at a concentration of 100 mg/mL x 6 ml_ per spray, administered as one spray per nostril, one time every week, for 4 weeks (28 days) (total of 8 sprays over 28 day period) beginning at 9 weeks of age (i.e. given once weekly during Age Weeks 9 , 10 , 11 and 12).

 

This question was posed to me:-

A nasal spray in a human is about 0.1 ml, how do you give a tiny mouse 6 ml per nostril?  Even 0.6 ml looks implausible.

 

Conclusion

Will Suramin pass a phase 3 trial?  I think if it is trialed on a random group of 400 young people with moderate or severe autism, it will very likely fail.

Professor Naviaux believes Suramin may be a unifying therapy, one that works in all autism.  The results from the PaxMedica study do not support this.

PaxMedica has the data showing the individual results.  Are there super-responders? Are there non-responders? Does Suramin perhaps make some people's autism worse?  All we can see is the average response, which is marginally better than the placebo; not what we expected after seeing the initial study.

Expecting Suramin to work well for everyone is raising the bar too high.  Try and identify markers for the responders and super-responders and then limit the phase 3 trial to these people.

Is intranasal delivery of Suramin going to achieve a therapeutic level inside the human brain?  Hopefully yes, but it may not work.

Is long term use of Suramin going to be safe? Will it require ever-increasing doses? Nobody knows, and note that safety was the original concern when Suramin’s use was proposed by Naviaux.

Intranasal administration has the best chance of being totally safe.  Spend a little extra money on the clever dispenser covered in this old post, that keeps 100% of the drug in the right place.

 

https://epiphanyasd.blogspot.com/2015/09/opn-300-oxytocin-and-autism.html

 

Maybe get someone other than a lawyer, to proof read your patent.

 

 

Pentoxifylline – Clearly an Effective add-on Autism Therapy for some

 

They also had Pentoxifylline for autism back in the 1970s – time for a revival?

 

Pentoxifylline and other more modern PDE inhibitors have been mentioned many times in this blog.

https://epiphanyasd.blogspot.com/search/label/PDE4

https://epiphanyasd.blogspot.com/search/label/Pentoxifylline

Pentoxifylline has been used in autism clinical trials dating back almost 50 years. A casual observer would naturally assume it cannot possibly be effective, or else surely its use would have caught on by now.

Some readers have long been using a PDE inhibitor as part of their child’s autism polytherapy. People have been asking me to let them know my thoughts on Pentoxifylline, the most accessible PDE inhibitor.

I think the key is that we are talking about an add-on, or adjunct, therapy.  We are no longer talking about pentoxifylline therapy vs no therapy, as they were in the 1970s.  Even in those decades-old studies there was a sub group of “super responders”.  Either the percentage of such responders, or the “super-response” itself was just too small to create waves leading to wider adoption.

In my autism world, I had been trying to develop more expressive language using sulforaphane and calcium folinate (leucovorin). A comment from Valentina prompted me to finally start my trial of Pentoxifylline.  It became apparent that the amount of expressive language was increasing, but the major factor was the Pentoxifylline not the calcium folinate (leucovorin).  To avoid GI side effects, I give Pentoxifylline after meals, which means it does sometimes get omitted/forgotten. It emerged that expressive language was clearly correlated to whether Pentoxifylline was taken or forgotten.

Reviewing the old studies, increased use of language does get a mention as an effect of Pentoxifylline.

 

What is the biological effect of Pentoxifylline?

Pentoxifylline is a non-selective PDE inhibitor, which you might think is a bad thing, since it looks like is it just PDE4 that we want to inhibit.

Pentoxifylline is also a non-selective antagonist of adenosine receptors A₁ and A_2A that are located in both the heart and brain.  These two adenosine receptors have important roles in the brain, regulating the release of other neurotransmitters such as dopamine and glutamate.

Pentoxifylline is normally prescribed because of its effects on your blood.  It improves red blood cell deformability, reduces blood viscosity and decreases the potential for platelet aggregation and blood clot formation.  So not a bad potential drug for the effects of severe Covid (which causes "sticky" blood), or indeed the extremely rare negative reaction to Astra Zeneca’s vaccine reported in Norway.  I had my Astra Zeneca Covid shot last week and Monty will be having his. Even young children with severe autism have been vaccinated where we live, at the parents' insistence. It looks like crossing international borders is going to to be much easier with proof of vaccination, so even if you had the virus the vaccine is useful.  Most people we know have had the virus, since where we live public policy was more towards protecting livelihoods than lives.  A lack of obesity and very old people kept the death rate quite low.  Now we seem to have more vaccines than demand for them.

Studies show that Pentoxifylline increases blood flow to the brain.  We know that blood flow to the brain in autism is impaired; the research describes it as unstable rather than just weak.

It sounds like Pentoxifylline is a polytherapy in itself, it has so many effects possibly relevant to autism.

 

Are Ibudilast and Roflumilast/Daxas an alternative to Pentoxifylline?

This question has come up already in the comments section.

We know that Ibudilast and Roflumilast are much more selective for PDE4 than Pentoxifylline.  We know that both Ibudilast and Roflumilast have interesting effects on the brain.

Pentoxifylline has some potentially beneficial effects that are not shared by Ibudilast or Roflumilast.  Pentoxifylline is cheap and proven safe in a series of trials in young children. 

I think that the typical autism dose of Pentoxifylline, 200mg twice a day, likely does not provide the effect on PDE4 provided by the small dose of Roflumilast/Daxas used in trials to improve cognition and sensory gating.

I think you would need to trial the drugs separately and, if they indeed provide a benefit, find the effective combination.  

So far I have trialed the 100 mcg dose of Roflumilast/Daxas on myself to check for GI side effects and see if it affects how thoughts and sensory inputs are processed, as the research suggests it does. I think it does indeed have the cognitive effects, but in me personally the GI effects also appear.  Some readers have told me this 100 mcg dose works for Aspies, and without side effects.

Some readers have tried Ibudilast.

Ling favours Pterostilbene, a natural PDE4 inhibitor. Pterostilbene has many other modes of action, including relating to inflammation, diabetes, aging and even cancer.

  

Conclusion 

Polytherapy is becoming fashionable these days and it is about time too.  Here it is all about MS (Multiple Sclerosis):-

 

UK to test existing drugs as treatment for MS in world-first trial

“Ultimately, MS will be treated with a combination of drugs,” said Gray. “You’ll have immunomodulatory drugs and anti-inflammatory drugs that stop the immune attacks, and they will be combined with treatments that can protect nerves from damage, and treatments that can repair the damaged myelin. That should stop MS.”

 

Each drug, given individually, will not deliver a dramatic result, but in combination the effective can be substantial.

Autism also requires polytherapy.  A few small steps can take you a large stride forwards. 

I did once consider using the analogy of fixing an old car, but I thought people might not like it and also autism develops very early in life not at the end; but Professor Ramaekers used the analogy on me, so I will follow suit.

You may need to fix many things on an old car, to get it back to its former glory.  The more problems you fix, the better the result will be.  You just have to start and keep on going.

In autism, and car restoration, the order in which you fix things does matter.  You probably need to learn this the hard way.

In a near perfect car (Asperger’s) really small issues, like faulty electric windows or squeaky suspension, can be extremely annoying, though the car remains perfectly functional; it gets you from A to B.

Pentoxifylline, by itself, is not going to “cure” anyone’s autism, but for some people it will be another step in that direction.

 

Another old idea has resurfaced - sodium phenylbutyrate (shortened to NaPB).

I think this drug was used for completely the wrong reasons, by a tiny number of people, a decade ago, but now common mouse models of autism are showing that this pan-HDAC inhibitor and ER-stress inhibitor has potent beneficial effects.  It is changing gene expression via an epigenetic mechanism.

If you look on Google, it appears as another quack therapy.

Four autism treatments that worry physicians – LA Times in 2009

Four that worry physicians. The Chicago Tribune examined four treatments in depth. Medical experts said that the therapies have not been proved to help children with autism and that each also carries risks. 

#4 Phenylbutyrate

Kennedy Krieger Institute: “No research conducted into use for autism.” -- Trine Tsouderos and Patricia Callahan

 

https://www.chicagotribune.com/lifestyles/ct-xpm-2009-11-23-chi-autism-science-nov23-story.html

Patricia Kane, who calls herself "the queen of fatty acid therapy," initially sounds like a skeptic of alternative autism treatments. She distances herself from the Defeat Autism Now! approach and says hyperbaric oxygen therapy, IVIG and chelation drugs all can be harmful.

"If you could see what happens to children when they're given some of these crazy interventions that ruin their life, and it's so painful," said Kane, whose office is in New Jersey. "Parents say, 'Patricia Kane will tell us the truth,' and I believe parents deserve the medical truth when it comes to their children."

One of her fans is Kent Heckenlively, a California science teacher who writes for ageofautism.com, self-described as the "daily web newspaper of the autism epidemic." After spending "a couple of hundred thousands" on treatments, from chelation to stem cell therapy, for his daughter with autism, Heckenlively said Kane appealed to him in part because her protocol includes lab tests run by the prestigious Kennedy Krieger Institute.

"I can trust them, I think," Heckenlively said.

Kane, who points to neuroinflammation as a feature of autism, discusses Pardo's study in a chapter she co-wrote on autism treatments for the book "Food and Nutrients in Disease Management."

Kane says many children with autism have a buildup in their brains of a substance called very-long-chain fatty acids. Her "PK Protocol" -- named after her initials -- is aimed at burning them off with a prescription drug, phenylbutyrate, that is normally used to treat extremely rare genetic disorders in which ammonia builds up in the body.

Side effects of phenylbutyrate include vomiting, rectal bleeding, peptic ulcer disease, irregular heartbeat and depression. No clinical trials have evaluated this drug as an autism therapy, and the idea that very-long-chain fatty acids have a role in autism is not proven by science.

Kane is not a medical doctor. When treating children with autism, she says, she works in concert with the child's physician, who supervises treatment.

She said she holds a doctorate in nutrition that was issued by Columbia Pacific University, an unaccredited institution that was shut down after a lengthy court battle with the state of California. An administrative law judge in 1997 found that the school awarded excessive credit for prior experiential learning, failed to employ qualified faculty and didn't meet requirements for issuing degrees.

Kane said Columbia Pacific granted her a doctorate after the school "consolidated my work," which Kane described as "clinical work" and continuing medical education courses for doctors. Her doctorate is valid, she said, because it was issued before the university ran into problems with the state.

Last year she was the subject of a television news investigation about her work with patients with ALS, also known as Lou Gehrig's disease. The disease, which affects motor neurons, is a death sentence.

but now in 2021, things have changed:-

 

Sodium phenylbutyrate reduces repetitive self-grooming behavior and rescues social and cognitive deficits in mouse models of autism

We found that acute and chronic treatment of NaPB remarkably improved, not only core ASD symptoms, including repetitive behaviors and sociability deficit, but also cognitive impairment in the BTBR mice. NaPB substantially induced histone acetylation in the brain of the BTBR mice. Intriguingly, the therapeutic effects of NaPB on autistic-like behaviors, such as repetitive behaviors, impaired sociability, and cognitive deficit also showed in the valproic acid (VPA)–induced mouse model of autism

These findings suggest that NaPB may provide a novel therapeutic approach for the treatment of patients with ASD.

Correcting miss-expressed genes is the holy grail for the treatment of many diseases and in particular for all those parents whose child has a single gene type of autism.  In this blog I also call them DEGs (differentially expressed genes); everyone with autism has some DEGs. There is a lot in this blog about HDAC inhibitors, these can modify gene expression via the epigenome.  HDAC inhitors therefore can potentially fix DEGs.  NaPB was approved 25 years ago by the FDA to treat urea cycle disorders and is used in children over 20 kg.  It is not cheap and as usual it is much more expensive in the United States, at a high dose it is crazily expensive like cancer drugs, many of which are also HDAC inhibitors.  NaPB is another bulk chemical they put in tablets and multiply that cost by whatever they feel like. There is a reaction against this trend in some countries, for example using cheap generic Potassium Bromide for Dravet syndrome, instead of the overly expensive tablets. 

NaPB is used off-label to treat ALS/motor neuron disease.

 

2021 Autism PollyPill To Do List – Speech ↑ and Misophonia ↓

 

 A few ideas remain to be fine-tuned

Having started to develop my son’s polytherapy for autism back in December 2012, is there anything left to develop in 2021?

As we have seen, the biggest impact from interventions is when you start them very young, but improvement is possible at any age.

I was asked at the recent Synchrony autism conference what is next for the PolyPill?  and I replied that more spontaneous expressive language is my main target.  I have a good idea of what may help.

·        Calcium folinate, increased over 6 weeks to 45mg/day

·        Sulforaphane, with added Myrosinase in the form of Wasabi

I was contacted by a researcher from that Synchrony conference, suggesting that Low Level LED Therapy (LLLT) was worth trying to improve the use of speech.  It does seem to benefit people with many types of brain injury.  I did write a post on LLLT using lasers, not LEDs, in autism and there was a promising trial in Havana, which I shared with the researcher.

 

https://epiphanyasd.blogspot.com/2018/12/low-level-laser-therapy-lllt-for-autism.html

https://epiphanyasd.blogspot.com/2019/07/homeclinic-based-photobiomodulationlase.html

 

Many of the suggested modes of action of LLLT were in this graphic.

Click to enlarge the graphic

Another suggested mode of action for LLLT concerns improved drainage of lymph from the brain.  This is a known problem in some forms of dementia. Among alternative autism practitioners there are all kinds of manual lymphatic draining therapies.

  

PDE4 inhibitors 

Some readers are using PDE4 inhibitors as the anti-inflammatory component of their personal autism polytherapy.

The 3 “common” choices are: -

·        Pentoxifylline, cheap and even trialled a few decades ago in children with autism. It has a short half-life and is a non-selective PDE inhibitor.  It also has an interesting effect on HDAC, that can make chemotherapy work better.

·        Roflumilast, more expensive and normally used to treat exacerbations in COPD, but patented at a lower dose as a cognitive enhancer. It is more selective for PDE4 than Pentoxifylline and has a long half-life.

·      Ibudilast, common in Japan as an asthma therapy and now a potential treatment for MS (multiple sclerosis).  It is available in Germany, imported to order, with a prescription.

 

PDE inhibitors are not very selective and so some people get side effects.  The big one seems to be nausea. Side effects may well fade over time.

I did try Roflumilast at the supposedly cognitively enhancing dose of 100mcg, a couple of years ago, but it did cause nausea. The nausea may well fade away after a few weeks.  Roflumilast may also reduce the sensory gating problem common, in autism, but only at a dose of 100mcg, higher doses lost this effect.  All is in this old post below.

Impaired sensory gating is driven by HCN channels that need to be blocked.  The science shows us various ways this can be achieved, as I explained in the post below. You can target alpha-2A adrenergic receptors, reduce stress or reduce cAMP.

What is cAMP?  Look here: -

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

 

Cognitive Loss/Impaired Sensory Gating from HCN Channels - Recovered by PDE4 Inhibition or an α2A Receptor Agonist

… in earlier post we saw that α7 nAChR agonists, like nicotine, improve sensory gating and indeed that people with schizophrenia tend to be smokers. It turns out that nicotine is also an HCN channel blocker.

Stress appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.

This would explain why stress makes people’s sensory gating problems get worse. So, someone with Asperger’s would get more distracted/disturbed at exam time at school for example, or when he goes for a job interview. Reducing stress is another method to improve sensory gating and indeed cognition. 

Alpha-2A adrenergic receptors near the HCN channels, on those dendritic spines, inhibit the production of cAMP and the HCN channels stay closed, allowing the information to pass through into the cell, connecting the network. These Alpha-2A adrenergic receptors are stimulated by a natural brain chemical norepinephrine, or by drugs like Guanfacine.

While the researchers at Yale patented the idea of HCN blockers to improve cognition, we can see how other existing ideas to improve cognition may indeed have the same mechanism, most notably PDE4 inhibitors.

One effect of a PDE4 inhibitor is that it reduces cAMP. So, a PDE4 inhibitor acts indirectly like an HCN blocker.

Not surprisingly recent research showed that low doses of Roflumilast improves sensory gating in those affected by this issue.

So rather than waiting for a brain selective HCN blocker, the potential exists to use a one fifth dose of Roflumilast today.

 

HCN channels play a role in many neurological conditions.  It does get rather complicated, but if you successfully target these ion channels you are definitely at the cutting edge of science. 

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: An Emerging Role in Neurodegenerative Diseases 

The low dose Roflumilast might be a good choice for Aspies who get bothered by noises like clocks ticking and people chewing gum.

Pentoxifylline is very cheap, but the short half-life means you might need to take it three times a day.

100mcg of Roflumilast is 1/5^th of a standard Daxas pill for COPD, which means crushing it and dividing in 5 parts.  This does also make it much cheaper, one pack would last you 5 months.

I will retry Roflumilast and also give Pentoxifylline a try. 

Based on the science, I think 100mcg of Roflumilast really should have a benefit in much autism.

I know other readers are using Pentoxifylline or Ibudilast.

All these PDE inhibitor drugs are normally used in adults. 

 

Misophonia

https://www.webmd.com/mental-health/what-is-misophonia#1

 

Misophonia is a disorder in which certain sounds trigger emotional or physiological responses that some might perceive as unreasonable given the circumstance. Those who have Misophonia might describe it as when a sound “drives you crazy.” Their reactions can range from anger and annoyance to panic and the need to flee.  The disorder is sometimes called selective sound sensitivity syndrome.

Individuals with Misophonia often report they are triggered by oral sounds  -- the noise someone makes when they eat, breathe, or even chew. Other adverse sounds include. keyboard or finger tapping or the sound of windshield wipers. Sometimes a small repetitive motion is the cause -- someone fidgets, jostles you, or wiggles their foot.

 

Impaired P50 gating

https://en.wikipedia.org/wiki/P50_(neuroscience)

 

In electroencephalography, the P50 is an event related potential occurring approximately 50 ms after the presentation of a stimulus, usually an auditory click.The P50 response is used to measure sensory gating, or the reduced neurophysiological response to redundant stimuli.

Research has found an abnormal P50 suppression in people with schizophrenia, making it an example of a biological marker for the disorder. Besides schizophrenia, abnormal P50 suppression has been found in patients with traumatic brain injury, recreational drug use, and post-traumatic stress disorder.

 

It looks to me that:-

 

Misophonia = Impaired P50 gating  = Impaired sensory gating

 

Recent clinical trials using Roflumilast: -

 

Cognitive Effects of Roflumilast in MCI Patients (ROMEMA)

dose 50 mcg   100 mcg

 

Roflumilast and Cognition (EEGrofl) 

dose 100mcg, 300mcg, 1,000 mcg

 

Roflumilast: A potential drug for the treatment of cognitive impairment?

 Roflumilast is the one and perhaps the only drug which shows a dose dependent occupancy of PED-4 in primate models and at doses proven to be very safe in humans, has shown its efficacy in enhancing memory and cognition.

 

An experimental medicine study of the phosphodiesterase-4 inhibitor, roflumilast, on working memory-related brain activity and episodic memory in schizophrenia patients

This study consisted of a randomised, double-blind, placebo-controlled, crossover design involving 15 schizophrenia patients. In 3 treatment periods, patients were given 8 days of placebo or one of the two doses of roflumilast (100 and 250 μg daily) with 14 days of washout between treatments.

Results

Verbal memory was significantly improved under 250 μg roflumilast (effect size (ES) = 0.77) compared to placebo. fMRI analyses revealed that increasing dose of roflumilast was associated with reduction of bilateral DLPFC activation during working memory compared to placebo, although this was not statistically significant (ES = 0.31 for the higher dose). Working memory was not improved (ES = 0.03).

Conclusions

Results support the mechanistic validation of potential novel strategies for improving cognitive dysfunction in schizophrenia and suggest that PDE4 inhibition may be beneficial for cognitive dysfunction in schizophrenia.

 

Improvisation

I did recently write about Desmopressin nasal spray as a possible alternative to specially compounded vasopressin nasal spray.  I did actually order some, but what arrived was the tablet form of Desmopressin.

The advantage of Desmopressin over Vasopressin is that there already exists a nasal spray in your pharmacy. There is currently a worldwide availability issue. 

Fine tuning Social Behavior in Autism with an existing pediatric drug, Desmopressin?

Having recently been making Christmas Pudding and sweet mincemeat for mince pies, from raw ingredients and improvising for those not available, I think I can safely make my own Desmopressin nasal spray, and with the correct excipients. 

Due to Covid, we did not go to England at Christmas; setting Christmas Pudding on fire is something that Monty looks forward to.

Christmas pudding takes days to make and 8 hours to cook, then you leave it to mature.  You re-heat for Christmas lunch.

 

Sweet mincemeat is something that came to England with the returning crusaders.  Nowadays it is just made with dried fruit.  When the English established colonies in New England, they took the older version with them, which included actual meat.  Today in the US you have store-bought sweet mincemeat with ground beef in it, in the UK it has been meat-free for many decades. 

The fat in sweet mincemeat is suet.  In the UK and US, pre-packaged suet sold in supermarkets is dehydrated suet.

I had no idea what suet was, but I know it is not in my supermarket.  Suet is actually raw, hard fat of beef or mutton, found around the loins and kidneys.  Jewish people are not supposed to eat suet, but Muslim people apparently seek it out.  These days I think most is actually a vegetable substitute.  To follow the recipe, a friend helped out with some of this fat; I put a chunk of it in the freezer for a couple of hours and then grated it. You are supposed to coat with rice flour, if you want to store it for later use.

The recipe said 300g (10 oz) of suet but having grated half, I decided it was pretty disgusting and substituted butter for the remainder.

In the recipe are raisins, currants and sultanas, they are actually all slightly different.  In effect they are all dried grapes

 

Raisins, sultanas and currants

 

In the US, the term raisin is applied to both raisins and sultanas. To distinguish the two, sultanas are referred to as “golden” raisins.

Where we live, they are all just “dried grapes”.  The different types exist, but are called the same thing.

Candied peel and glace cherries were also a struggle to find, by this time I had decided to add dried blueberries and cranberries.

One day after the mincemeat jars were already full and maturing in the garage, candied peel and glace cherries turned up and got added.  There is a lot of brandy in the recipe and this is why you leave the jars to mature.

 

It was a lot of bother to make, but the resulting mince pies were really good.  The brandy carries the spices making it very fragrant, not at all like store-bought mince pies.

The Christmas pudding was set alight, in fact twice for good measure.

Compared to all that, how hard can it be to make desmopressin nasal spray?  It only has a handful of ingredients, after all. 

Sulforaphane

I first wrote about Sulforaphane from broccoli, back in 2014. Johns Hopkins have been researching this substance for decades.

What has happened to Sulforaphane for autism? Stuck as Complementary and Alternative Medicine (CAM) therapy forever?  Apparently so.

Sulforaphane has anti-cancer effects and is suggested for common cancers like that of the prostate.  A stable man-made version (an analog) was developed in the UK as drug to treat prostate cancer.  In France a modified broccoli-based OTC product is sold as another prostate therapy.

 

When it comes to autism, there have been a series of positive clinical trials.

Sulforaphane treatment for autism spectrum disorder: A systematic review

Autism Spectrum Disorder (ASD) is defined as a neurodevelopmental condition characterized by social communication impairment, delayed development, social function deficit, and repetitive behaviors. The Center for Disease Control reports an increase in ASD diagnosis rates every year. This systematic review evaluated the use of sulforaphane (SFN) therapy as a potential treatment option for individuals with ASD. PubMed.gov, PubMed Central, Natural Medicines, BoardVitals, Google Scholar and Medline were searched for studies measuring the effects of SFN on behavior and cognitive function. All five clinical trials included in this systematic review showed a significant positive correlation between SFN use and ASD behavior and cognitive function. The current evidence shows with minimal side effects observed, SFN appears to be a safe and effective treatment option for treating ASD.

 

The Johns Hopkins' researchers did spin off the idea to commercially exploit their findings.  The result is “True broc” from Brassica Protection Products.

 

https://truebroc.com/what-is-truebroc/ 

 

https://brassica.com/

 

Here you will find Avmacol and Thorne Crucera-SGS, among the products than include “True broc”.  

These products, along with Prostamol from France, are actually used in clinical trials.

The UK company Evgen is developing its stable analog of Sulforaphane for autism and other conditions.

https://evgen.com/technology/

I spoke to Evgen a few years ago and suggested their prostate drug might be used for autism.  You still cannot buy it, but there is a clinical trial for autism planned.

 

Do you need expensive broccoli supplements?

There are numerous cheap broccoli supplements and some moderately priced ones.

We know from the research that supplements generally are not reliable, because they often do not contain what is on the label.  This matters more with some products than others.  With broccoli products the big question is whether they really contain active myrosinase.  This is an enzyme that you need to make Sulforaphane when you eat broccoli.

Several years ago, when I started with Sulforaphane, I bought large tubs of Australian broccoli powder and one pack of Daikon radish powder.  Daikon radishes are rich in myrosinase and it is relative stable, so it can survive processing.  My idea was to start with just the broccoli powder and then, if not effective, add some Daikon radish powder for the extra myrosinase.  In the end I did not need to even open the Daikon radish powder.  A small scoop of this broccoli powder produced a profound effect, euphoria after minutes and then much more “speech”. Back then “speech” was more like babbling single words – but it was some kind of speech at least. 

Many people report broccoli powder improved speech, even parents of young Aspies report it. 

Some people found the effect on mood to be remarkable.

Long term users report that over time they have to increase the dose to maintain the effect.

It is important to note that for some people the benefit may not be from Sulforaphane, but rather from indole-3-carbinol (I3C).

 

Here I am quoting myself …

 

“PTEN is best known as a tumor suppressor affecting RAS-dependent cancer, like much prostate cancer. Activating PTEN is good for slowing cancer growth. As I mentioned in a recent comment to Roger, many substances are known to activate PTEN; a good example being I3C (indole-3-carbindol) which is found in those cruciferous vegetables (broccoli, Brussels sprouts, cabbage etc) that many people choose not to eat. PTEN is a well-known autism gene.” 

The research has now caught up: - 

Study hints at dietary chemical as therapy for type of autism

A compound derived from cruciferous vegetables, such as broccoli and kale, might limit the impact of certain mutations in a top autism gene, a new study suggests.

The compound, called indole-3-carbinol, or I3C, acts on the gene PTEN, a tumor suppressor. 

This does raise questions about the prostate cancer research.  A sulforaphane analog drug contains no indole-3-carbinol (I3C).

  

Does Broccomax “work” 

The easy to buy product is Broccomax.  In the research they do not seem to like it, but it does not include the True Broc product from the Johns Hopkins spin-off.

Anecdotally, Broccomax does “work” for autism, but less so than some expensive products.

My Australian broccoli powder is no longer made, but it was not expensive and it did “work”.

 

Spice up Broccoli with Wasabi?

In the original research from decades ago, the Johns Hopkins researchers combined Daikon radish sprouts with broccoli sprouts, the Daikon radish sprouts where there to provide myrosinase.  The product had to kept deep frozen.

Daikon radish is widely available and is a good source of myrosinase.

I was re-reading old research and noted one researcher advocating putting Wasabi on your broccoli – the spicier the better apparently. Wasabi is Japanese horseradish and is widely available.  If it comes on a large bottle is likely fake wasabi - yes like they fake saffron, they fake wasabi.

Is it crazy to add wasabi to your broccoli capsules?

Look at what is in the expensive Avmacol supplement that they only sell in North America.

 

 

In the research they found that adding just 0.25% Daikon to frozen broccoli “brought it back to life” and sulforaphane was found in the person eating it. 

If you are using gelatine capsules with broccoli powder you can open them and, using a pointed knife, add a small amount of wasabi, re-seal and then swallow.  There is no taste or smell of wasabi.

It is bit fiddly to do this, but you soon master doing it.

 

Calcium Folinate (Leucovorin)

 

There is a lot in this blog already about Calcium Folinate.  It should give some benefit to the 75% of autism who have a problem with folate transport across the blood brain barrier. 

One of the most prominent effects in responders is improved speech. Just look at the tittle of the clinical trial

 

Leucovorin for the Treatment of Language Impairment in Children With Autism Spectrum Disorder

The only issue with Calcium Folinate (Leucovorin) are the side effects, but Professor Ramaekers assures me that if you gradually increase the dose over several weeks, there should not be any.

The summer before Covid, at 45mg a day of Calcium Folinate, my son had much more expressive language and it was also more complex language.  The problem was aggression.

 

Conclusion

As you can see the 2021 to do list is mainly tying up the loose ends remaining from previous ideas, so I anticipate success.

Broccoli powder does still have an effect, but much milder than a few years ago.  Does wasabi increase the effect?  This is very subjective, having bought the little jar of Wasabi, I will continue to adding it to two capsules of Broccomax before breakfast.

Calcium Folinate did increase speech significantly at the large dose (3 x 15mg a day) in my original trial.  At the lower dose of 15mg the effect is present, but is mild, and short-lived for the first few days.   I will very gradually increase from a starting dose of 15 mg a day and see if it possible to avoid the negative effects.

I do like the idea of the tiny dose of Roflumilast.  It has multiple potential benefits:-

1.     Improve sensory gating and reduce Misophonia

2.     Improve cognition

3.     Potentially reduce NKCC1/KCC2 expression and so make bumetanide more effective.

Can this be achieved without nausea? I think it is likely a matter of perseverance.  In COPD the starting dose of roflumilast is half the maintenance dose, but the likely “autism dose” of 100mcg in an adult is less than half the COPD starting dose of 250mcg. 

The research already tells us the effective dosage (for 1 & 2), 100mcg in an adult, and importantly that the effect is lost at higher dosage; indeed, the recent trial in Mild Cognitive Impairment (MCI) included a dose as low as 50mcg.

You would have to find the therapeutic window.  You are changing the intracellular level of cAMP, which will have numerous effects, not just on HCN channels, but also on things like pCREB and BDNF.

I think 80mcg will be a good place to start.

There may, or may not be, an equivalent dose of Pentoxifylline/Ibudilast that gives a similar effect.  Ideally you would want all 3 effects.

A dose higher than 100mcg might have a beneficial anti-inflammatory effect and so help reduce NKCC1/KCC2 expression which increases (3) but at the loss of (1) and (2).

It would be interesting to know if Maja’s daughter has/had Misophonia and what has been the effect of her Pentoxifylline use.

The next question is how to reliably measure such small doses of Roflumilast.  This drug does not dissolve in water, but is highly soluble in ethanol.  You have the choice of cutting a pill containing 500mcg into 5-6 pieces (fortunately, it is a large pill), or just crushing the pill and then using microscales to fill new capsules, or make a tincture.  The tincture should be the most accurate.  Tinctures are widely used for OTC remedies like propolis.  A tincture has the advantage that you can easily vary the dose. In phase 1, where I just try it on myself, I have opted for the tincture. One tablet dissolves in 2ml of vodka (dilute ethanol) to make a paste, but was much more fluid in 3 ml (the 3rd ml added probably could be just water).  One half of an old propolis pipette contains 100 mcg duly dissolved in 0.6 ml of vodka. It tastes exactly like the original propolis tincture, because all you really notice is the ethanol. Most commercial propolis tincture is made with alcohol and uses a much more concentrated ethanol than you will find in vodka. 

I was asked by an autism Grandad at the 2019 Thinking Autism conference how his Grandson could be helped.  The young man is highly intelligent, but has a severe problem with sound sensitivity.  His family paid extra money for him to sit his final school exams in a room with no other students, but the invigilator was opening up candy to chew all through the exams and so the boy flunked the exams.   This young man has Misophonia and I bet would exhibit impaired P50 gating if given an EEG. Before exam time, he needs to block some of the HCN channels in his brain and reduce stress/anxiety.  He might well benefit from Roflumilast 100 mcg and Propranolol 20mg and then sail through his exams. 

I actually think that many people reading this post likely have Misophonia, that is if they are a relative of someone with polygenic autism.  In the literature Misophonia is claimed to affect more women than men, but I doubt that is actually true.  If you have autism, your doctor is highly unlikely to add a diagnosis of Misophonia. 

Is Desmopressin going to be helpful?  I had put Vasopressin down as a potential therapy more for Aspies, but our reader whose young child was prescribed Desmopressin nasal spray by her neurologist, noted a broad range of substantial improvements. Desmopressin is water soluble, so no vodka required.