Pentoxifylline and cGP (an IGF-1 normalizer) from Blackcurrants, for Autism?

 

 

Readers may be wondering at what point Peter will run out of things to write about.  I do sometimes wonder the same thing. I was going to also write about Loperamide (Imodium), but the post would have been too long. Next time!

Pentoxifylline

Pentoxifylline has been in use to treat autism for 50 years. The original studies did suggest its effect was greatest among small children.  I have been in some discussions with a US psychiatrist, Dr Powell, who is a big fan of the off-label use of this drug to affect the brain in adults.  He has even written a book on the subject.

My previous posts on Pentoxifylline can be found here: 

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

Dr Powell’s patients with autism tend to be older children, not the toddlers who did well in clinical trials in Japan in the 1970s.  He sees significant improvement in many, but not all, of his patients with autism.  The parents report improved social interactions and having higher-level discussions with their child.

What is notable is that he uses frequent dosing, 4 times a day, always after food to avoid the GI side effects.

Pentoxifylline is inexpensive, but its effect does not last long, hence the frequent dosing.  Some people take taking this drug 5-6 times a day.

Pentoxifylline has multiple modes of action, it should increase blood flow to the brain and it is broadly anti-inflammatory.  It is a non-selective PDE inhibitor, normally used treat muscle pain in people with peripheral artery disease. It increases red blood cell flexibility and it reduces the viscosity of blood.

There are PDEs 1 to 11. It all gets quite complicated, for example PDE1 subtype A2 has a potential role in neurodegenerative diseases, including:

·        Parkinson's disease

·        Axonal neurofilament degradation

·        Motorneuronal degradation

·        Neuronal ischemia

·        Alzheimer's disease

·        Epilepsy

Recall that PDE4 inhibitors are used to treat asthma and COPD. We can potentially repurpose those to improve myelination in MS, or autism, and at specific low doses they can improve cognition.

 

cGP (from Black Currants)

I did write quite a lot in this blog about growth factors and autism.  The familiar ones are BDNF, NGF and IGF-1, but there are many more. 

My previous posts on IGF-1 can be found here: 

https://www.epiphanyasd.com/search/label/IGF-1

We know that growth signaling in autism is disturbed, but it is not simple.  As the disease progresses (the fetus develops, the baby is born and grows into a toddler) the imbalance in growth signaling changes.  This means that what would be helpful in a 6 month old baby might well be inappropriate in a 6 year old.  This is a good example of what I call the what, when and where of treating autism. Here it is the “when” that matters.

Some people lack BDNF while others have too much. Very possibly, this changes over time in the same child.

One possible therapy for autism is injections of IGF-1 (Insulin-like Growth Factor 1).  IGF-1 plays an important role in childhood growth.

A synthetic analog of IGF-1 is used in children for the treatment of growth failure.  This drug called Mecasermin was used in autism trials and in Rett syndrome trials.

In Rett syndrome the search has been on for an oral therapy.

Trofinetide (NNZ-2566) is a potential therapy for Rett syndrome being developed by Neuren Pharmaceuticals in Australia.

Trofinetide is derived from IGF-1.

Trofinetide got to phase 2 trials as a therapy for Fragile-X in 2015.

The second product in development at Neuren is NNZ-2591.  It is aimed at normalizing the level of IGF-1.

This is in the pipeline to treat:

• Phelan-McDermid syndrome (Shank3 gene and others not working)
• Angelman syndrome (UBE3A gene not working)
• Pitt Hopkins syndrome (TCF4 gene not working)
• Prader-Willi syndrome (MAGEL2 gene and others not working)

https://www.neurenpharma.com/irm/content/product-development-pipeline.aspx?RID=483&RedirectCount=1

 

What is NNZ-2591?

It is an analogue (modified version) of cyclic glycine proline (cGP)

Cyclic glycine-proline (cGP), a metabolite of IGF-1, is neuroprotective through improving IGF-1 function.

There is also research focused on Parkinson’s and Alzheimer’s where it seems that cGP is reduced.

In New Zealand they found that supplementation of Blackcurrant anthocyanins (pigments) increased cGP in the spinal fluid of patients with Parkinson’s.

This also led the way to the idea of increasing cGP as means of protecting the brain during aging. There is now a commercial OTC product in New Zealand to do just this.

Our reader Daniel, who has a daughter with Rett syndrome, is assessing the benefit of cGP, using the OTC product cGPMAX. The results so far are promising.

Rett is very specific because we know for sure that IGF-1 and NGF are disturbed.

Is cGP going to be beneficial in broader autism?  May be yes, but we come back to the what, when and where.  It may well depend on when a specific person takes it.  We have both hypoactive pro-growth signalling autism and hyperactive pro-growth signalling autism.

 

 

Unfortunately, what the clever researchers who came up with the above concept did not consider is that you may start out hyper in the womb and switch to hypo a few short years later.

  

Conclusion

Frequently dosed Pentoxifylline looks like a potentially interesting therapy for many with autism, including some with high IQ.  Take note our Aspie readers.

Daniel’s idea to look at the Neuren’s non-Rett therapy as a Rett therapy is interesting.  In effect you do not need to wait for the Australian drug, you can hop across the Tasman Sea to New Zealand and use their cGP supplement, developed for protection against dementia.

You would also think that parents of children with:

• Phelan-McDermid syndrome (Shank3 gene and others not working)
• Angelman syndrome (UBE3A) gene not working)
• Pitt Hopkins syndrome (TCF4 gene not working)
• Prader-Willi syndrome (MAGEL2 gene and others not working)

might want to follow Daniel’s lead.

As you can see, there is a lot of trial and error in science.  Back in 2009 NNZ-2566 was in clinical trials for the treatment of cognitive deficits following traumatic brain injury.  That must not have worked out.  Fragile-X did not work out and now it is phase 3 for Rett girls, which seems to be going well.

 

IGF-1 for old people

The same growth factor IGF-1 that is key during development also plays a key role in aging. Dr Jian Guan made a world first discovery. She discovered that cGP (cyclic Glycine-Proline) was responsible for controlling the IGF-1 hormone in our body. Thus by increasing the level of cGP in our body, the cGP will essentially command the IGF-1 to build more blood vessels.

Dr Jian Guan, was then recognised as the world-wide authority on cGP. In 2017 she discovered that New Zealand blackcurrants contained high volumes of natural cGP which could regulate optimum levels of IGF-1 in the body.

So now we have Antipodeans/Kiwis fending off dementia, and potentially metabolic syndrome, by taking their locally made cGPMax.

Will it help you case of autism? Who knows, but if it does not, just give the leftover pills to Grandma, Granddad or take them yourself!

 

All the supporting papers from New Zealand.

https://cgpmax.com/pages/our-science

 

Update on Roflumilast/Daxas as a PDE4 inhibitor for Autism

 

There is already quite a lot in this blog about using a PDE (Phosphodiesterase) inhibitor to potentially treat autism.

Readers might have seen the recent article below, in which a PDE-4D inhibitor raised cognition in adults with Fragile-X.

Drug boosts cognition in men with fragile X syndrome 

The study drug, BPN14770, is developed by Tetra Therapeutics, a clinical-stage biotechnology company in Grand Rapids, Michigan. It blocks the activity of phosphodiesterase-4D, an enzyme in the brain that degrades cyclic AMP. In a mouse model of fragile X, BPN14770 increased cyclic AMP and eased several fragile-X-related traits.

 

For the new work, 30 men with fragile X participated in a 24-week double-blind crossover study of the drug. The researchers randomly assigned each man to one of two treatment sequences: 12 weeks on the drug followed by 12 weeks on a placebo, or 12 weeks of placebo crossing over to 12 weeks on the drug. Researchers assessed all of the participants at the start of the study and during week 6 and week 12 of each trial sequence. They also asked parents and caregivers to rate changes in the men’s language, daily function and anxiety.

The treatment produced “significant improvement in the language and daily function measures that the families were rating, in conjunction with improvement on this objective test [NIH Toolbox] that’s very hard to have a placebo effect on,” says Elizabeth Berry-Kravis, professor of child neurology at Rush University Medical Center in Chicago, Illinois, who led the study.

 

Later on in the post is the science, which it does help to read. if you want apply it.

The research drug BPN14770 used in the Fragile-X trial is not something you can buy at the pharmacy, but there are PDE inhibitors available today.

I have written a post recently about the use of Pentoxifylline, which is a very cheap drug that is not selective, if affects many types of PDE not just PDE-4D. 

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

 

Today I am looking at Roflumilast/Daxas which mainly affects PDE-4.  There are 4 sub-types (isoforms) A, B, C and D.  Drugs that affect all these sub-types are called PDE4 pan inhibitors and they usually cannot be used in humans. due to severe nausea.

Roflumilast/Daxas is used to treat COPD/severe asthma at a dose just on the limit, where it begins to be effective and inhibit PDE in the lungs but before the nausea makes it unusable. There is research to make an inhaled version, which would make a lot of sense.

We are interested in PDE4 in the brain, not the lungs.  The effect of Roflumilast on PDE4 is unusual in that it is very dose dependent; too little and there is no effect, too much and there is no effect.  So, the amount of Roflumilast and its metabolites in your blood stream need to be within a tight range.

The median plasma half lives of Roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively.

This means if you give the same dose every day, the level of the metabolites will reach a steady state only after about 5 days.

As mentioned in an early post, roflumilast is not soluble in water, but it is in alcohol.  This means you can make a tincture, just like they do with bee propolis.  In fact, I am using an old propolis bottle, the type with a screw-on pipette.

We know from the research that in healthy adults a dose of 100mcg may be cognitive enhancing.

My target dose was 80mcg, but I wanted to be able to easily vary it.

Take an old propolis bottle and clean it with alcohol/ethanol/vodka.

In a small glass, dissolve 5 tablets (5 x 500mcg Daxas) in 15ml of vodka.  The tablets slowly dissolve; mix well and then use the pipette to transfer the fluid to the bottle and also figure out where on the pipette equates to 0.5ml. When I recently did this it took me 31 squirts, so by eye I was giving on average 83 mcg.

When I first started there was one day of dramatically increased speech, which I could not reproduce.  The first day of Pentoxifylline also had this effect. Pentoxifylline has a very short half-life.

Since at school Monty is having his year-end exams, I decided to focus on cognition.  I think my original dose was too high, more like 100 mcg.  Giving a little extra is something you have to resist.

Being a bit stingy (ungenerous) with the pipette, is what you have to be.

At close to 80 mcg a day, I am getting feedback from school that cognition is great.

Exams started and Monty is doing really well.  They are 90-minute exams and the fact that he is even there is amazing to me; that is down to 8 years of Bumetanide.

It looks like 80 mcg of Roflumilast does give an extra boost to cognition in a 60 kg boy.

Is it worth it?

One pack of 30 x 500mcg Roflumilast/Daxas tablets costs about EUR 40 (about 50 USD) in Europe, but at the 80 mcg daily dose it will last 6 months.

Monty has had been no side effects (nausea, GI etc), but this is very specific to the person. I myself did get GI side effects from 100 mcg.

   

Science that supports the use of a PDE4 inhibitor

There are many different types of PDE (Phosphodiesterase) and there has been a lot of research looking at their relevance to a wide range of neurological conditions.

The table below gives a useful summary, by disorder.

 

Neurodevelopmental disorders are highlighted in red. AD Alzheimer disease; ASD autism spectrum disorder; BP bipolar disorder; DS down syndrome; HD Huntington disease; ID intellectual disability; FXS fragile X syndrome; MDD major depression disorder, RTT Rett syndrome, SCZ schizophrenia.

 

This table is from an excellent paper published earlier this year.

 

Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

Phosphodiesterases (PDEs) are enzymes involved in the homeostasis of both cAMP and cGMP. They are members of a family of proteins that includes 11 subfamilies with different substrate specificities. Their main function is to catalyze the hydrolysis of cAMP, cGMP, or both. cAMP and cGMP are two key second messengers that modulate a wide array of intracellular processes and neurobehavioral functions, including memory and cognition. Even if these enzymes are present in all tissues, we focused on those PDEs that are expressed in the brain. We took into consideration genetic variants in patients affected by neurodevelopmental disorders, phenotypes of animal models, and pharmacological effects of PDE inhibitors, a class of drugs in rapid evolution and increasing application to brain disorders. Collectively, these data indicate the potential of PDE modulators to treat neurodevelopmental diseases characterized by learning and memory impairment, alteration of behaviors associated with depression, and deficits in social interaction. Indeed, clinical trials are in progress to treat patients with Alzheimer’s disease, schizophrenia, depression, and autism spectrum disorders. Among the most recent results, the application of some PDE inhibitors (PDE2A, PDE3, PDE4/4D, and PDE10A) to treat neurodevelopmental diseases, including autism spectrum disorders and intellectual disability, is a significant advance, since no specific therapies are available for these disorders that have a large prevalence. In addition, to highlight the role of several PDEs in normal and pathological neurodevelopment, we focused here on the deregulation of cAMP and/or cGMP in Down Syndrome, Fragile X Syndrome, Rett Syndrome, and intellectual disability associated with the CC2D1A gene.

  

It looks like idiopathic autism has the least research, but there is an interesting old paper.

  

Expression of Phosphodiesterase 4 is altered in brain of subjects with autism

 

The cyclic adenosine monophosphate-specific phosphodiesterase-4 (PDE4) gene family is the target of several potential therapeutic inhibitors and the PDE4B gene has been associated with schizophrenia and depression. Little, however, is known of any connection between this gene family and autism, with limited effective treatment being available for autism. We measured the expression of PDE4A and PDE4B by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting in Brodmann's area 40 (BA40, parietal cortex), BA9 (superior frontal cortex), and cerebellum from subjects with autism and matched controls. We observed a lower expression of PDE4A5, PDE4B1, PDE4B3, PDE4B4, and PDE4B2 in the cerebella of subjects with autism when compared with matched controls. In BA9, we observed the opposite: a higher expression of PDE4AX, PDE4A1, and PDE4B2 in subjects with autism. No changes were observed in BA40. Our results demonstrate altered expressions of the PDE4A and PDE4B proteins in the brains of subjects with autism and might provide new therapeutic avenues for the treatment of this debilitating disorder.

  

Conclusion

It looks like Roflumilast/Daxas should join Pentoxifylline on the to-trial list for people with autism.

In my opinion the actions of Pentoxifylline and Roflumilast/Daxas are sufficiently different that conceivably some people might benefit from taking both.

I cannot see why someone with Fragile X should wait another decade for BPN14770 to maybe get commercialized.

There are PDE4 inhibitors in the pipeline for Alzheimer’s.  In my opinion the focus should be more on prevention.  By the time people get diagnosed with Alzheimer’s, it is too late to reverse it.

 

 

 

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.

 

Immune modulatory treatments for autism spectrum disorder

Need a wizard, or your local doctor?

I was intrigued to come across a recent paper on immune modulatory treatments for autism by a couple of doctors from Massachusetts General Hospital for Children.  The lead author has interests in:

·      Autism spectrum disorders

·      Psychopharmacology

·      Developmental Disabilities

·      Williams syndrome

·      Angelman syndrome

·      Down syndrome

Apparently, he is an internationally-recognized expert in the neurobiology and neuropsychopharmacology of childhood-onset neuropsychiatric disorders including autistic disorder.  Sounds promising, hopefully we will learn something new.

The paper is actually a review of existing drugs, with immunomodulatory properties, that have already been suggested to be repurposed for autism. The abstract was not very insightful, so I have highlighted the final conclusions and listed the drugs, by category, that they thought should be investigated further.

All the drugs have already been covered in this blog and have already been researched in autism.

One important point raised in the conclusion relates to when the drugs are used.  Autism is a progressive condition early in life and there are so-called “critical periods” when the developing brain is highly vulnerable.

For example, Pentoxifylline has been found to be most effective in very young children.  This does not mean do not give it to a teenager with autism, it just means the sooner you treat autism the better the result will be.  This is entirely logical.

Some very clever drugs clearly do not work if given too late, for example Rapamycin analogs used in people with TSC-type autism.

Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain

Importantly, each of these developmental abnormalities that are caused by enhanced mTOR pathway has a specific window of opportunity to respond to rapamycin. Namely, dyslamination must be corrected during neurogenesis, and postnatal rapamycin treatment will not correct the cortical malformation. Similarly, exuberant branching of basal dendrites is rectifiable only during the first 2 weeks postnatally while an increase in spine density responds to rapamycin treatment thereafter.  

Back to today’s paper.

Immune modulatory treatments for autism spectrum disorder

The identification of immune dysregulation in at least a subtype ASD has led to the hypothesis that immune modulatory treatments may be effective in treating the core and associated symptoms of ASD. In this article, we discussed how currently FDA-approved medications for ASD have immune modulatory properties.

“Risperidone also inhibited the expression of inflammatory signaling proteins, myelin basic protein isoform 3 (MBP1) and mitogen-activated kinase 1 (MAPK1), in a rat model of MIA. Similarly, aripiprazole has been demonstrated to inhibit expression of IL-6 and TNF-α in cultured primary human peripheral blood mononuclear cells from healthy adult donors.”

We then described emerging treatments for ASD which have been repurposed from nonpsychiatric fields of medicine including metabolic disease, infectious disease, gastroenterology, neurology, and regenerative medicine, all with immune modulatory potential. Although immune modulatory treatments are not currently the standard of care for ASD, remain experimental, and require further research to demonstrate clear safety, tolerability, and efficacy, the early positive results described above warrant further research in the context of IRB-approved clinical trials. Future research is needed to determine whether immune modulatory treatments will affect underlying pathophysiological processes affecting both the behavioral symptoms and the common immune-mediated medical co-morbidities of ASD. Identification of neuroimaging or inflammatory biomarkers that respond to immune modulatory treatment and correlate with treatment response would further support the hypothesis of an immune-mediated subtype of ASD and aid in measuring response to immune modulatory treatments. In addition, it will be important to determine if particular immune modulating treatments are best tolerated and most effective when administered at specific developmental time points across the lifespan of individuals with ASD.

Here are the drugs they listed:-

1.     Metabolic disease

Spironolactone

Pioglitazone

Pentoxifylline

Spironolactone is a cheap potassium sparing diuretic. It has secondary effects that include reducing the level of male hormones and some inflammatory cytokines.

Pioglitazone is drug for type 2 diabetes that improves insulin sensitivity.  It reduces certain inflammatory cytokines making it both an autism therapy and indeed a suggested Covid-19 therapy.

Pentoxifylline is a non-selective phosphodiesterase (PDE) inhibitor, used to treat muscle pain.  PDE inhibitors are very interesting drugs with a great therapeutic potential for the treatment of immune-mediated and inflammatory diseases.  Roflumilast and Ibudilast are PDE4 inhibitors that also may improve some autism.  The limiting side effect can be nausea/vomiting, which can happen with non-selective PDE4 inhibitors.

I did try Spironolactone once; it did not seem to have any effect.  It is a good match for bumetanide because it increases potassium levels.

I do think that Pioglitazone has a helpful effect and there will be another post on that.

PDE inhibitors are used by readers of this blog. Maja is a fan of Pentoxifylline, without any side effects. Roflumilast at a low dose is supposed to raise IQ, but still makes some people want to vomit. The Japanese drug Ibudilast works for some, but nausea is listed as a possible side effect.

2.     Infectious disease

Minocycline

Vancomycin

Suramin

Minocycline is an antibiotic that crosses in to the brain.  It is known to stabilize activated microglia, the brain’s immune cells.  It is also known that tetracycline antibiotics are immunomodulatory.

Vancomycin is an antibiotic used to treat bacterial infections, if taken orally it does not go beyond the gut.  It will reduce the level of certain harmful bacteria including Clostridium difficile.

Suramin is an anti-parasite drug that Dr Naviaux is repurposing for autism, based on his theory of cell danger response.

  

3.     Neurology

Valproic acid

Valproic acid is an anti-epileptic drug.  It also has immunomodulatory and HDAC effects, these effects can both cause autism when taken by a pregnant mother and also improve autism in some people.

Valproic acid can have side effects. Low dose valproic acid seems to work for some people. 

4.     Gastroenterology

Fecal microbiota transplant (FMT)

FMT is currently used to treat recurrent Clostridium difficile infection and may also be of benefit for other GI conditions including IBD, obesity, metabolic syndrome, and functional GI disorders.

Altered gut bacteria (dysbiosis) is a feature of some autism which then impairs brain function.  Reversing the dysbiosis with FMT improves brain function.  

5.     Oncology

Lenalidomide

Romidepsin

  

Lenalidomide is an expensive anti-cancer drug that also has immunomodulatory effects.

Romidepsin is a potent HDAC inhibitor, making it a useful cancer therapy.  HDAC inhibitors are potential autism drugs, but only if given early enough not to miss the critical periods of brain development. 

6.     Pulmonology

N-acetylcysteine

Many people with autism respond well to NAC. You do need a lot of it, because it has a short half-life.

7.     Nutritional medicine and dietary supplements

Omega-3 fatty acids

Vitamin D

Flavonoids

Nutritional supplements can get very expensive.  In hot climates, like Egypt, some dark skinned people cover up and then lack vitamin D.  A lack of vitamin D will make autism worse.

Some people with mild brain disorders do seem to benefit from some omega-3 therapies.

Flavonoids are very good for general health, but seem to lack potency for treating brain disorders.  Quercetin and luteolin do have some benefits. 

8.     Rheumatology

Celecoxib

Corticosteroids

Intravenous immunoglobulin (IVIG)

Celecoxib is a common NSAID that is particularly well tolerated (it affects COX-2 and only marginally COX-1, hence its reduced GI side effects).

NSAIDS are used by many people with autism.

Steroids do improve some people’s autism, but are unsuitable for long term use.  A short course of steroids reduces Covid-19 deaths – a very cost effective therapy.

IVIG is extremely expensive, but it does provide a benefit in some cases. IVIG is used quite often to treat autism in the US, but rarely elsewhere other than for PANS/PANDAS that might occur with autism.

9.     Regenerative medicine

Stem cell therapy

I was surprised they gave stem cell therapy a mention. I think it is still early days for stem cell therapy.

Conclusion

I have observed the ongoing Covid-19 situation with interest and in particular what use has been made of the scientific literature.

There are all sorts of interesting snippets of data. You do not want to be deficient in Zinc or vitamin D, having high cholesterol will make it easier for the virus to enter your cells.  Potassium levels may plummet and blood becomes sticky, so may form dangerous clots. A long list of drugs may be at least partially effective, meaning they speed up recovery and reduce death rates. Polytherapy, meaning taking multiple drugs, is likely to be the best choice for Covid-19.

Potential side effects of some drugs have been grossly exaggerated, as with drugs repurposed for autism.  Even in published research, people cheat and falsify the data. In the case of hydroxychloroquine, the falsified papers were quickly retracted.

The media twist the facts, to suit their narrative, as with autism.  This happens even with Covid-19. Anti-Trump media (CNN, BBC etc) is automatically anti-hydroxychloroquine, and ignores all the published research and the results achieved in countries that widely use it (small countries like China and India). 

Shutting down entire economies when only 5-10% of the population have been infected and hopefully got some immunity, does not look so smart if you are then going to reopen and let young people loose.  They will inevitably catch the virus and then infect everyone else. Permanent lockdown restrictions, if followed by everyone, until a vaccine which everyone actually agreed to take, makes sense and living with the virus makes sense, but anything in between is not going to work. After 3 months without any broad lockdown, and allowing young people to socialize, most people would have had the virus and then those people choosing to shield could safely reemerge. The death rate with the current optimal, inexpensive treatment, as used in India or South Africa is very low, in people who are not frail to start with. Time to make a choice.  Poor people in poor countries cannot afford to keep going into lockdown, they need to eat.

What hope is there for treating a highly heterogeneous condition like autism, if it is not approached entirely rationally and without preconceptions and preconditions?  In a pandemic we see that science does not drive policy and translating science into therapy is highly variable.  The science is there for those who choose to read it.

I frequently see comments from parents who have seen some of the research showing that autism has an inflammatory/auto-immune component.  They ask why this has not been followed up on in the research.  It has been followed up on.  It just has not been acted upon.

Why has it not been acted on?

This missing stage is called “translation”.  Why don’t doctors translate scientific findings into therapy for their patients?

What is common sense to some, is “experimental” to others. “Experimental” is frowned upon in modern medicine, but innovation requires experimentation.

Many people’s severe autism is unique and experimental polytherapy/polypharmacy is their only hope.

The cookie cutter approach is not going to work for autism. 

Thankfully, for many common diseases the cookie cutter approach works just fine.

Do the authors of today’s paper, Dr McDougle and Dr Thom, actually prescribe to their young patients many of the drugs that they have written about?  I doubt it and therein lies the problem.  

Time for that wizard, perhaps? 

A few years ago I did add the following tag line, under the big Epiphany at the top of the page. 

An Alternative Reality for Classic Autism - Based on Today's Science

You can choose a different Autism reality, if you do not like your current one.  I am glad I did. I didn't even need a wizard.  

There are many immuno-modulatory therapies for autism that the Massachusetts doctor duo did not mention, but it is good that they made a start.