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.