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Showing posts with label Daxas. Show all posts
Showing posts with label Daxas. Show all posts

Thursday 22 June 2023

Autism Research Merry-go-round Keeps Turning

 


Today’s post again shows that many issues raised in previous posts keep on coming back  is that good news? Only you can decide.

I start with the “old chestnut” (English idiom to imply “a tired old story”) of the Autism Tsunami. 

Then we see what has come up in the world of autism interventions in the research in the last 3 weeks, most of which regular readers will already be aware of.

·        Autism Tsunami – real or not?

·        Vitamin D

·        Bumetanide

·        Ibudilast

·        Niclosamide

·         Non-invasive brain stimulation

·         Simvastatin 

I noted the research about autism incidence coming from Northern Ireland because it was published in the Belfast News Letter.  These days it has a tiny subscription, but I am one of those who know it is the world's oldest English-language general daily newspaper still in publication, having first been printed in 1737. In 1972 a bomb warning was called in to the paper's office and, as people evacuated, an explosion went off nearby killing several people and injuring many more. Back in the early 1990s, when some people in Northern Ireland were still blowing up others with bombs, I made a visit to Northern Ireland to meet the management of this newspaper. 

Their recent article on autism incidence is very well researched considering how only about 8,000 copies are published. Keep up the good work!

Idea that 5% of all Northern Ireland's children are autistic is 'a fantasy' claims international expert

Professor Laurent Mottron was speaking to the News Letter following a claim that the rate of autism in Northern Ireland is double the rate in the rest of the UK.

Back in 2019 Prof Mottron had authored a report warning about a tsunami of over-diagnosis, saying that soon "the definition of autism may get too vague to be meaningful, trivializing the condition"

“If this trend holds, the objective difference between people with autism and the general population will disappear in less than 10 years," he had said then – and has now indicated that this “fuzziness” is what’s helping swell the numbers in Northern Ireland.

Meanwhile Jill Escher, the president of the National Council on Severe Autism, takes a different view.

She says that evidence indicates the "skyrocketing" rate of autism in Northern Ireland is real, adding: "It boggles my mind that it is not the subject of the highest possible alarm and inquiry."

"One in 20 children in Northern Ireland of school age has a diagnosis of autism," he told MPs.

"[It is] one in 57 in the rest of the UK. The need in Northern Ireland is significantly different."

To put that in perspective, that would mean 5% of Northern Irish children are diagnosed with autism, compared with 1.8% in the rest of the UK.

Prof Mottron, a psychiatrist based at Montreal University, told the News Letter "numbers such as 5% are pure fantasy... these numbers correspond to the part of the general population which has less overt socialisation, which has minimally to do with prototypical autism". 

There is a "current fuzziness of autism diagnosis and over-inclusivity," he said, leading to "a situation of perfect confusion between autistic traits and prototypical autism" (that is, mixing up people who exhibit some tendencies of autistic people with people who actually have the full-blown condition). 

"The scientific 'quasi consensus' would be around 1% everywhere on the planet,” he added.

 

So on one side we have Jill Escher and her NCSA and on the other we have a French/Canadian researcher.  This time Laurent Mottron but in my blog posts I quoted Éric Fombonne.

A paper that was mentioned both in my blog and critiqued by Jill about autism incidence and cost just got retracted.  In reality a better word is “cancelled.”  The 3 authors are very much in the politically incorrect camp of the autism debate.

I was surprised it ever got published.  

Controversial ‘cost of autism’ paper retracted 

Citing methodological issues and undeclared conflicts of interest, an autism journal has retracted a paper that forecast the prevalence and cost of autism.

The retraction note, posted last week, comes two years after Spectrum reported on backlash surrounding the paper, which was published in the Journal of Autism and Developmental Disorders in July 2021. A month after publication, the journal added an editor’s note that the study was under investigation because of criticisms of its conclusions. 

“I am glad to see that it was retracted, although at a pace that maybe is a bit frustrating in terms of how long it took. But it was the right choice,” says Brittany Hand, associate professor of health and rehabilitation sciences at Ohio State University in Columbus.

Outside experts who reviewed the paper on the journal’s behalf found that it misrepresented the rise in autism diagnoses and gave “insufficient attention” to some potential causes of the increase, such as improved surveillance and changes to the diagnostic criteria. The authors also used “higher estimates and assumptions that inflated costs,” according to the retraction note.

The authors — Mark Blaxill, Toby Rogers and Cynthia Nevison — all disagree with the journal’s decision, the note also says.

The cancelled paper is here:-

Autism Tsunami: the Impact of Rising Prevalence on the Societal Cost of Autism in the United States

 

I assume Blaxill was the driving force behind all the math, because he is the ex- management consultant, with a son with severe autism that his dad attributes to vaccines.

What I found bizarre in their paper was that they has a prevention scenario, based on what they think has already happened in rich parts of California, where they think autism incidence is falling.  It is not falling, all that is happening is that wealthy Californians are paying for treatment using insurance or their own money, and no longer burdening the State.

The “rainbow” researchers that wanted the paper retracted think that preventing autism is akin to eugenics and Dr Mengele. According to Peter, treating autism is good, while Dr Josef Mengele, byname Todesengel (German: “Angel of Death”) was as bad as you can get.    

Jill Escher and her NCSA think that you cannot prevent autism.  According to Peter, you can both minimize the incidence and severity of autism. 

A bugbear of our reader Tanya is that the NCSA have a pet hate of facilitated communication and in particular the rapid prompting method (RPM). This method worked for Tanya’s son and it opened the door to independent, un-facilitated communication. 

Always keep an open mind.

 

 

 

“our Prevention scenario is based on real rates observed among wealthy white and Asian children in the California DDS.  Severe ASD prevalence has flattened and even declined among these children since birth year 2000, suggesting that wealthy parents have been making changes that effectively lower their children’s risk of developing ASD. The Prevention scenario assumes that these parental strategies and opportunities already used by wealthy parents to lower their children’s risk of ASD can be identified and made available rapidly to lower income children and ethnic minorities, who are currently experiencing the most rapid growth in ASD prevalence”

 

New Paper Makes Case that Autism Tsunami May Threaten American Economy

A major weakness in the analysis was the “Prevention Scenario” in which future costs were projected based on “what might be possible if strategies for reducing ASD risk are identified and addressed in the near future.” As I think everyone knows, at this time there is no way to prevent autism. But the authors use the observation that autism in the DDS is declining among wealthier white families, and thus “suggesting that wealthy parents have been making changes that effectively lower their children’s risk of developing ASD.” No, it’s far more likely that wealthier families are not entering their children into the system because they access services through insurance and school districts instead.

 

Vitamin D as a cause of autism has been discussed for decades.  As the title below puts it – a never-ending story. Our reader Seth Bittker even wrote a paper about it. He later wrote a paper about the use Acetaminophen/Paracetamol in children under two as a risk factor in developing autism. Good work Seth!

 

Maternal Vitamin D deficiency and brain functions: a never-ending story 

A large number of observational studies highlighted the prevalence rates of vitamin D insufficiency and deficiency in many populations as pregnant women. Vitamin D is well known to have a crucial role in differentiation and proliferation, as well as neurotrophic and neuroprotective actions in brain. Then, this micronutrient can modulate the neurotransmission and synaptic plasticity. Recent results from animal and epidemiological studies indicated that maternal vitamin D deficiency is associated with a wide range of neurobiological disease including autism, schizophrenia, depression, multiple sclerosis or developmental defect. The aim of this review is to provide a state of the art on the effect of maternal vitamin D deficiency on brain functions and development.

4.2.2. Autism

Autism spectrum disorder (ASD) is a complex neurodevelopmental disease with repetitive behaviour and difficulties in social interaction, communication and learning. Several murine studies and cohorts have demonstrated that early exposure to low levels of VD during pregnancy could be a risk factor for ASD. In 2019, Ali et al. aimed to find out the impact of a maternal VDD on early postnatal, adolescent and adult offspring. By assessing righting reflex and negative geotaxis, they found out that the pups from deficient dams showed a delay in their motor development. P12 rats from deficient females also exhibited increased ultrasound vocalization indicating an alteration in their vocal communication. Adolescent and young adult rats displayed an altered stereotyped repetitive behaviour as they had a reduced digging behaviour. Adolescent rats had less social interaction with longer latency to interact, which was not found in adult rats; however, adults were more hyperactive but showed no anxiety like behaviour.  In another animal study, maternal VDD induced an increase in the vocalizations of the pups accompanied with a decrease in cortical FoxP2, decrease in social behaviour and impaired learning and memory were observed in adult males (Table 1). Using data from the Stockholm youth cohort, Magnusson et al. examined a population of 4-17-year-old children exposed to low levels of VD during gestation and was able to report a positive association between maternal VDD and ASD. Analysing the same cohort, Lee et al. suggested that high levels of VD during pregnancy were associated with a moderate decrease in risk of ASD in the offspring. A prospective study of a multi-ethnic cohort in the Netherlands (generation R study) has also shown an association between maternal mid-gestation VDD and a two-fold increase in the risk of autism in children (Table 2). Interestingly, VD supplementation seems to clinically improve ASD symptoms of affected children.

 

People do associate this blog with Bumetanide.  Yet another paper has been published showing the benefits of this therapy for autism.

 

EEG-based brain connectivity analysis in autism spectrum disorder: Unravelling the effects of bumetanide treatment 


Highlights

 

·        We investigated the nonlinear brain connectivity and topological changes in brain networks of people with autism spectrum disorders (ASD) after a three-month course of bumetanide treatment.

·        We found statistically significant differences between pre and post intervention in the connectivity patterns using repeated measures analysis of variance (ANOVA).

·        We found that the number of strong connections in response to sad image stimuli seem to be less compared with that of the other two stimuli, especially in the central area.

·        We found that the changes in brain connectivity between pre and post intervention is more significant in response to sad image stimuli.

 

Emerging evidence suggests that cognitive impairment associated with brain network disorders in people with autism could be improved with medications such as bumetanide. However, the extent to which bumetanide is effective in improving brain function in these individuals has not been adequately studied. The main purpose of this study is to investigate the nonlinear brain connectivity and topological changes in brain networks of people with autism spectrum disorders (ASD) after a three-month course of bumetanide treatment. We used electroencephalography (EEG) data of nine participants recorded during the face emotion recognition activity in two stages before and after bumetanide treatment. Brain connectivity matrix was calculated using a neural network-based estimator. Graph criteria and statistical tests have been used to determine the effects of bumetanide treatment on children and adolescents with autism. Bumetanide treatment significantly alters the brain connectivity networks based on stimuli type. Differences in brain connectivity related to the sad stimuli are more significant. The most of the significant changes of the strength graph metric was in the occipital electrodes and electrodes related to the right hemisphere. These results suggest that bumetanide may affect effective connectivity and be used a promising treatment for improving social interactions in patients with autism. It also suggests that brain connectivity patterns can be considered as a neural marker to be used in the development of new therapies. 

I have also covered in sometimes painful details the potential to treat autism and increase cognitive function using PDE (Phosphodiesterase) inhibitors. One of our psychiatrist readers is a huge fan of Pentoxifylline and takes it himself.

I was recently asked how to obtain Ibudilast.  It is approved in Japan as an asthma drug. Sometimes it is called Ketas and you can get it from an “International Pharmacy” in Germany/Switzerland if you have a prescription. 

I also wrote about repurposing Roflumilast, which as Daxas is approved all over the world as a therapy for severe asthma (COPD). This drug at a 1/5th dose has been patented as a cognitive enhancer.

 

Phosphodiesterase inhibitor, ibudilast alleviates core behavioral and biochemical deficits in the prenatal valproic acid exposure model of autism spectrum disorder

 

Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder, presenting with a variety of aetiological and phenotypical features. Ibudilast is known to produce beneficial effects in several neurological disorders including neuropathic pain, multiple sclerosis, etc. by displaying its neuroprotective and anti-inflammatory properties. Here, in our study, the pharmacological outcome of ibudilast administration was investigated in the prenatal valproic acid (VPA)-model of ASD in Wistar rats.

Methods

Autistic-like symptoms were induced in Wistar male pups of dams administered with Valproic acid (VPA) on embryonic day 12.5. VPA-exposed male pups were administered with two doses of ibudilast (5 and10 mg/kg) and all the groups were evaluated for behavioral parameters like social interaction, spatial memory/learning, anxiety, locomotor activity, and nociceptive threshold. Further, the possible neuroprotective effect of ibudilast was evaluated by assessing oxidative stress, neuroinflammation (IL-1β, TNF-α, IL-6, IL-10) in the hippocampus, % area of Glial fibrillary acidic protein (GFAP)-positive cells and neuronal damage in the cerebellum.


Key findings: Treatment with ibudilast significantly attenuated prenatal VPA exposure associated social interaction and spatial learning/memory deficits, anxiety, hyperactivity, and increased nociceptive threshold, and it decreased oxidative stress markers, pro-inflammatory markers (IL-1β, TNF-α, IL-6), and % area of GFAP-positive cells and restored neuronal damage.

Conclusions

Ibudilast treatment has restored crucial ASD-related behavioural abnormalities, potentially through neuroprotection. Therefore, benefits of ibudilast administration in animal models of ASD suggest that ibudilast may have therapeutic potential in the treatment of ASD.

 

 

I have also written widely about repurposing certain anti-parasite medicines to treat autism. This is not because I think parasites cause autism, it is the secondary modes of action.

 

 

Repurposing Niclosamide as a plausible neurotherapeutic in autism spectrum disorders, targeting mitochondrial dysfunction: a strong hypothesis

 

 

Autism Spectrum Disorders (ASD) are a complex set of neurodevelopmental manifestations which present in the form of social and communication deficits. Affecting a growing proportion of children worldwide, the exact pathogenesis of this disorder is not very well understood, and multiple signaling pathways have been implicated. Among them, the ERK/MAPK pathway is critical in a number of cellular processes, and the normal functioning of neuronal cells also depends on this cascade. As such, recent studies have increasingly focused on the impact this pathway has on the development of autistic symptoms. Improper ERK signaling is suspected to be involved in neurotoxicity, and the same might be implicated in autism spectrum disorders (ASD), through a variety of effects including mitochondrial dysfunction and oxidative stress. Niclosamide, an antihelminthic and anti-inflammatory agent, has shown potential in inhibiting this pathway, and countering the effects shown by its overactivity in inflammation. While it has previously been evaluated in other neurological disorders like Alzheimer’s Disease and Parkinson’s Disease, as well as various cancers by targeting ERK/MAPK, it’s efficacy in autism has not yet been evaluated. In this article, we attempt to discuss the potential role of the ERK/MAPK pathway in the pathogenesis of ASD, specifically through mitochondrial damage, before moving to the therapeutic potential of niclosamide in the disorder, mediated by the inhibition of this pathway and its detrimental effects of neuronal development.

 

Note that in earlier posts I explored RASopathies as potentially treatable types of intellectual disability (ID). We also have RAS-dependent cancers as a discrete treatable sub-type of cancer.


The ERK/MAPK pathway is known to interact with multiple genes that have been implicated in autism, and genome-wide association analysis of the same have supported these findings. As such, a dysregulation of this pathway has been found to result in many CNS disorders, including ASD-related syndromes, in many studies. These syndromes are collectively known as Rasopathies, due to the fact that the affected genes include those encoding for elements which function together with Ras, a G-protein responsible for activating ERKs (Levitt and Campbell 2009; Tidyman and Rauen 2009). It has been found that ASD is linked to the occurrence of many Rasopathies, and there have been multiple reports suggesting the possible relation of ERK/MAPK pathway defects with the incidence of ASD (Vithayathil et al. 2018; Aluko et al. 2021)⁠⁠. Moreover, a detailed study has found that single nucleotide polymorphisms (SNPs) in the ERK/MAPK-related genes are more common in subjects presenting with idiopathic ASD.

 

Niclosamide is an FDA-approved antihelminthic drug which is routinely used to treat tapeworm infections by inhibiting their mitochondrial oxidative phosphorylation and ATP production. In addition, it has long been known to have significant immunomodulating activity, and has been shown to inhibit a number of signaling pathways, including the Wingless-related integration site (Wnt)/β-catenin, nuclear factor kappa B (Nf-κB), signal transducer and activator of transcription 3 (STAT3), and mammalian target of rapamycin (mTOR) (Chen et al. 2018). However, while these targets are known to be rather well-characterized in terms of the effect that niclosamide has on them, there are also other targets, including the phosphoinositode 3 kinase/Akt (PI3K/Akt) and ERK/MAPK pathways, that are seen to be downregulated by the agent. Hence, given the possible relation of the ERK pathway in autism, there has been interest in the potential role of niclosamide in the management of the prognosis of ASD. This article aims to discuss the possible therapeutic benefit of niclosamide in the treatment of autism spectrum disorders.

 

Now I know that parents like the idea of treating autism with various gadgets you can strap on to your head  things like Transcranial Magnetic Stimulation (TMS). I must say I liked my old post on Photobiomodulation/cold laser/low level laser therapy.


Epiphany: Low Level Laser Therapy (LLLT) for Autism – seems to work in Havana


From China we have a new round-up paper, but the full text does not yet seem to be ready.

 

Non-invasive brain stimulation for Patient with Autism A Systematic Review and Meta-Analysis

Objective: To comprehensively evaluate the efficacy of non-invasive brain stimulation (NIBS) in patients with autism spectrum disorder (ASD) in randomized controlled trials (RCT),providing reference for future research on the same topic.

Methods:Five databases were searched (Pubmed,Web of science,Medline,Embase and Cochrane library) and track relevant references,Meta-analysis was performed using RevMan 5.3 software.

Results: Twenty-two references(829 participants) were included. The results of meta analysis showed that, NIBS had positive effects on repetitive and stereotypical behaviors, cognitive function and executive function in autistic patients. Most of the included studies had a moderate to high risk of bias, Mainly because of the lack of blinding of subjects and assessors to treatment assignment, as well as the lack of continuous observation of treatment effects.

Conclusions: Available evidence supports an improvement in some aspects of NIBS in patients with ASD. However, due to the quality of the original studies and significant publication bias, these evidences must be treated with caution. Further large multicenter randomized double-blind controlled trials and appropriate follow-up observations are needed to further evaluate the specific efficacy of NIBS in patients with ASD.


Unfortunately, the Chinese have concluded that most of these studies are not reliable. So no laser for me to go out and buy just yet.

No need to dent your bank balance with the next therapy.  We are back to one of the world's most prescribed and therefore affordable drugs, its Simvastatin (Zocor). 

There is masses of information in this blog about the potential to treat sub-types of autism with Atorvastatin, Simvastatin or Lovastatin. They are each slightly different.

 

Effect of simvastatin on brain-derived neurotrophic factor (BDNF)/TrkB pathway in hippocampus of autism rat model 

Purpose: To study the effect of simvastatin on behavioral performance in a rat model of autism, and its effect on hippocampal brain-derived BDNF-TrkB pathway. 

Methods: Twelve rats with valproic acid (VPA)-induced autism were randomly divided into model group and simvastatin group, while six healthy rats served as normal control group. Rats in the simvastatin group received the drug (5 mg/kg) via i.p. route, while rats in model group and normal control group were injected with equivalent volume of normal saline in place of simvastatin. Capacity for interaction and repetitive stereotyped behavior, as well as results of Morris water maze test were determined for each group. The expressions of BDNF-TrkB proteins were assayed with immunoblotting. 

Results: The frequencies of sniffing normal saline, alcohol and rat urine were significantly higher in model and simvastatin rats than in normal rats, but they were significantly lower in simvastatin-treated rats than in model rats (p < 0.05). There was higher duration of turning, jumping and grooming in the model group and simvastatin group than in the normal rats, but the duration was significantly reduced in simvastatin rats, relative to model rats. Escape latency times was significantly longer in model and simvastatin rats than in controls, but number of target quadrant crossings was significantly reduced. However, escape latency time was lower in simvastatin rats than in model rats, but number of target quadrant crossings was significantly higher. The model and simvastatin rats had down-regulated levels of BDNF and TrkB protein, relative to control rats, but there were markedly higher levels of these proteins in simvastatin-treated rats than in model rats. 

Conclusion: Simvastatin improves the behavioral performance of autistic rats by regulating BDNF/TrkB signal axis. This finding may be useful in the development of new drugs for treating autism.

  

Conclusion

What is the conclusion? Well, I could say give up reading the new research and just read my old posts.  It seems you are not going to miss very much.

Of course, back in the real world, it is true that things do take time to change and after a few decades the leap might be taken from the research to the doctor’s office.

There already is plenty of research on the causes of autism and what steps can be taken by those who want to treat aspects of it.  It is far from a complete picture, but it is enough to get started.  There are no guarantees of success, but if you want 100% certainty you will wait forever.








Tuesday 1 June 2021

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.

 



 

 

Wednesday 24 March 2021

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 A2A 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.