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Showing posts with label ADHD. Show all posts
Showing posts with label ADHD. Show all posts

Friday, 18 September 2020

Betahistine is in the Pipeline for ADHD, but will it help Autism? Maybe for some, but not for others





 Will Betahistine provide a benefit?

Today’s post is the logical follow on from the post showing that the new drug compound E-100 gives a benefit in two models of autism.

Another Potential Autism Therapy - novel compound E100 from Krakow, a combined histamine H3 receptor blocker (H3R antagonist) and an acetylcholine esterase inhibitor (AChEI)



We saw that E-100 has two modes of action, thought to be complementary:-

·        Acetylcholinesterase inhibitor (AChEI)
·        Histamine H3 antagonists (H3R antagonist)

I think our reader Rene is thinking along the lines I suggested that you might achieve the same effects with existing generic drugs.  One combination would be Donepezil plus Betahistine.

Donepezil has long been studied in autism, a recent example is here:


The safety and efficacy of a novel combination treatment of AChE inhibitors and choline supplement was initiated and evaluated in children and adolescents with autism spectrum disorder (ASD). Safety and efficacy were evaluated on 60 children and adolescents with ASD during a 9-month randomized, double-blind, placebo-controlled trial comprising 12 weeks of treatment preceded by baseline evaluation, and followed by 6 months of washout, with subsequent follow-up evaluations. The primary exploratory measure was language, and secondary measures included core autism symptoms, sleep and behavior. Significant improvement was found in receptive language skills 6 months after the end of treatment as compared to placebo. The percentage of gastrointestinal disturbance reported as a side effect during treatment was higher in the treatment group as compared to placebo. The treatment effect was enhanced in the younger subgroup (younger than 10 years), occurred already at the end of the treatment phase, and was sustained at 6 months post treatment. No significant side effects were found in the younger subgroup. In the adolescent subgroup, no significant improvement was found, and irritability was reported statistically more often in the adolescent subgroup as compared to placebo. Combined treatment of donepezil hydrochloride with choline supplement demonstrates a sustainable effect on receptive language skills in children with ASD for 6 months after treatment, with a more significant effect in those under the age of 10 years.

I was not aware that a lot of money is being spent preparing to bring Betahistine to the US as a treatment for ADHD (Attention Deficit Hyperactivity Disorder).

Outside the US, Betahistine is cheap generic drug that is widely available.  It is used in adults for vertigo and tinnitus etc.  It is not approved for use in children, but that just means its use was never studied in children.  It was envisaged as a drug for older people.

In the US, Betahistine is not an approved drug, so if the promoter gets it approved for ADHD they will not have any cheap competition.  They might even make it in the form of nasal spray, which they say makes Betahistine much more bioavailable.  It would also make it look like a modern drug, rather than just an old drug sold for a high price.


48 mg Oral dose vs varying intranasal doses



The promoter’s idea is to use a lower dose of Betahistine intranasally and yet be more potent/effective than the oral tablet now used to treat vertigo.  They also want to use it to treat antipsychotic-induced weight gain, which seems to be a huge problem and a $600 million a year market they suggest.  It appears after this they want to use Betahistine to treat ADHD and depression.




Life on an anti-psychotic, without Betahistine

Betahistine might start as a drug for young adults with ADHD, but ADHD is normally seen as a childhood disorder (something like 7% of US school children have taken ADHD drugs) the promoter will have to carry out studies to show it is safe for pediatric use.  They are actually trialing quite high doses orally for ADHD.


Betahistine in autism, without ADHD

I am not sure that Betahistine, or E-100, is going to have a good overall effect in autism in humans.  E-100 does look good in two mouse models of autism.

Acting via the histamine H3 receptor, Betahistine will increase the levels of neurotransmitters histamineacetylcholinenorepinephrineserotonin, and GABA.  In any specific case of idiopathic autism, some of these effects may be beneficial, but quite possibly not all.

If you have GABA still working in reverse, as in some Bumetanide-responsive autism, increasing the level of GABA will cause agitation and aggression, just like taking Valium does.

The active metabolite of Betahistine is something called 2-PAA and the level peaks in your blood about an hour after taking the pill. There certainly is potential for a negative reaction, but it would fade gradually over the next few hours.  The half-life is 3.5 hours.

In the ADHD trials of Betahistine agitation was listed as a possible side effect. The promoter does say that overall the drug is very well tolerated.


Auris Medical Announces Closing of Two US Patent Acquisitions Related to the Use of Betahistine for the Treatment of Depression and ADHD

 Betahistine is a small molecule structural analog of histamine, which acts as an agonist at the H1 and as an antagonist at the H3 histamine receptors. Unlike histamine, it crosses the blood-brain-barrier. It is known to enhance inner ear and cerebral blood flow, increase histamine turnover and enhance histamine release in the brain, increase release of acetylcholine, dopamine and norepinephrine in the brain and to result in general brain arousal. Betahistine for oral administration is approved in about 115 countries, with the US being a notable exception, for the treatment of vertigo and Meniere’s disease. The compound has a very good safety profile, yet it is also known that its clinical utility is held back by poor bioavailability. Intranasal administration of betahistine has been shown to result in 4 to 26 times higher bioavailability.



Safety first



Betahistine, a potent histamine H3 receptor antagonist, is being developed for the treatment of attention deficit hyperactivity disorder (ADHD) that manifests with symptoms such as hyperactivity, impulsivity and inattention. This study describes the pharmacokinetics of betahistine in ADHD subjects at doses higher than 50 mg. These assessments were made during a randomized, placebo-controlled, single blind, dose escalation study to determine the safety, tolerability and pharmacokinetics of once daily doses of 50 mg, 100 mg and 200 mg of betahistine in subjects with ADHD. Plasma levels of 2-pyridylacetic acid (2-PAA), a major metabolite of betahistine were quantified using a validated LC-MS/MS method and used for pharmacokinetic analysis and dose proportionality of betahistine. A linear relationship was observed in Cmax and AUC0-4 of 2-PAA with the betahistine dose (R2 0.9989 and 0.9978, respectively) and dose proportionality coefficients (β) for the power model were 0.8684 (Cmax) and 1.007 (AUC0-4). A population pharmacokinetic model with first-order absorption of betahistine and metabolism to 2-PAA, followed by a first-order elimination of 2-PAA provides estimates of clearance that underscored the linear increase in systemic exposure with dose. There were no serious adverse events reported in the study, betahistine was safe and well tolerated at all the dose levels tested.


Pharmacokinetics and Dose Proportionality of Betahistine in Healthy Individuals


Betahistine dihydrochloride is widely used to reduce the severity and frequency of vertigo attacks associated with Ménière’s disease. Betahistine is an analogue of histamine, and is a weak histamine H1 receptor agonist and potent histamine H3 receptor antagonist. The recommended therapeutic dose for adults ranges from 24 to 48 mg given in doses divided throughout the day. Betahistine undergoes extensive first-pass metabolism to the major inactive metabolite 2-pyridyl acetic acid (2PAA), which can be considered a surrogate index for quantitation of the parent drug due to extremely low plasma levels of betahistine. The aim of the present investigation was to assess the pharmacokinetics and dose proportionality of betahistine in Arabic healthy adult male subjects under fasting conditions. A single dose of betahistine in the form of a 8, 16, or 24 mg tablet was administered to 36 subjects in randomized, cross-over, three-period, three-sequence design separated by a one week washout period between dosing. The pharmacokinetic parameters Cmax, AUC0–t, AUC0–∞, Tmax, and Thalf were calculated for each subject from concentrations of 2-PAA in plasma, applying non-compartmental analysis. The current study demonstrated that betahistine showed linear pharmacokinetics (dose proportionality) in an Arabic population over the investigated therapeutic dose range of 8–24 mg



Conclusion

I think Rene is right to be curious about whether the benefit of E-100 in autism models can be replicated today with cheap generic compounds.  Our readers who are doctors outside the US will be familiar with Betahistine, a cheap drug sitting on the shelf in their local pharmacy.

In my N=1 case of autism I am not so optimistic, because I did once follow up on another idea in the published literature.  That idea was to “fix” GABAA receptors with bumetanide/bromide and then “increase GABA”, in lay-speak. It was in this post from 2015:  “More GABA” for Autism and Epilepsy? Not so Simple







GABA is not supposed to cross the blood brain barrier (BBB), but when combined with niacin the Russians discovered it does, the result was the prodrug Picamilon (until recently sold in the US as a supplement). Some people with autism do take Picamilon.

In my case of autism, a single small dose of Picamilon had a pronounced negative effect, which I interpreted as GABA still acting as excitatory (it should be inhibitory).  It is possible that the niacin part of Picamilon was the problem.

Taurine is an agonist of GABAA receptors, so it will also act like “increasing GABA”



Very many people with autism take Taurine. Some people with autism who take Leucovorin (calcium folinate) also take Taurine to reduce its side effects.

Some people take Bumetanide and Taurine, which is surprising.

The original intended use of Leucovorin is for people undergoing chemotherapy, to reduce its side effects. Taurine is also used to reduce the side effects of chemotherapy. So not a surprise to see that Leucovorin is often together prescribed with Taurine, but that is in people fighting cancer.

In autism, there is no chemotherapy and so what is the rational to prescribe Taurine with Leucoverin?

Perhaps, by chance more than anything else, Taurine does reduce the aggression that is a common side effect of Leucovorin.  I hope it does.

My conclusion is that for plenty of people with autism, and particularly those who tolerate/use Taurine or Picamilon,  Betahistine’s effect on GABA should not cause a problem. When Betahistine gets FDA approval for pediatric use in ADHD, parents in the US will likely have little difficult getting a prescription for their child with autism. ADHD is highly comorbid with autism.

If Betahistine gives a benefit and is well tolerated, all you have to do is add Donepezil or Galantamine and you have something very similar to the research drug E-100, that shines in those two mouse models of autism.

I think the effect of Betahistine  increasing the levels of neurotransmitters histamineacetylcholinenorepinephrineserotonin, and GABA released from the nerve endings is likely to be occur from the first dose. It makes sense that the effect on your inner ear takes weeks/months to develop.

I think the ADHD version of betahistine will be a much more potent dose than current generic tablets and it will be achieved intranasally.

Betahistine was withdrawn from sale in the US many years ago because it was thought not to be effective;  the chart further below shows otherwise. 

If you are an adult outside the US, with some hearing loss, it looks like you might want to ask your doctor for a trial of Betahistine.  It is safe and very cheap.  While researched for Ménière's disease, you can have sudden onset reduction in hearing caused by an inflammatory response due to a virus or bacteria, that produces something very similar in the inner ear to what gets diagnosed as Ménière's disease, as I discovered myself. 

Sudden onset hearing loss (SOHL) is a 30 dB or greater hearing loss over less than 72 hours, it is usually idiopathic (you never get to know what caused it).  It is thought that most people do not go to their doctor – big mistake. If you treat SOHL immediately with steroids, hearing loss should be temporary. For people with the inner ear disease Ménière's, it looks like they should benefit from Betahistine, and then be able to hear sounds 6 decibels quieter.  Is Betahistine going to benefit SOHL that was not treated in time?  It might be worth finding out.

 


Betahistine, acting via H3 receptors, reduces the pressure of the fluid that fills the labyrinth in the inner ear; it also is thought to improve blood supply.  The diuretic acetazolamide, covered in this blog because of its effects on ion channels relevant to autism, is also used to reduce fluid build-up in the inner ear in Ménière's disease.

When I had sudden onset hearing loss (SOHL), it was initially misdiagnosed and steroid therapy started very late, so I added some acetazolamide from my autism stock pile.  It all worked out well.

If someone reading this post goes on to try Betahistine off-label for:-

·        ADHD
·        Depression
·        Autism
·        Weight gain associated with antipsychotics, particularly Olanzapine
·        Previously untreated, sudden onset hearing loss (SOHL)

it would be interesting to know your results.

Take note that Betahistine is also a mild agonist of H1 receptors, which explains why it may cause mild nausea (H1 blockers are used to reduce nausea) for a short while after taking it.  This side effect seems not to appear if Betahistine is taken with or after a meal. Betahistine may also reduce the H1 histamine receptor effect of any H1 antihistamine drugs being taken.

Ultimately the new E-100 drug may well be the best solution.  Hopefully the UAE researchers will persevere to human trials, but that is something that would need a lot of time and money and probably will not happen.











Thursday, 3 October 2019

Elevated Prenatal Estradiol in Mothers/Babies – a protective reaction to stress that also predicts who will develop Autism? Time for Fetal Medicine?


There has been little mention in this blog about fetal medicine, but it is an area that does hold great promise.  At the Children’s Hospital of Philadelphia, they have been surgically treating babies with spina bifida prior to their birth for nearly twenty years. Early surgical intervention to the spine even allows for malformation of the brain to be self-repaired and this is visible on MRI scans. Such prenatal treatment can be 100% successful, resulting in there being no physical disability in adulthood. 

The more you read about neuroscience the more you realize how little we really know and so encouraging the brain to self-repair may indeed be the best strategy.  This is an avenue of research and not just with stem cells.  A similar approach is proving successful in treating skin cancer, you do not attack the cancer with drugs, you modify the immune system with a drug so it "wakes up" and does its job and kills the cancer cells.

        Skin cancer: Half of people surviving advanced melanoma

Hormones are an often-ignored area of autism research, but they are they on my Venn diagram simplification of autism.



We have seen how female hormones can be highly neuroprotective and that the estradiol/testosterone balance affects a key “switch” that controls gene expression RORalpha.

Today we see that researchers in Utah suggest that stress in the developing fetus with autism causes an increase in estradiol, as a protective mechanism, and this increase in estradiol can then be measured in the mother’s blood. They propose that this elevated estradiol is an advance warning of a baby with autism.



University of Utah researchers have discovered a link between increased levels of a type of estrogen in babies in their second trimester and risk for autism, according to a new study.

The findings could eventually help doctors identify babies at risk of autism early in their mothers’ pregnancies and monitor them more closely, as well as provide early interventions to ensure the children’s well-being, said Dr. Deborah A. Bilder, the study’s first author.

Both the control group and the group of mothers whose children had autism were selected so that 50% of each group had an exposure to a condition such as gestational diabetes, hypertension and preeclampsia. Previous studies have shown links between those conditions and autism risk.

The researchers looked at several different steroids in the blood samples. Bilder said she expected to find increased levels of steroids that were known to be associated with the conditions, like testosterone. She found those steroids, but they did not reach a statistical significance, according to Bilder.

Bilder also expected progesterone and testosterone in the kids who developed autism to be elevated.

“But that’s not what I found. Instead, what I found, is estradiol being elevated in the children who developed autism,” she said.

Estradiol is a type of estrogen. Lower levels of estradiol in a baby usually indicate a concern with the baby, and high estrogen levels are not currently associated with abnormal conditions.

But as the researchers looked at the steroid hormones that were measured, “what we realized is that the higher estrogen levels being produced by the placenta actually may be stimulating the baby’s development of his or her stress response.”
Usually, a baby’s stress response takes time so that when the pregnancy reaches full term, the baby has developed its own stress response. But elevated levels of estrogen cause the baby’s stress response to develop early, Bilder said.
That prepares babies, when there is an issue, to survive outside the mom. It causes early growth of the lungs, gut and skin so that if the baby doesn’t make it all the way through pregnancy, it’s more likely to survive, she said.

The findings indicated that in the babies with autism, something set off their stress response early.

Studies have shown that children with autism have an abnormal stress response, according to Bilder. She believes the mechanism that triggers the early stress response during pregnancy may still be affecting children with autism past delivery.

Bilder doesn’t think doctors should target the higher estradiol levels or try to lower them. Instead, because it signals a “protective mechanism, that baby is surviving,” doctors should target something that doesn’t jeopardize the baby’s survival.

“By being able to have a way of looking at the baby’s well-being in that regard, I think that opens up the door to considering how can you reduce the stress on that baby?” Bilder explained.
                                                                                 
The full paper:-

Early Second Trimester Maternal Serum Steroid-Related Biomarkers Associated with Autism Spectrum Disorder


Epidemiologic studies link increased autism spectrum disorder (ASD) risk to obstetrical conditions associated with inflammation and steroid dysregulation, referred to as prenatal metabolic syndrome (PNMS). This pilot study measured steroid-related biomarkers in early second trimester maternal serum collected during the first and second trimester evaluation of risk study. ASD case and PNMS exposure status of index offspring were determined through linkage with autism registries and birth certificate records. ASD case (N = 53) and control (N = 19) groups were enriched for PNMS exposure. Higher estradiol and lower sex hormone binding globulin (SHBG) were significantly associated with increased ASD risk. Study findings provide preliminary evidence to link greater placental estradiol activity with ASD and support future investigations of the prenatal steroid environment in ASD.


Fig. 1 The placenta produces estradiol from DHEA of both maternal and fetal origin and shunts over 90% of estradiol into the maternal circulation. The volume of DHEA substrate determines placental estradiol production and subsequently maternal serum estradiol levels. DHEA exists primarily in its conjugated form DHEAS


This is interesting as are some other findings linking steroid hormones to future autism. Another paper highlights a mechanism where maternal stress only has damaging effects on the male fetus (Placental adaptation in response to PNMS is sex-dependent, leading to an increased risk of adverse neurodevelopmental effect in male compared to female).

This paper looks at the effect of maternal stress on serotonin and another group of hormones (Glucocorticoids).

Effects of prenatal maternal stress on serotonin and fetal development

Fetuses are exposed to many environmental perturbations that can influence their development. These factors can be easily identifiable such as drugs, chronic diseases or prenatal maternal stress. Recently, it has been demonstrated that the serotonin synthetized by the placenta was crucial for fetal brain development. Moreover, many studies show the involvement of serotonin system alteration in psychiatric disease during childhood and adulthood. This review summarizes existing studies showing that prenatal maternal stress, which induces alteration of serotonin systems (placenta and fetal brain) during a critical window of early development, could lead to alteration of fetal development and increase risks of psychiatric diseases later in life.




`


         Fig. 1. Proposed mechanism of fetal programming of psychiatric disorders involving placental serotonin system. Cortisol and placental serotonin are essential for fetal brain development. Prenatal maternal stress alters glucocorticoid (11b-HSD2, GR and CRH) and serotonin (SERT, 5-HT1A and 5-HT2A) systems as well as serotonin and glucocorticoid interaction in the placenta. These placental alterations lead to adverse neurodevelopment and programming leading to psychiatric disorders later in life. Placental adaptation in response to PNMS is sex-dependent, leading to an increased risk of adverse neurodevelopmental effect in male compared to female. 11b-HSD2: Type 2 11-beta hydroxysteroid dehydrogenase, GR: Glucocorticoid receptor, CRH: Corticotrophin releasing hormone, SERT: Serotonin transporter, 5-HT1A: Serotonin 1A receptor, 5-HT2A: Serotonin 2A receptor


Conclusion    
         
It should be noted that estradiol is supposed to be elevated during pregnancy. Indeed, this elevation is suggested to explain why females with ADHD have far less symptoms during pregnancy (estradiol is good for ADHD). The study is highlighting a level of estradiol during pregnancy that is even higher than that normally expected.

Spina bifida is normally detected by ultrasound before 18 weeks of pregnancy. This is around the same time that in autism there appears to be elevated estradiol.  Hopefully other biomarkers will also be found.

Given this advance warning, there is potential for fetal medicine.

Only very recently was the first person in the UK treated for spina bifida using fetal surgery, almost two decades after the first operations in the US.

Fetal medicine for autism would not be surgical, rather pharmacological.  In mouse models it has already started.

Estradiol has many effects and I did write about DHED, an orally active, centrally selective estrogen and a biosynthetic prodrug of estradiol. DHED is estradiol just for the brain, without affecting the rest of the body.  I think many people would benefit from DHED, across the range from ADHD to TBI (Traumatic Brain Injury).

DHED, delivering Estradiol only to the Brain, also Lupron and Spironolactone


Estradiol may indeed prove to be a fetal biomarker for autism and DHED might be a useful drug for someone with autism (via ERβ and RORalpha).









Friday, 30 August 2019

Cesarian Delivery and Autism – another inconvenient truth?


Brasil is the C-section capital of the world, with rates in the public sector of 35–45%, and 80–90% in the private sector.

A recent study from the Karolinska Institute in Sweden, analysing 61 previous studies, has again shown a connection between birth by Cesarian Section and an increased risk of autism or indeed ADHD. 

C-sections account for just 16% of births in Sweden, but 32% in North America.

This of course prompted a reaction to reassure future mothers that they have nothing to fear, from experts in obstetrics who of course know nothing about the etiology of autism.  Mothers should be reassured, but trashing the study helps nobody.  Instead of a 1% risk of non-trivial autism, it rises to 1.3%. You still have more than a 98% chance of having a neurotypical child, all other factors being equal.  Without a medically necessary C-section, death is a real possibility.

It was a couple of years ago that the Karolinska Institute highlighted the fact that those with severe autism currently have a life expectancy of under 40 years.  Another inconvenient truth.


Association of Cesarean Delivery With Risk of Neurodevelopmental and Psychiatric Disorders in the Offspring 

Question  Is birth by cesarean delivery associated with an increased risk of neurodevelopmental and psychiatric disorders in the offspring compared with birth by vaginal delivery?
Findings  In this systematic review and meta-analysis of 61 studies comprising more than 20 million deliveries, birth by cesarean delivery was significantly associated with autism spectrum disorder and attention-deficit/hyperactivity disorder.
Meaning  The findings suggest that understanding the potential mechanisms behind these associations is important, especially given the increase in cesarean delivery rates for nonmedical reasons.
Abstract
Importance  Birth by cesarean delivery is increasing globally, particularly cesarean deliveries without medical indication. Children born via cesarean delivery may have an increased risk of negative health outcomes, but the evidence for psychiatric disorders is incomplete. 
Conclusions and Relevance  The findings suggest that cesarean delivery births are associated with an increased risk of autism spectrum disorder and attention-deficit/hyperactivity disorder, irrespective of cesarean delivery modality, compared with vaginal delivery. Future studies on the mechanisms behind these associations appear to be warranted. 
Very many things are known to slightly increase the odds of a person having autism and the more risk factors you have the more severely autistic you may be.  This ranges from maternal stress (anything from experiencing a hurricane, work stress, life trauma) to maternal/paternal age, obesity, gestational diabetes, alcohol/drug abuse, illness during pregnancy etc. This combines with whatever is in the parents’ DNA and random mutations that are bound to occur.    

A more rational reaction might be to investigate further why there might be a link and how you could counter any risk to children born by cesarian section.  You only have to read the existing research, or this blog.

There are 2 very good reasons why there should be a link between autism and C section, both have been covered in this blog.

1.     The microbiome comes from the mother. Science is only recently starting to understand the role of bacteria in health, but we know that it plays a key role in conditioning/calibrating the immune system of babies.  Once the immune system has been calibrated it is set for life.  Early exposure to bacteria is necessary and humans evolved to expect it.  If your immune system is over/under sensitive there will be consequences. Birth via C-section avoids exposure to bacteria in the birth canal, unless the newly arrived baby is “seeded” with bacteria from the mother. Mother’s milk is another key source of transferring the mother’s microbiome to the baby. 

2.     We saw that the birthing hormone Oxytocin plays a key role in triggering the “GABA switch” in new-borns. This is the process which transforms immature neurons with high chloride to mature neurons with low chloride shortly after birth.  During natural birth there is a surge in the hormone Oxytocin that is transferred to the baby, this causes the chloride transporter KCC2 to be further expressed and the “opposing” transporter NKCC1 to fade away.  In many people with severe autism their neurons remain in the immature state their entire life.  Just as you can replace the bacteria transfer lost in birth via C-section, there would be absolutely no reason why you could not replicate the surge in Oxytocin to "flip the GABA switch".

The recent study showed that elective C-sections (where the baby is in perfect health and not distressed) are associated with the elevated risk of both Autism and ASD.

Regular readers of this blog would probably be surprised if C-section did not increase autism prevalence.

The important thing is to acknowledge this likely connection and mitigate it, rather than try and fault the numerous studies that have shown the same effect.

The same of course applies to reducing the very small risk from vaccines, rather than construct new studies in a contrived way to show there is zero risk.   If you can safely and cheaply reduce the risk of a negative reaction to vaccines, why wouldn’t you?  Just follow Johns Hopkins example and give Ibuprofen or Montelukast (Singular) for a few days before and after and remember to never give Paracetamol/Acetaminophen (Tylenol) in response to fever after a vaccine. Paracetamol/ Acetaminophen reduces the body’s key antioxidant GSH just when the baby/child may need its neuroprotection most.

Some conditions are associated with preterm births, a good example is Cerebral Palsy (CP), which is twice as common in babies born very early. CP is rarely genetic and is usually considered to be caused by a complication during pregnancy, birth or shortly thereafter. I think you would find a correlation between C-sections and CP, but in this case I doubt you would find it in elective C-sections.   In other words C-sections do not “cause” CP, but they may be associated with it. The ID/MR often found in CP might be elevated by C-section and, if so, would be treatable.


Conclusion

In order to halt the rise in incidence of the disabling kinds of autism there should be steps taken to reduce some of the very many factors that are driving the increase, albeit each one sometimes by a tiny amount.

This would be a good application of all those thousands of autism research papers, many of which have shown what factors contribute to increased risk, that now sit gathering dust.

We are not at the stage of wide scale gene editing, but many simple steps can be taken today to improve future health.  This does not mean do not vaccinate, or avoid medically necessary C-sections; vaccinations and C-sections have saved millions of lives. But, why would you not want to take a good thing and make it even better?  That is what we humans tend to be good at, like the Swedes and their Volvos.

Perhaps take your C-section with a generous smear of Mum's bacteria and a shot of synthetic oxytocin?  

There will be more on Cerebral Palsy in a later post on D-NAC (Dendrimer N-Acetyl Cysteine). 

                                                               



Monday, 11 December 2017

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

Today we have a complex dysfunction, but we have a plausible understanding of the detailed biological underpinnings and several therapeutic options. It is relevant to people with autism who have impaired sensory gating (they find noises like a clock ticking annoying), and perhaps those who struggle with complex thought. It is very likely to be disturbed in some people with ADHD and many with schizophrenia.

Trouble in the Pre-Frontal Cortex


For a recap on sensory gating, here is an earlier post:-

Sensory Gating in Autism, Particularly Asperger's


Today’s dysfunction relates to HCN channels located on those tiny dendritic spines in a part of the brain called the pre-frontal cortex. These are a type of voltage gated potassium channel found in your brain and heart, there are 4 types, it looks to me that HCN2 is the key one today.
The pre-frontal cortex (PFC) is seen as the part of the brain most affected by mental illness (schizophrenia, bipolar, ADHD etc.), although medicine’s current understanding looks rather medieval to me.
These HCN channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network (created by numerous interacting neurons) is effectively disconnected.
By keeping these channels closed, it is thought that you can improve working memory and reducing distractibility. Now you might think distractibility is an odd word, and it is not a word I expected to encounter, what it really means is impaired sensory gating. This is a core feature of Asperger’s, ADHD and schizophrenia.
One of the key risk genes for schizophrenia, DISC1, also affects HCN channels and this may account for some of the cognitive deficit found in schizophrenia. High level thinking is particularly affected.  It is thought that loss of DISC1 function in the PFC would likely prevent proper PDE4 function, leading to a dysregulated build-up of cAMP in dendritic spines resulting in excessive opening of HCN channels


I did wonder how nicotine fits in, since in earlier post we saw that α7 nAChR agonists, like nicotine, improve sensory gating and indeed that people with schizophrenia tend to be smokers. It turns out that nicotine is also an HCN channel blocker. For a change, everything seems to fit nicely together. There are different ways to block HCN channels, some of which are indirect. One common ADHD drug, Guanfacine, keeps these channels closed, but in a surprising way.
Alpha-2A adrenergic receptors near the HCN channels, on those dendritic spines, inhibit the production of cAMP and the HCN channels stay closed, allowing the information to pass through into the cell, connecting the network. These Alpha-2A adrenergic  receptors are stimulated by a natural brain chemical norepinephrine, or by drugs like Guanfacine.
Stress appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.
This would explain why stress makes people’s sensory gating problems get worse. So someone with Asperger’s would get more distracted/disturbed at exam time at school for example, or when he goes for a job interview. Reducing stress is another method to improve sensory gating and indeed cognition. In Monty, aged 14 with ASD, the only time he exhibits significantly impaired sensory gating, is when he has stopped all his Polypill therapies for several days. I think stress/anxiety is what has changed and this opens those HCN channels. Then even the sound of someone eating food next to him makes him angry.
Excessive opening of HCN channels might underlie many lapses in higher cognitive function.
While the researchers at Yale patented the idea of HCN blockers to improve cognition, we can see how other existing ideas to improve cognition may indeed have the same mechanism, most notably PDE4 inhibitors.
The University of Maastricht holds patents on the use of Roflumilast, a PDE4 inhibitor, to improve cognition; most interestingly, this takes effect at one fifth of the COPD dosage, for which it is an approved drug. At high doses PDE4 inhibitors have annoying side effects, but at low doses they tend to be trouble-free.
One effect of a PDE4 inhibitor is that it reduces cAMP. So a PDE4 inhibitor acts indirectly like an HCN blocker.
Not surprisingly recent research showed that low doses of Roflumilast improves sensory gating in those affected by this issue.
So rather than waiting for a brain selective HCN blocker, the potential exists to use a one fifth dose of Roflumilast today. This is something that should indeed be investigated across different types of cognitive dysfunction.
There are numerous dysfunctions that can impair cognition and they can occur in different diagnosis. For example impaired autophagy is a key feature of Huntington’s, impaired remyelination defines multiple sclerosis, low levels of nerve growth factor are a key feature of Rett syndrome. Less severe dysfunctions of these processes occur in entirely different conditions.
It is thought that people with Alzheimer’s might benefit from PDE4 inhibition. If it was me, I would try it in all types of dementia or cognitive loss of any kind.

PDE4 Inhibitors
There have been many mentions of PDE4 inhibitors elsewhere in this blog. They are broadly anti-inflammatory and anti-oxidant, but currently only widely used to treat asthma in Japan and COPD in Western countries. COPD is a kind of very severe asthma.
Traditionally a PDE4 inhibitor is thought of as drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP). That all sound complicated, just think of it as increasing cAMP.
Now cAMP is a messenger in many biological processes, one of which relates to PKA (Protein Kinase A). In autism we know that PKA, PKB and PKC are often disturbed. These PKs are very important because they have the ability to literally change the function of thousands of proteins in your body. This is similar to how epigenetic tags can switch on or switch off a particular gene. PKs, via a different mechanism we will look at in another post, change the function of proteins, so it is very important that you have the correct level of PKA, PKB and PKC.
We saw in a recent post that the Pitt Hopkins gene TCF4 is regulated by PKA and that under-expression of TCF4 is also a feature of some ID and schizophrenia. So more PKA, please.

You can use a PDE4 inhibitor to increase cAMP, which then increases PKA.

Other effects of PDE4 inhibitors
Today’s post is about sensory gating and the effect here of PDE4 inhibitors is via the effect of cAMP on those HCN channels in your tiny dendritic spines.
There are numerous other effects of PDE4 that may also be therapeutic. One interesting effect is that inhibition of PDE4 can mimic calorie restriction by activating AMPK/SIRT1 pathway.
Calorie restriction has just been shown in a large trial to be able to reverse type 2 diabetes, if initiated with a few years of the disease developing.
Humans have evolved based to periods of feast and famine. Periods of fasting may be therapeutic for many modern conditions.
Not surprisingly one side effect of PDE4 inhibitors is weight loss. Many psychiatric drugs cause troubling weight gain.

Acute administration of Roflumilast enhances sensory gating in healthy young humans in a randomized trial. 

Abstract

 

INTRODUCTION:

Sensory gating is a process involved in early information processing which prevents overstimulation of higher cortical areas by filtering sensory information. Research has shown that the process of sensory gating is disrupted in patients suffering from clinical disorders including attention deficit hyper activity disorder, schizophrenia, and Alzheimer's disease. Phosphodiesterase (PDE) inhibitors have received an increased interest as a tool to improve cognitive performance in both animals and man, including sensory gating.

METHODS:

The current study investigated the effects of the PDE4 inhibitor Roflumilast in a sensory gating paradigm in 20 healthy young human volunteers (age range 18-30 years). We applied a placebo-controlled randomized cross-over design and tested three doses (100, 300, 1000 μg).

RESULTS:

Results show that Roflumilast improves sensory gating in healthy young human volunteers only at the 100-μg dose. The effective dose of 100 μg is five times lower than the clinically approved dose for the treatment of acute exacerbations in chronic obstructive pulmonary disease (COPD). No side-effects, such as nausea and emesis, were observed at this dose. This means Roflumilast shows a beneficial effect on gating at a dose that had no adverse effects reported following single-dose administration in the present study.

CONCLUSION:

The PDE4 inhibitor Roflumilast has a favourable side-effect profile at a cognitively effective dose and could be considered as a treatment in disorders affected by disrupted sensory gating.


Background Information
Selective phosphodiesterase (PDE) inhibition has been considered as a very promising target for cognition enhancement.
Roflumilast is a PDE4 inhibitor that has been developed by Takeda for Chronic Obstructive Pulmonary Disease (COPD). In recent year, Maastricht University has been collaborating with Takeda to develop Roflumilast for cognitive impairments
In 2015 Takeda sold COPD indication of Roflumilast to AstraZeneca, and ownership of IP for treatment of cognitive impairment returned to Maastricht University.
Compelling clinical results
A single administration of Roflumilast improves episodic memory in mice, and in young and elderly healthy subjects at a non-emetic dose
As shown in the figure, healthy (A) and memory impaired (B) elderly subjects showed better performances in the delayed recall of the Verbal Learning Task after roflumilast

Key Features and Advantages
Opportunities to reposition a clinically-proven safe compound with a well-established pharmacology.
Compelling preclinical and clinical evidences showing that Roflumilast effectively deliver to the brain to produce robust cognitive enhancement.
Pro-cognitive effects at low dose (5 times lower than COPD indication), which allows to circumvent the emetic effects commonly observed with other PDE4 inhibitors
Maastricht University has a strong IP protection extending to at least 2033.

PDE inhibitors in psychiatry--future options for dementia, depression and schizophrenia?

Author information

Abstract

Phosphodiesterases are key enzymes in cellular signalling pathways. They degrade cyclic nucleotides and their inhibition via specific inhibitors offers unique 'receptor-independent' opportunities to modify cellular function. An increasing number of in vitro and animal model studies point to innovative treatment options in neurology and psychiatry. This review critiques a selection of recent studies and developments with a focus on dementia/neuroprotection, depression and schizophrenia. Despite increased interest among the clinical neurosciences, there are still no approved PDE inhibitors for clinical use in neurology or psychiatry. Adverse effects are a major impediment for clinical approval. It is therefore necessary to search for more specific inhibitors at the level of different PDE sub-families and isoforms.


The current study found that brain cells in PFC contain ion channels called hyperpolarization-activated cyclic nucleotide-gated channels (HCN) that reside on dendritic spines, the tiny protrusions on neurons that are specialized for receiving information. These channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network is effectively disconnected. Arnsten said inhibiting cAMP closes the channels and allows the network to reconnect.
Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility," she said. "This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels."
Arnsten said the excessive opening of HCN channels might underlie many lapses in higher cognitive function. Stress, for example, appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.
The study also found alpha-2A adrenergic receptors near the channels that inhibit the production of cAMP and allow the information to pass through into the cell, connecting the network. These receptors are stimulated by a natural brain chemical  norepinephrine or by medications like guanfacine.
 “Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility,” she said. “This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels.”
Yale has submitted a patent application on the use of HCN blockers for the treatment of PFC cognitive deficits based on the data reported in the Cell paper.

The full Yale paper:

The prefrontal cortex (PFC) is among the most evolved brain regions, contributing to our highest order cognitive abilities. It regulates behavior, thought, and emotion using working memory. Many cognitive disorders involve impairments of the PFC. A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits. This work has led to the identification of therapeutic targets to treat cognitive disorders. Recent research has found that the noradrenergic α2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of cAMP-potassium channel signaling in postsynaptic spines. Guanfacine is now being used to treat a variety of PFC cognitive disorders, including Tourette’s Syndrome and Attention Deficit Hyperactivity Disorder (ADHD). This article reviews the history of Yale discoveries on the neurobiology of PFC working memory function and the identification of guanfacine for treating cognitive disorders.

Molecular modeling suggests that, similarly to ZD 7288, nicotine and epibatidine directly bind to the inner pore of the HCN channels. It is therefore likely that nicotine severely influences rhythmogenesis and high cognitive functions in smokers.

Modulation of HCN channels in lateral septum by nicotine


Conclusion
I think many people stand to benefit from the drugs mentioned in today’s post, but for different biological reasons. A person with Pitt Hopkins may benefit from Roflumilast because it will upregulate PKA and then increase expression of their remaining TCF4 gene.
In a person with schizophrenia there are multiple reasons these drugs might help them and it will depend on which genes they have that are misexpressed (TCF4, DISC1 etc.).
In a person with idiopathic Asperger’s and impaired sensory gating it looks like the effect on HCN channels is what is important.
I think low dose Roflumilast has great potential for many. The Japanese drug Ibudilast very likely will provide similar benefits, but at what dosage?
PDE4 inhibitors do have side effects at higher doses in part because there are several different types of PDE4 (PDE4A, PDE4B, PDE4C etc) and different drugs effect different subtypes differently.
Ibudilast is used as a daily drug therapy for asthma in Japan and is being studied as a therapy for Multiple Sclerosis (MS) in the US.
Roflumilast is sold by Astra Zeneca as Daxas/Daliresp but at a high dose of 500mcg to treat flare ups of COPD (Chronic Obstructive Pulmonary Disease) it does cause troubling side effects, but it reduces your chance of dying from COPD.
The cognitive dose used in research is 100mcg. Higher doses had no cognitive/sensory gating benefit.
Further investigation of the ADHD drug Guanfacine should be made, because some of the people who benefit from a PDE4 inhibitor might get a similar effect from Guanfacine. People with Pitt Hopkins would not be in this category. A person with Asperger’s and impaired sensory dating should respond to Guanfacine, a cheap drug.
At the end of the day, choice of therapy will come down to side effects and cost. In the US, Roflumilast is expensive ($330), seven times more expensive than in some other countries; in the UK the price of the same 30 tablets is $50. One pack would be enough for 5 months at the suggested dose.