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Wednesday, 28 February 2018

Winter Olympics




Today’s post is about the non-academic benefits of treating classic autism, which mainly seem to come from raising cognition (IQ).

Our reader Liz from Australia, whose five year old daughter has been using Bumetanide for two years, was telling us recently in her comments how her daughter can now go surfing with her four brothers.
While we do all want success at school and mastering practical skills like doing up shoe laces, the importance of being able to actively participate with siblings should not be underestimated.
Some siblings may be angels, but quite often there is resentment about having a sibling with special needs. One way to compensate is to have cool talents like surfing, skiing, fencing - something you can do well.

When I started this blog I was contacted by an Australian doctor who has a son with autism, she went to the same university as me. Her son was diagnosed early with severe autism with MR/ID, but progressed remarkably well and attended a mainstream school. His chosen sport at school was fencing (sword fighting). At that time Monty’s big brother was also having fencing classes and had all the equipment. I recall at the time thinking there is no way Monty could ever do that. Five years later though, Monty and his big brother are fighting together with homemade swords.
Fencing can look very impressive and certainly seems to count as a cool activity by modern day teenagers.

The main sport of Monty, now aged 14 with autism, is swimming - particularly underwater. While people with classic autism are at a greatly elevated risk of drowning, that is no longer something we have to worry about. Monty is more likely to be the rescuer than the one in trouble. If we lived in Australia, he too would be going to the beach to surf.
We did have swimming lessons, but only post-Polypill did Monty get competent. Now he swims really well and can swim a very long way underwater.

I do think that things that improve exercise endurance may be helpful to those with a neurological condition like autism. Just look what Nordic skiers, cyclists and tennis stars get into trouble for taking - much relates to getting more output from your mitochondria.  High altitude training is not an option for us, but swimming underwater may have a similar effect. There actually is research about what changes biologically in endurance divers (holding their breath) and people who train at high altitude. I suspect that moderate diving may improve brain perfusion, extreme diving is different because they are functioning when a typical person would have lost consciousness due to lack of oxygen. Moderate diving, like high altitude training, should increase how much oxygen your blood can carry.
Native Andean and Himalayan populations have better oxygenation at birth, enlarged lung volumes throughout life, and a higher capacity for exercise. Tibetans demonstrate a sustained increase in cerebral blood flow, but a typical hemoglobin concentration, whereas in the Andes they have significantly elevated levels of hemoglobin. Hemoglobin/haemoglobin is the protein in your blood that transports the oxygen around your body.  How do the Tibetans manage without extra hemoglobin?

“The Tibetan hemoglobin distribution closely resembled that from a comparable, sea-level sample from the United States whereas the Aymara (Andes) distribution was shifted toward 3-4 gm/dl higher values.”


The performance-enhancing effect of altitude training appears not to be due to increased red blood cell count or increased hemoglobin, as thought until recently, but rather something called Red Blood Cell (RBC) Hypoxic Metabolic Reprograming.
In essence, the hemoglobin becomes better at holding on to oxygen. Perhaps this is what Tibetans do.
Lay people suggest that:
More hemoglobin = More oxygen delivery.
It appears that you do not need more hemoglobin, you just need to make your existing hemoglobin work better.  And for that you need to give it a challenge; perhaps regularly swimming a long way on a single breath counts?


When scientists examined the oxygen-carrying proteins, known as hemoglobin, in volunteers’ red blood cells, they found multiple changes affecting how tightly it hung onto its oxygen load. Roach says a simplistic analogy is comparing this to what happens when baseball players loosen their grip on a mitt. “If I relax my hand, it will let go of the ball,” he says. Such changes had been observed before in the lab, but never in humans, and never at high altitude, the team reports this month in the Journal of Proteome Research. The scientists also found that the metabolic processes producing these changes were considerably more complex than suspected. And because red blood cells live for about 120 days, the changes last as long as the cells do.



Skiing
Skiing is popular where we live and most children from our school go once a year, either with school or with their family. 

Unless you live in the mountains, skiing is not a sport people do very often and so you could question whether it is worth all the expense. 
Monty started skiing when he was five with a couple of instructors who had recently started a ski school in Zell am See in Austria, just for children with disabilities like autism.

In the beginning just putting on all the equipment and riding up the mountain in the cable car was a big challenge.  It certainly was a case of stepping out of his comfort zone.  Having started we did persevere, in part so that big brother also had his chance to learn to ski.
2018 was the first week of skiing without any lessons.

This year big brother was concerned that he would have no one to ski with and was planning to make new friends on the slopes.
He did agree that he would ski with little brother, but much to his surprise spent the whole week skiing with him. It was not at all what he had expected. They could ski all over the resort using multiple types of ski lift. Who lost his ski while on a chair lift and had it fall into the trees? Not Monty, who had to ski by himself to the bottom of the slope while big brother retrieved his ski.
Being left alone at the top of the mountain, might have been a cue for one of those old-time “meltdowns”, but much to big brother’s surprise, Monty just skied alone down the mountain and waited for him, once he had found his missing ski. No awkward explaining to parents what had happened to Monty was required.
So then big brother decided to teach Monty how to do ski jumps, just like any regular teenager.
Both have been skiing for 8 years. Monty skis on red slopes (medium difficulty), whereas his brother would also go on the black slopes (the hardest).

Regarding myelination from a recent post, many people (like me) who learn skiing in adulthood often never myelinate their “skiing neuronal pathways” and so each year you come back as a near beginner. This is clearly not the case with Monty, he now retains his skiing skills, even though he has not used them for a year. 

Other Sports
Trampolining is something remarkably popular among people with severe autism. I suppose this is all about seeking sensory stimulation. Monty loves water slides and we used to know twins with autism/Asperger’s who were obsessed with roller coasters.

There is a common view that if you have a mental disability you must have a physical disability. Monty’s new teachers at high school were surprised when they learnt he skis just like a regular boy. Of course he showed the ski jump video to his classmates.

Conclusion
While you can ski with an IQ less than 70, as in Down Syndrome and most Classic Autism, it goes even better when you boost IQ.
I imagine the same applies to surfing and other water sports like sailing.
Clearly raising IQ means parents have far less safety issues to worry about.
Music of course is another great potential area for people with autism and Asperger’s. I wrote a post a long time ago about talents and savants, suggesting that people with autism really should be encouraged to use their abundant free time to develop such skills. Many people already do. Most of the Asperger’s people I have come across are now very talented musicians, practising hours every day. One is also an excellent skier on black slopes.





at 16 comments:

Friday, 23 February 2018

Verapamil or Rezular (R-verapamil) for Irritable Bowel Syndrome (IBS)?



A nasty condition that is equally nasty to spell - diarrhoea/diarrhea


Today’s post may help to explain why some people’s GI problems seem to vanish when they take Verapamil for their autism.

 Verapamil is usually prescribed as an L-type calcium channel blocker, to lower blood pressure. This type of ion channel is widely expressed in the brain, the heart and the pancreas. The pancreas is where your body makes those digestive enzymes. Mast cells that release histamine also contain L-type calcium channels.

 Verapamil blocks the L-type calcium channel Cav1.2, which in posts a few years ago I showed could be relevant for some types of autism. An extreme dysfunction of this ion channel leads to Timothy Syndrome, which is a single gene variant of autism with severe heart defects.  There is now some more recently published research which I have highlighted below.


L-type calcium channels are present in most electrically excitable cells and are needed for proper brain, muscle, endocrine and sensory function. There is accumulating evidence for their involvement in brain diseases such as Parkinson disease, febrile seizures and neuropsychiatric disorders. Pharmacological inhibition of brain L-type channel isoforms, Cav1.2 and Cav1.3, may therefore be of therapeutic value. Organic calcium channels blockers are clinically used since decades for the treatment of hypertension, cardiac ischemia, and arrhythmias with a well-known and excellent safety profile. This pharmacological benefit is mainly mediated by the inhibition of Cav1.2 channels in the cardiovascular system. Despite their different biophysical properties and physiological functions, both brain channel isoforms are similarly inhibited by existing calcium channel blockers. In this review we will discuss evidence for altered L-type channel activity in human brain pathologies, new therapeutic implications of existing blockers and the rationale and current efforts to develop Cav1.3-selective compounds.


The L-type calcium channels (LTCCs) Cav1.2 and Cav1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. Separately, CACNA1D has been found to be associated with BD and autism spectrum disorder, as well as cocaine dependence, a comorbid feature associated with psychiatric disorders. Despite growing evidence of a significant link between CACNA1C and CACNA1D and psychiatric disorders, our understanding of the biological mechanisms by which these LTCCs mediate neuropsychiatric-associated endophenotypes, many of which are shared across the different disorders, remains rudimentary. Clinical studies with LTCC blockers testing their efficacy to alleviate symptoms associated with BD, SCZ, and drug dependence have provided mixed results, underscoring the importance of further exploring the neurobiological consequences of dysregulated Cav1.2 and Cav1.3. Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Cav1.2- and Cav1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.

I have crossed these ion channels off my “to do” list because I have found an effective therapy that works for my son and for the children of some other readers.  It does not work for everyone, but that should not come as a surprise. I think those with mast cell disorders and/or major GI problems are most likely to be responders. 

 As well as halting the cascade of anxiety towards self-injury, reducing allergy, it was reported that Verapamil made long term GI symptoms vanish.

 In your pancreas β-cells make insulin. These β-cells have Cav1.2 calcium channels. In people with type-1 diabetes their β-cells have died so their pancreas produces no insulin. In people with the increasingly common type-2 diabetes, they start out with enough insulin but their body has a reduced sensitivity to it; often as they age their β-cells begin to die, at which point they start having to inject insulin like a type-1 diabetic. We saw that by blocking Cav1.2 you can stop these β-cells from dying. This means that a person with type-2 diabetes should take Verapamil to maintain their pancreas producing insulin.

Without wanting to go further into how the pancreas functions, I assumed that perhaps there were other Cav1.2 calcium channels involved in producing enzymes in the pancreas that might result in digestive problems in some people, that in turn produce symptoms of IBS.

 I already highlighted in a post that Verapamil also affects an interesting potassium channel called Kv1.3. This channel is involved in the inflammatory response and this is the channel that TSO parasites use to trick their host into not attacking and expelling them.

 It appears that Kv1.3 is over expressed in auto-immune diseases including MS. So inhibitors of this ion channel are potential treatments for MS. Add TSO parasites to that list of novel MS therapies!

 Some venoms are Kv1.3 inhibitors and may form the basis of new drugs.


Since autism is in-part an auto-immune disease a Kv1.3 inhibitor could be therapeutic.
Verapamil does inhibit Kv1.3, but I do not know if it is to a therapeutic extent.  Most drugs have numerous effects but only one dominant one.


 Melatonin MT1 and Serotonin 5-HT2b receptors

 Today we learn that two further receptors are affected by Verapamil, one Melatonin and one Serotonin.

 Melatonin, at high doses, we saw in an old post has potent beneficial effects on some GI conditions and trials showed it to be as effective as prescription drugs for those conditions. Melatonin is very cheap, but cannot be patented, so will not be researched seriously.

The two isomers of Verapamil

 When you think of a chemical you may think of its formula, but it can be more complex, as you might have learnt in high school chemistry.

 The two compounds below are both thalidomide. R-thalidomide is effective against  insomnia and morning sickness, but the mirror image called L-thalidomide can cause birth defects.
This was discovered too late, for many people.

 Many drugs are a mixture of Right and Left, confusingly they like to also call Left “S”. In Latin sinister is the adjective left and dexter is the adjective for right.

 Recall Arbaclofen (R-Baclofen) ? I am sure Roche does, a $40 million bet that did not pay off.

 Now we have R-Verapamil.

Pharmacology of R-Verapamil: A Novel Therapy in IBS
John Devane, Mary Martin, John Kelly

Racemic verapamil, primarily a cardiovascular agent, has been widely used off-label in patients with irritable bowel syndrome (IBS). Initial observations of its usefulness followed recognition of a high incidence of constipation with use in cardiovascular conditions. The enantiomers of verapamil are known to differ in cardiovascular potency, the S-isomer being much more potent than the R-isomer. In addition we found the S-isomer to be equiactive in relaxing vascular and colonic smooth muscle but the R-isomer to be 5-times more potent in relaxing colonic than vascular muscle. This selectivity led us to develop R-verapamil (Rezular) as a gut selective treatment in IBS and we have shown doses from 60mg/day to 240mg/day to greatly improve symptoms in non-constipation IBS patients. To better understand the mechanism by which R- verapamil improved the symptoms of IBS, we undertook an in-vitro screen of binding of R-verapamil to 147 receptors/receptor sub-types. Specific ligand binding was initially assessed using 10x-5 M verapamil and if there was greater than 50% inhibition of control specific binding, then binding at 8 different concentrations was tested andIC50 values (concentrationfor half-maximalinhibition of controlspecific binding (x10 -7M)) calculated. The therapeutic plasma concentration range of free R-verapamil was conservatively set at 0.1-3x10-7 M. Within this range R-verapamil showed affinity for 3 receptors: melatonin (MT1)(IC50 0.6), 5-HT2b (IC50 1.1) and L-type calcium channel (IC50 2.4). In addition compared with S-verapamil, R-verapamil showed stereoselectivity x40)for MT1 binding, whereas S-verapamil showed stereo selectivity (x3) for L-type calcium channel binding. R-Verapamil was selective for 5-HT2b relative to other 5-HT receptor sub types and affinity was low for 5-HT3(IC 50 3,400) or 5-HT4(>100) receptors.It was also highly selective for MT1(IC50 0.6) versus MT2 (IC50 >100) receptors. We conclude that R verapamil most likely exerts its therapeutic effects in IBS via a previously unrecognized mechanism involving combined effects at melatonin receptors, serotonin receptors and L type calcium channels

  

"In May 2009, Rezular (arverapamil) failed in Phase III development, where it underwent extensive evaluation in the ARDIS clinical trial programme in patients with IBS-D.

Phase III trials were taken up with patients already receiving treatment in the ARDIS-1 trial. In this randomised, double-blind, placebo-controlled, parallel group the efficacy and safety of Rezular (arverapamil) was assessed in about 1,200 patients.

Three doses of Rezular (arverapamil) were compared with placebo over a 12-week treatment period.

In September 2009, AGI announced that it plans to consider alternative uses of Rezular. The company believes that Rezular can prove effective in treating diarrhoea and non-diarrhoea related problems.

IBS is a common, but until recently poorly understood, disorder of the gastrointestinal (GI) tract. It is described as a functional disorder of the GI tract, in which there is no obvious underlying pathology.

IBS has proved notoriously difficult to diagnose and treat effectively. Until recently no drugs were specifically indicated for the treatment of IBS. Instead, patients would often seek over-the-counter (OTC) remedies to treat constipation, diarrhoea, abdominal pain and bloating associated with IBS.
AGI Therapeutics, Rezular (arverapamil) is a single enantiomer moiety of racemic verapamil, a cardiovascular drug that has been in clinical use for 35 years.

However, in contrast to currently available commercial forms of racemic verapamil (a mixture of two enantiomers), arverapamil shows preferential activity in treating the symptoms of IBS-D without the traditional cardiovascular actions of the racemic drug. It combines affinity at L-type calcium channels with 5-HT2b and melatonin (MT1) receptor binding.

Gut function is controlled by both the enteric (intestinal) nervous system (ENS) and CNS, in which the neurotransmitter serotonin (5-HT) plays a fundamental role. Serotonin is present in large amounts in the ENS where it is involved in sensory, motor and secretory processes within the gut. It modulates gut motility and the perception of pain and also mediates intestinal secretion. Minor disturbances in serotonergic function can lead to symptoms of IBS described above."

Irritable bowel syndrome (IBS) is a common comorbidity of autism.

 According to the Mayo Clinic:-
l-syndrome/symptoms-causes/syc-20360016

IBS is a chronic condition that you'll need to manage long term.
Only a small number of people with IBS have severe signs and symptoms. Some people can control their symptoms by managing diet, lifestyle and stress. More-severe symptoms can be treated with medication”

The precise cause of IBS isn't known. Factors that appear to play a role include:
·       Muscle contractions in the intestine. The walls of the intestines are lined with layers of muscle that contract as they move food through your digestive tract. Contractions that are stronger and last longer than normal can cause gas, bloating and diarrhea. Weak intestinal contractions can slow food passage and lead to hard, dry stools.
  • Nervous system. Abnormalities in the nerves in your digestive system may cause you to experience greater than normal discomfort when your abdomen stretches from gas or stool. Poorly coordinated signals between the brain and the intestines can cause your body to overreact to changes that normally occur in the digestive process, resulting in pain, diarrhea or constipation.
  • Inflammation in the intestines. Some people with IBS have an increased number of immune-system cells in their intestines. This immune-system response is associated with pain and diarrhea.
  • Severe infection. IBS can develop after a severe bout of diarrhea (gastroenteritis) caused by bacteria or a virus. IBS might also be associated with a surplus of bacteria in the intestines (bacterial overgrowth).
  • Changes in bacteria in the gut (microflora). Microflora are the "good" bacteria that reside in the intestines and play a key role in health. Research indicates that microflora in people with IBS might differ from microflora in healthy people.

Triggers
Symptoms of IBS can be triggered by:
  • Food. The role of food allergy or intolerance in IBS isn't fully understood. A true food allergy rarely causes IBS. But many people have worse IBS symptoms when they eat or drink certain foods or beverages, including wheat, dairy products, citrus fruits, beans, cabbage, milk and carbonated drinks.
  • Stress. Most people with IBS experience worse or more frequent signs and symptoms during periods of increased stress. But while stress may aggravate symptoms, it doesn't cause them.
  • Hormones. Women are twice as likely to have IBS, which might indicate that hormonal changes play a role. Many women find that signs and symptoms are worse during or around their menstrual periods.
Research shows that some people with IBS report improvement in diarrhea symptoms if they stop eating gluten (wheat, barley and rye) even if they don't have celiac disease.



Rezular – Patent for Oral Treatment for IBS

 http://www.google.com.na/patents/WO2009090453A2?cl=ko


  
Conclusion

I guess we may never know why some people’s IBS responds to Verapamil. It is likely because of one of the following:-

The experts suggested:-
     ·      Cav1.2
·      Melatonin MT1
·      Serotonin 5-HT2b

I earlier proposed (in addition to Cav1.2)

  •   ·      Kv1.3

R-Verapamil failed in its trial for IBS-D (IBS that causes increased diarrhoea is often called IBS-D).

But Verapamil clearly does help some types of IBS, you would just have to try it. I did try it on myself and it worked for me.

This post again shows the limitations of clinical trials, because we actually do know Verapamil does resolves the GI problems of some people.

Perhaps they got it all wrong and should have trialed S-Verapamil, or indeed just the regular mixture of Verapamil. They did not do the latter because how do you patent/make money out of an existing ultra-cheap generic drug? One pack costs $1.

 It looks strange to me that people with Type-2 diabetes are not prescribed Verapamil, it might save a lot of insulin injections later in their lives. 







at 22 comments:

Sunday, 18 February 2018

Online Autism Communities



I am often surprised what counts as academic research these days, but I stumbled upon one such paper that I thought might be of general interest.
It is a study from 2017 of the 550,000 comments left on two popular forums, autismweb.com and autism-pdd.net. Both of these forums have since closed down.

A large number of patients discuss treatments in online health communities (OHCs). One research question of interest to health researchers is whether treatments being discussed in OHCs are eventually used by community members in their real lives. In this paper, we rely on machine learning methods to automatically identify attributions of mentions of treatments from an online autism community. The context of our work is online autism communities, where parents exchange support for the care of their children with autism spectrum disorder. Our methods are able to distinguish discussions of treatments that are associated with patients, caregivers, and others, as well as identify whether a treatment is actually taken. We investigate treatments that are not just discussed but also used by patients according to two types of content analysis, cross-sectional and longitudinal. The treatments identified through our content analysis help create a catalogue of real-world treatments. This study results lay the foundation for future research to compare real-world drug usage with established clinical guidelines.

Top 10 treatment by number of users, identified in the ASD data set:-

Term
Number of users

Probiotics
819
speech therapy
565
Chelation
520
early intervention
475
special education
395
Melatonin
391
Antibiotics
381
Enzymes
352
Zinc
332
Vitamins
283


The most important building block of future work following this study is to compare the list of treatments discovered in OHCs automatically by the computational tool with established clinical guidelines. For example, while effectiveness of chelation is still under investigation by researchers, it already becomes a rather popular choice among autism community members. It is therefore critical to further quantify how broad the gap is between established guideline and patients’ actual practice. The future work will contribute to understanding how information support and consumption in OHC affect members’ decision makings regarding disease management, and hence how OHC participation makes physical and psychological impact.

I think what is happening is these kind of discussions have moved to other channels like Facebook and also that discussions are going on in closed groups, rather than in public.
Online communities for very rare, but well defined, disorders seem like a great idea and allow people to connect with others facing the same challenges.
This blog is public and so all kinds of people read it, some of whom would never join a closed group. Most readers are parents who come via Google or Facebook, some are regular readers, some are doctors, but there are researchers and even drug producers. Readership is very much skewed to North America. Australia and Eastern Europe are over-represented while the United Kingdom is slightly under-represented. There are almost no readers from Germany and Austria (the original home of autism and Asperger’s), but a fair number from France and not only Bumetanide researchers

The experimental approach put forward here is unorthodox and I know that some researcher readers do not entirely approve, but it is the end result that matters. 
I think the fact that some researchers are aware that lay people are reading about their research, and some are even applying it, is a good thing.
The online communities tend to be discussing supplements and the protocols of alternative doctors. This blog is looking at science and, based on that, seeing what drugs might be therapeutic; this narrows the potential audience somewhat because things do get rather complicated. 
I do not know if anyone has analysed all the comments in this blog, if they did they would see that a small but growing number of people have impressive long term results from repurposing some safe old generic drugs.  Because most people want to be anonymous, these comments do not carry the weight of case reports published in journals, but I think they can still be very useful.
I think only a small proportion of readers actually get access to the novel therapies indicated by the research, it all depends on where you live. Living in a Latin country, or being a doctor clearly helps.





at 13 comments:

Thursday, 8 February 2018

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










The Hungarian flag, for clever Laszlo Prokai

  

Lupron – partially right, but for the wrong reason? 

In the US there undoubtedly are some quack therapies for autism, however on occasion we have seen that you can stumble upon an effective therapy for entirely the wrong reason. In the history of medicine there are drugs that were stumbled upon, or created by accident.
In the case of the “Lupron protocol” which was promoted by a father and son (Geier and Geier), an extremely expensive therapy was apparently applied to hundreds of children, before being shut down by the medical regulators.
Without going into all the details, Geier’s therapy combined chelation (antioxidants) and a drug called Lupron that causes a dramatic reduction in testosterone levels.  In the jargon, it causes hypogonadism - diminished functional activity of the gonads (the testes in males or the ovaries in females). Lupron is another of those drugs that costs ten times more in the US than in the normal world. So a single injection of Lupron, depending on the dose,  costs up to $1000 in the US. Lupron is approved for use in children, male and female, with early onset puberty.
The case attracted media attention because Geier was also heavily involved in the idea that vaccines could cause autism and because patients were reportedly paying up to $50,000 for the complete therapy.
Geier was naturally a target for the anti-quack movement and why treat autism at all movements. He features in their books and blogs. 

Autism's False Prophets: Bad Science, Risky Medicine, and the Search for a Cure  (no link provided on purpose)

Still making the news in 2018.

Regulators who targeted controversial autism doctor may pay millions for humiliating him 

In this case I think Geier stumbled upon a rather extreme, partially effective therapy but for the wrong reason. I doubt such an expensive  potent drug is needed to produce the same beneficial effect, in that sub-group that appear to respond.

The fact that Lupron is so expensive in the US, may indeed contribute to the desire parents had for it.  There is a term in economics called a “Giffen good”; it is for the type of good that the more it costs the more you want it, like those very expensive hand bags people buy.

Personally I like inexpensive autism therapies, available to all.

Having read so much about autism, I am much less critical of those putting forward alternative ideas and therapies. It is very easy to get something right for entirely the wrong reason in medicine, which is something that is highly unlikely in many areas of science.

What I do not like is the predatory nature of some people with unusual ideas and therapies who treat autism. This is almost exclusively a North American phenomenon. Some parents will pay nothing to treat autism, for example some in countries with socialized medicine, while others would sell their house for a hope of an improvement.

The name Geier comes from the German word for vulture, maybe not the ideal surname for a healthcare worker.

If you read the following article from the Baltimore Sun you will see that there likely were some responders to this therapy:-

Lupron therapy for autism at center of embattled doctor's case 

"Wessels, who lives in Rock Rapids, Iowa, took Sam to see Geier in his Indianapolis office two years ago. She said there were months of genetic and hormone tests, and then the diagnosis. She began injecting Sam with Lupron daily.
She said the diagnosis made sense to her. Sam was not only having trouble communicating and difficulty learning, but he was tall for his age, had hair on his legs and began constantly masturbating by the time he was 5.
She said there was no "wow" moment where Sam snapped out of his autism, a spectrum of disorders where sufferers lack an ability to communicate and interact properly. But in the course of the next year, Sam's reading improved from 35 words a minute to 85 and he focused in class. He stopped masturbating as much.
Wessels thought Sam was naturally advancing and planned to taper the Lupron at some point — at 9, he had reached the generally accepted age limit for a precocious puberty label.
The day came abruptly four months ago when a nationwide shortage cut off Sam's supply. Wessels said she saw Sam return to his old habits, from flapping his hands, to pacing, to forgetting how to get to his classes.
"I felt like I got a glimpse of the child my son was meant to be, not the one autism gave me," said Wessels, fighting back tears. "It's so sad to watch your child fade away again."


Lupron and RORalpha

Regular readers of this blog may have noticed an entirely different reason Lupron might be beneficial in a sub-group of people with autism. It has nothing to do with vaccines and mercury-containing thimerosal preservative.

Reducing testosterone in boys is going to have effects like increasing estradiol.
















The schematic illustrates a mechanism through which the observed reduction in RORA in autistic brain may lead to increased testosterone levels through downregulation of aromatase. Through AR, testosterone negatively modulates RORA, whereas estrogen upregulates RORA through ER. 

androgen receptor = AR 
estrogen receptor = ER 

We have seen that RORA is suggested to act like a central point/nexus that affects dozens of biological processes disturbed in autism, making it a key target for therapy.



Other drugs that affect androgen receptors and are suggested in some autism?

Are there any other alternative autism therapies that affect testosterone and so androgen receptors? The answer is yes; this time a very cheap one called Spironolactone, that has been mentioned earlier in this blog.
The MAPS doctor known to some readers of this blog, Dr Rossignol, was one of the coauthors with the late Dr Bradstreet, in a hypothesis regarding Spironolactone.


Spironolactone is a potassium sparing diuretic, but also has the effect of shifting the balance between testosterone/estradiol towards estradiol, this makes it a useful therapy to treat acne for which it is sometimes prescribed. It seems to help some with autism.

I think any drug/supplement suggested to affect RORA in the right direction, will likely be reported to also improve acne, even if that sounds rather odd. If it does not improve acne, it lacks potency. Not all acne remedies will affect RORA.
In fact there are numerous ways to affect testosterone and estradiol and they are well documented on the internet because of all the males who are trying to become females (the transgender community).
Donald Trump and his personal physician declared they take a small daily dose of the drug finasteride, which is why both of them have such a full head of hair, and why Trump can brag about his low PSA result. This drug is used to treat an enlarged prostate and at a lower dosage, hair loss.  It works by decreasing the production of dihydrotestosterone (DHT), an androgen sex hormone, in certain parts of the body like the prostate gland and the scalp. 
Lupron might be too expensive in the US for males becoming females, but the other testosterone/estradiol modifying drugs seem to be very widely used/abused, depending on your views.

“Normal” levels of male/female hormones  
One criticism of Geier was that while he did many different tests to measure testosterone in his patients, he seemed over willing to prescribe his highly potent testosterone reducing drug. It was reportedly not the case that he only used Lupron on patients with extremely elevated levels of testosterone.
In fact what are normal levels of male/female hormones?
There does not seem to be a normal level, rather a very wide range. the charts below are in adults.


Serum total T (A) and bioavailable T (B) levels as a function of age among an age-stratified sample of Rochester men (solid lines, squares) and women (dashed lines, circles).



Serum total estrogen (A) and bioavailable estrogen (B) levels as a function of age among an age-stratified sample of Rochester men (solid lines, squares) and women (dashed lines, circles).



Affecting Testosterone/Estradiol Just in the Brain
I do sometimes receive comments asking about possible future autism drugs in the pipeline, I even once had a section called “Future Drugs”. Things move so slowly I now really only focus on repurposing what is already available.
However, a really interesting new drug, DHED, is being developed to increase the level of the hormone estradiol just in the brain. Now as regular readers will know, in autism there is a lack of estradiol and a reduction in the expression of estrogen receptor beta. We know that estradiol is highly neuroprotective and that estrogen receptors in the brain modulate RORa, which is one of those switches that control a large group of genes often disturbed in autism. So a new drug developed to help post-menopausal women has potential to be repurposed to treat neurological disorders like autism and indeed Alzheimer’s. 
Interestingly for me is that the lead researcher, a Hungarian called Laszlo Prokai, also researches another hormone, TRH, that I wrote about extensively a long ago in this blog. TRH is potentially another very useful therapy inside the brain.  
Thyrotropin-releasing hormone (TRH), is a releasing hormone, produced by the hypothalamus, that stimulates the release of thyroid-stimulating hormone (TSH) and prolactin from the anterior pituitary.  Thyroid-stimulating hormone (TSH) then goes on to stimulate the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body.
As I discovered a few years ago, TRH does much more within the brain, as a result it has antiepileptic properties and mood enhancing properties. The US Army is funding the development of a TRH nasal spray for ex-combatants with mood disorders and a risk of suicide. Antidepressants like Prozac have the odd side effect of increasing suicidal tendencies.
A TRH super-agonist (Ceredist) already exists in Japan, so I could never really understand why the US Army did not just get that drug approved by the FDA.  

More Laszlos please
The big gap in all neurological disorders is translational research, which means actually converting all the existing knowledge into usable therapies for humans.
So it looks like we need more people like Laszlo; in fact there is another - Katalin Prokai-Tatrai, I assume it is his wife.
So like we already have the very talented duo Chauhan & Chauhan, we have Prokai & Prokai. What we would ideally want is Prokai & Prokai to translate the knowledge of Chauhan & Chauhan into human therapies.
As described in one of their papers:
Our laboratory has been involved in medicinal chemistry-driven research with attention to facilitating drug delivery of central nervous system (CNS) agents via prodrug approaches.

This is important because there are clever drugs that would be useful to treat brain disorders but you cannot get them through the blood brain barrier (BBB). So making a new compound that can cross the BBB and then converts back to the original drug is a neat solution. 

Dr. Prokai's current research focuses on
(1) Novel therapies against neurodegenerative and ophthalmic diseases using site-selective prodrugs
(2) Development and use of proteomics in aging research, studying neurodegenerative diseases and cancer, with especial attention to quantitative expression profiling and oxidative stress-associated posttranslational modifications
(3) Discovering new therapeutic agents based on neuropeptides and peptidomimetics as lead molecules.

In particular:
·         Molecular mechanisms of estrogen neuroprotection

·         Molecular pharmacology of thyrotropin-releasing hormone




“10β,17β-Dihydroxyestra-1,4-dien-3-one (DHED) is an orally active, centrally selective estrogen and a biosynthetic prodrug of estradiol which was discovered by Laszlo Prokai and colleagues. Upon systemic administration, regardless of route of administration, DHED has been found to selectively and rapidly convert into estradiol in the brain, whereas no such conversion occurs in the rest of the body. Moreover, DHED itself possesses no estrogenic activity, requiring transformation into estradiol for its estrogenicity. As such, the drug shows selective estrogenic effects in the brain (e.g., alleviation of hot flashes, neuroprotection) that are said to be identical to those of estradiol, whereas it does not produce estrogenic effects elsewhere in the body.  DHED has been proposed as a possible novel estrogenic treatment for neurological and psychiatric conditions associated with hypoestrogenism (e.g., menopausal hot flashes, depression, cognitive decline, Alzheimer's disease, and stroke) which uniquely lacks potentially detrimental estrogenic side effects in the periphery


Highlights


·         Treatment with 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective prodrug of 17β-estradiol, for 8 weeks decreased amyloid precursor protein in APPswe/PS1dE9 double-transgenic mice
·         DHED treatment reduced brain amyloid-β peptide levels
·         DHED-treated APPswe/PS1dE9 double-transgenic mice had higher cognitive performance compared to untreated control animals
·         DHED treatment faithfully replicated positive neurobiochemical effects and consequent behavioral improvement observed for 17β-estradiol
·         DHED did not stimulate uterine tissue, whereas 17β-estradiol treatment did.  

By the same author Laszlo Prokai: 

Design and Exploratory Neuropharmacological Evaluation of Novel Thyrotropin-Releasing Hormone Analogs and Their Brain-Targeting Bioprecursor Prodrugs

Medicinal Chemistry: Compound could lead to estrogen therapies with fewer side effects

Estrogen levels drop in the brains of women who have gone through menopause or had surgeries to remove their ovaries. This hormone deficiency can lead to hot flashes, depression, trouble sleeping, and memory deficits. Hormone replacement therapies can improve women’s quality of life, but taking estrogen has its own problems, such as increased risk of breast and uterine cancer.

A new compound could avoid the source of these side effects—the action of estrogen on cells outside the.

Laszlo Prokai of the University of North Texas Health Science Center and coworkers identified 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), which is converted to the main human estrogen, 17β-estradiol, in the brain and not elsewhere in the body. An enzyme expressed only in the brain reduces DHED to estradiol.

The researchers injected DHED into female rodents without ovaries and showed that estrogen levels jumped in the brain but not in other tissues. Then, through a series of experiments, they demonstrated that the compound had only neurological effects.

“It’s exactly the right strategy for avoiding the cancer risks and gaining the benefits in the brain,” says Bruce S. McEwen, a neuroendocrinologist at Rockefeller University. He thinks the next step is to show that the compound doesn’t have toxicity problems so that clinical trials in people can start.  The researchers are planning such studies in hopes of moving the compound “from the bench to the bedside,” Prokai says.



Why is Estradiol good for your brain?
You may be wondering why I give so much time on this blog to female hormones. There is a lot of evidence beyond RORa, that estrogen/estradiol and its receptors are very important to healthy brain function. 
The paper below is very interesting and worth a read. 

Sex hormones, particularly estrogens, possess potent antioxidant properties and play important roles in maintaining normal reproductive and non-reproductive functions. They exert neuroprotective actions and their loss during aging and natural or surgical menopause is associated with mitochondrial dysfunction, neuroinflammation, synaptic decline, cognitive impairment and increased risk of age-related disorders. Moreover, loss of sex hormones has been suggested to promote an accelerated aging phenotype eventually leading to the development of brain hypometabolism, a feature often observed in menopausal women and prodromal Alzheimer’s disease (AD). Although data on the relation between sex hormones and DNA repair mechanisms in the brain is still limited, various investigations have linked sex hormone levels with different DNA repair enzymes. Here, we review estrogen anti-aging and neuroprotective mechanisms, which are currently an area of intense study, together with the effect they may have on the DNA repair capacity in the brain. 
However, estrogen actions on mitochondria are not exclusively related to such mechanism. Estrogen also regulates mitochondrial functions through their classical nuclear mechanism, i.e., transcriptional regulation of nuclear-encoded mitochondrial proteins. It is known that estrogen regulates the nuclear transcription of different proteins affecting mitochondrial function such as nuclear respiratory factor-1 (NRF-1) and peroxisome proliferator-activated receptor-gamma coactivator 1 (PCG-1). Hence, this regulation is critical for the activation of nuclear genes encoding proteins involved in mitochondrial biogenesis as well as in the mitochondrial electron transport chain complexes. It also regulates the transcription of mitochondrial transcription factor A (TFAM), which translocates into mitochondria and initiates transcription and replication of mtDNA

Note PCG-1 above, (a typo for PGC-1, I believe) for all those interested in treating mitochondrial dysfunction.  We saw previously that PGC-1α is a master regulator of mitochondrial biogenesis.
It turns out that Estrogen is key to many aspects of Mitochondria, and the paper  below from 2017 probably deserves its own post. Lack of estrogen or miss-expression of estrogen receptors in the brain is inevitably going to disrupt mitochondrial function.

Estrogens coordinate and integrate cellular metabolism and mitochondrial activities by direct and indirect mechanisms mediated by differential expression and localization of estrogen receptors (ER) in a cell-specific manner. Estrogens regulate transcription and cell signaling pathways that converge to stimulate mitochondrial function- including mitochondrial bioenergetics, mitochondrial fusion and fission, calcium homeostasis, and antioxidant defense against free radicals. Estrogens regulate nuclear gene transcription by binding and activating the classical genomic estrogen receptors α and β (ERα and ERβ) and by activating plasma membrane-associated mERα, mERβ, and G-protein coupled ER (GPER, GPER1). Localization of ERα and ERβ within mitochondria and in the mitochondrial membrane provides additional mechanisms of regulation. Here we review the mechanisms of rapid and longer-term effects of estrogens and selective ER modulators (SERMs, e.g., tamoxifen (TAM)) on mitochondrial biogenesis, morphology, and function including regulation of Nuclear Respiratory Factor-1 (NRF-1, NRF1) transcription. NRF-1 is a nuclear transcription factor that promotes transcription of mitochondrial transcription factor TFAM (mtDNA maintenance factorFA) which then regulates mtDNA-encoded genes. The nuclear effects of estrogens on gene expression directly controlling mitochondrial biogenesis, oxygen consumption, mtDNA transcription, and apoptosis are reviewed. 
Estrogens exert direct and indirect effects on mitochondrial function in a cell-specific manner through activation of membrane-initiated ERα, ER β, and GPER activity and by direct genomic binding of ERα and ERβ to regulate nuclear gene transcription. While still controversial, estrogens also activate mitochondrial localized ERα and ERβ in a celltype-dependent manner. One key nuclear gene increased by E2 is NRF-1 that regulates the transcription of nuclearencoded mitochondrial genes, including TFAM which increases transcription of mtDNA-encoded genes. Thus, E2 coordinates nuclear and mitochondrial gene transcription via NRF-1. Activation of UPRmt also activates ERα and increases NRF-1. E2 also regulates the transcription of genes regulating mitochondrial morphology, enzymes in the TCA cycle and OXPHOS pathways, and mitochondrial protein Snitrosylation. Depending on the cell type, E2 regulates mitochondrial biogenesis and bioenergetic function.   

17β-estradiol is not only a reproductive hormone that is important only in women but it is also of immense importance for development and health in men. Although there is strong evidence from both human and animal studies that estrogen is protective in various brain diseases however, its adverse effect in classic target tissues such as uterus (17β-estradiol behaves as a full agonist on both estrogen receptor (ER) isoforms) is a matter of debate. ER subtype selective ligands are valuable tools for deciphering the specific roles of ER (α and β) in physiology and diseases. These compounds have a strong potential for development as therapeutics as these initiate estrogen signaling in brain but lack the mitogenic effects in other tissues such as ovaries and breast. Moreover, the existing and newer ERsubtype selective agonists will continue to be very valuable tool for deciphering the specific roles of ERα and ERβ 

Severity of symptoms of schizophrenia is greater in males as compared to premenopausal females. Women have been shown to differ in symptom severity depending on the phase of the menstrual cycle. Higher rates of relapse in women with schizophrenia are also observed during the postpartum period (low estrogens), whereas relapse is low during pregnancy (high estrogens). During menopause, women are at risk of developing a new schizophrenic illness. Additionally, premenopausal women appear to have a superior response to typical antipsychotics compared to men and postmenopausal women. Estrogen plays a protective role in women with schizophrenia. Estrogen treatment may reduce negative symptoms in schizophrenic women. Estradiol may exert neuroprotection by several mechanism that may even vary among different brain regions.


Non drug therapies:-
Overeating and smoking will increase your level of estrogen. We saw earlier that in males testosterone is converted to estradiol in fat tissue. 

Not to forget the other part of the Mediterranean Diet:-



Conclusion
Just as we saw that using high doses of antioxidants is beneficial in numerous medical conditions, where nobody calls it chelation, drugs that reduce testosterone or increase estradiol in the brain are not quack therapies, even when proposed by apparent vultures. It pays to keep an open mind.
Hormone replacement therapy (HRT) is a big business and if you can introduce a drug with less side effects, it should sell at a premium price, meaning DHED really should get commercialized.
DHED should be more effective than estradiol for treating neurological disorders because it can be given at a higher dose. In males there is no risk of feminization.
Contrary to what is sometimes quoted, estradiol lowers the risk of prostate cancer and is used to treat aggressive forms of it. High levels of testosterone are linked to prostate cancer and that is why Lupron is sometimes used.
Circulating levels of estradiol vary dramatically. People with a low level of estradiol might well be able to safely increase body-wide 17β-estradiol, rather than waiting a decade for DHED.
High levels of estrogen/estradiol in males may contribute to the extended healthy life expectancy in those with a soy-rich diet, as we will see in the forthcoming post on the Okinawan Diet and aging.



Spironolactone does have the advantage of increasing potassium levels, so someone with autism who responds to bumetanide and has high testosterone/ low estradiol and/or reduced expression of ERβ might see a benefit; I think it might require a high dose.
DHED looks interesting particularly for those with higher plasma estradiol but reduced ERβ in the brain.
I think the lady from Rock Rapids, Iowa in the earlier press report on Lupron, whose son had very hairy legs and responded to Lupron, should try some estradiol, or just get him to drink a great deal of soy milk.  This really should have a similar kind of effect.
It appears that some mitochondrial disease is linked to estradiol and estrogen receptors ERα and ERβ. DHED might be a very clever treatment to what is otherwise pretty much un-curable. So there will be a post on estrogens regulating life and death in mitochondria.
The implication is pretty simple – more estrogen/estradiol please, if you want to live a bit longer, or if your brain does not work so well.





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