Apple Cider Vinegar (ACV), Phloretin, Phloridzin, Chlorogenic Acid, OAT3, Autism and Colon Cancer

Today’s post is only marginally related to autism, but does again show how some common food products have potential medical benefits.

Where I currently live people have been using apple cider vinegar (ACV) as a home remedy for generations. It is the apple part, rather than the vinegar part that is most interesting. I think they should continue with this home remedy, just be careful not to dissolve the enamel on their teeth. 

Rather surprisingly we can link ACV to improving Bumetanide effectiveness in autism and the chemoprotective effect of statins.

I have read so much research about statins, I do take Atorvastatin myself. The only downside is that research shows it does increase fasting glucose levels by about 0.4 mmol/L, exactly why nobody is quite sure.

If you want to further boost the chemoprotective power of statins it seems you may need a little help from something called Phloretin. Phloretin is a phenol that occurs in apples and the leaves of apple trees.  Apple cider vinegar (ACV) is rich in Phloretin.

Synergistic inhibition of colon cancer cell growth by a combination of atorvastatin and phloretin

Viability of HCT 116 colon cancer cells 48 hours after treatment with:-

PT = Phloretin

ATST = Atorvastatin

PT+ATST =  Phloretin + Atorvastatin

The closer to zero the better the result.  

If you want to improve insulin sensitivity and reduce fasting glucose levels it looks like it is the Phloridzin, a close relative of Phloretin, in apple cider vinegar that is useful.

If you want to improve the pharmacokinetics (how a drug is absorbed, distributed, metabolized, and excreted) of bumetanide you may also be able to use apple cider vinegar (ACV).  ACV also contains Chlorogenic acid which we we saw in an earlier post inhibits excretion of bumetanide through OAT3 (Organic acid transporter 3). Chlorogenic acid is also found in coffee.

In theory ACV will cause the level of bumetanide in blood to be higher, which might increase the amount that crosses the blood brain barrier and so make bumetanide a more potent autism drug. 

One odd proposed benefit of ACV is on GERD/reflux. You might have thought taking an acid would be the last thing that would help.

You would have thought that strong alcohol (also low pH, so very acidic) would also upset people with GERD/esophagitis, but some people I know swear that it is very beneficial.

In the case of GERD/esophagitis rather bizarrely I think it is the acetic acid (low pH) that is the reason why ACV seems to help some people.  I think it may help via feedback loops to trick the body into reducing its own acid production.

The drawbacks of Apple Cider Vinegar (ACV)

The acetic acid in apple cider vinegar can damage your teeth and your esophagus.  People avoid these problems by diluting ACV in a glass of water and rinsing their mouth with clean water afterwards.

ACV can lower potassium levels and it will lower blood glucose levels, which is good thing for most people, but diabetics would need to take care. Low potassium seems to worsen behaviour and increase sound sensitivity.

The Phloridzin in ACV is likely to reduce appetite, which for most people is a good thing, but for those few who struggle to gain weight it might be an issue.

ACV should lower triglycerides significantly, which might be bad for somebody. 

Apple phytochemicals and their health benefits

Synergistic inhibition of colon cancer cell growth by a combination of atorvastatin and phloretin

The results of the present study demonstrated that the antitumor efficacy of ATST could be enhanced at a relatively low dosage through the synergistic action with PT, which suggested the potential interaction of statins with other compounds in the food matrix. This interaction affects the efficacy of statins, and may explain the controversial results obtained in prior studies regarding the associations between statin use and the risk of colon cancer-associated mortality (27,28). As the dietary composition is different for each individual, this can result in varying statin efficacy. Conversely, different statins have different antitumor effects. In six colorectal cancer cell lines, including DLD1, HT29, SW620, HCT116, LoVo and colo320, simvastatin and fluvastatin showed strong growth suppressive effects. Atorvastatin demonstrated a relatively weak growth suppressive effect, whereas no growth suppressive effect was observed with pravastatin (29). This may be another reason for the paradoxical results regarding the antitumor effects of statins.

Therefore, the p21 gene may be the potential regulatory target underlying the G₂/M phase arrest following the synergistic action of ATST and PT; more in depth future investigations are warranted.

In summary, the present study demonstrated that PT and ATST produce a powerful synergistic interaction in suppressing colon cancer cell growth. This process was accomplished via the synergistic induction of apoptosis and the arrest of the cell cycle at the G₂/M checkpoint, which resulted from downregulated cdc2 activation following combined treatment.

Polyphenols: food sources and bioavailability

Screening of bioactive components in grape and apple vinegars: Antioxidant and antimicrobial potential

Vinegars contain several bioactive compounds that are characterized according to the type of the raw material, such as grape vinegars and apple vinegars. Liquid chromatography coupled to diode array detection and electrospray ionization tandem mass spectrometry was used for identification and quantification of phenolic compounds. Antioxidant properties of vinegars were determined by 2,2‐diphenyl‐1‐picrylhydrazyl and 2,2′‐azino‐bis‐3‐ethylbenzthiazoline‐6‐sulphonic acid assays. Antimicrobial activities of vinegars were examined with an agar disc diffusion method with Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Gallic acid and chlorogenic acid were found to be the major phenolic acids accounting for the largest proportion of the total phenolic acid contents in grape vinegars and apple vinegars. Within the flavonols, quercetin‐3‐O‐galactoside and quercetin were detected as the major compounds in grape vinegars. Apple vinegars were characterized by phloridzin, phloretin and high chlorogenic acid content. Antimicrobial activity results indicated that grape vinegars exhibited higher antimicrobial activity against tested bacterial strains correlated with their higher antioxidant capacity.

In conclusion, gallic acid, tyrosol, protocatechuic acid, caftaric acid, catechin, epicatechin and syringic acid constituted the highest proportion of the total phenolic contents in GV. Chlorogenic acid, phloridzin and phloretin were found to be the major phenolic compounds in AV. With respect to antimicrobial and antioxidant activity results, GV showed higher antimicrobial and antioxidant activity than AV. With regard to phenolic composition of vinegars with their antioxidant capacities, two separate groups were obtained and characterized the vinegars with PCA based on the type of raw material. The results we obtained in this study extend our knowledge about the composition of vinegars obtained from different raw materials consumed in Turkey and allow the consumer to compare vinegar brands with the highest contents of beneficial compounds.

OAT3 inhibitors for Bumetanide - Probenecid, but also Aspirin, Chlorogenic acid (Coffee), Epicatechin (Cocoa, Cinnamon) and more.

Coffee = chlorogenic acids  = 1,3- and 1,5-dicaffeoylquinic acid

Interaction of Natural Dietary and Herbal Anionic Compounds and Flavonoids with Human Organic Anion Transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11)

Five compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acids (15 : 1) and (17 : 1), and epicatechin, significantly inhibited hOAT3 transport under similar conditions

3.2. Inhibition of hOAT3 by Natural Anionic Compounds and Flavonoids

Human OAT3 expressing cells showed about 4-fold greater accumulation of ES as compared to background control cells ( versus  pmol mg 10  , resp.). Similar to hOAT1, hOAT3-mediated ES uptake was completely (>96% inhibition) blocked by probenecid (Figure 4). Five of the compounds, 1,3- and 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acids (15 : 1) and (17 : 1), significantly inhibited hOAT3-mediated transport at 50-fold excess (Figure 4). 1,3-Dicaffeoylquinic acid and ginkgolic acid (17 : 1) exhibited 41% inhibition, while 30–35% reduction of hOAT3-mediated ES uptake was observed for 1,5-dicaffeoylquinic acid, epicatechin, and ginkgolic acid (15 : 1). Catechin, 18β-glycyrrhetinic acid, and ursolic acid failed to produce significant inhibition. Based on the level of inhibition observed, values for all of these compounds would be greater than 50 μM, much higher than clinically relevant concentrations (Table 1). Therefore, further dose-response studies were not performed.

Phloridzin reduces blood glucose levels and improves lipids metabolism in streptozotocin-induced diabetic rats.

Abstract

Phloridzin is the specific and competitive inhibition of sodium/glucose cotransporters in the intestine (SGLT1) and kidney (SGLT2). This property which could be useful in the management of postprandial hyperglycemia in diabetes and related disorders. Phloridzin is one of the dihydrochalcones typically contained in apples and in apple-derived products. The effect of phloridzin orally doses 5, 10, 20 and 40 mg/kg body weight on diabetes was tested in a streptozotocin-induced rat model of diabetes type 1. From beneficial effect of this compound is significant reduction of blood glucose levels and improve dyslipidemia in diabetic rats. As a well-known consequence of becoming diabetic, urine volume and water intake were significantly increased. Administration of phloridzin reduced urine volume and water intake in a dose-dependent manner. Phloretin decreases of food consumption, as well as a marked lowering in the weight. In conclusion, this compound could be proposed as an antihyperglycemic and antihyperlipidemic agent in diabetes and potential therapeutic in obesity.  

Harvard Medical School vs the BBC?

You might expect when it comes to investigating health claims about apple cider vinegar (ACV) that Harvard would give you the science and the BBC would be just superficial.

While neither actually bother to use google to find what the active constituents of ACV might be, the BBC do actually make a trial in humans and measure the results in a lab.                                                                                             

https://www.health.harvard.edu/blog/apple-cider-vinegar-for-heartburn-2018032813530

https://www.bbc.com/news/magazine-37229792

It looks like if you have high triglycerides, or indeed high blood glucose, ACV is a potentially interesting non-drug therapy.

The guys at Harvard should watch the BBC and try a little harder next time.

Conclusion

Apple cider vinegar (ACV) is one home remedy that now has some science to support it. It is cheap and easy to access.

It is perhaps not relevant to many people with autism, but does show how medicine turns a blind eye to some old treatments that were stumbled upon as being effective hundreds of years ago.

When it comes to chemoprevention, the majority of cancers in males (prostate, colon, esophagus, bladder etc) have been shown in the research to be inhibited by statins. Some people know they have a familial risk of one or more of these cancers, would it not make sense that they be informed about chemoprevention?  It is much better to avoid cancer than to have to try to treat it.  In colon cancer it appears that phloretin from ACV might even be helpful.

We also saw that people with type 2 diabetes often find the beta cells in their pancreas die and so they stop making insulin, and yet a cheap calcium channel blocker can protect those insulin-producing cells and put off the day that insulin injections are required.

I did actually borrow my “polypill” name for my son’s autism therapy from another polypill that was designed to extend the healthy life expectancy of older people. Their pill has not been a huge success.

What is needed is a personalized polypill, whether it is for people with autism or typical adults from the age of 50.

I imagine, in 50 years time, when your family doctor has your genome on file, you probably will have a personalized little pill to help you minimize the risk of developing preventable disease. 

Education and Autism

This blog mainly concerns personalized medicine, which is a therapy targeted to a specific person, or sub-group.  Personalized medicine can include drugs, OTC supplements, diets and, importantly, non-drug medical therapies like vagal nerve stimulation.  Some non-drug medical therapies were covered in previous posts and others will be covered in future posts.

The other part of the bigger puzzle can be called personalized education; anything from ABA to music therapy to what you do at school.

Eleven years ago, when starting with our first ABA consultant, just about his first question was “are you following any special diets or biomedical therapies”. He was clearly against such therapies, seeing them as a big distraction from the all-important ABA and Verbal Behavior (VB).  He did indeed have a point, you do have to focus your attention on multiple tasks and avoid being obsessed with vaccines, gluten or candida, as some people appear to be.

ABA does have its limits, as our first ABA consultant found with his own son. In the case of severe autism it may well help a lot, but it usually is not enough. Rather ironically this ABA consultant eventually came back to me years later to ask about personalized medicine.

Some people report terrible experiences with ABA and, if these are genuine, I think there must be some terrible ABA therapists out there. We had very positive experiences with ABA consultants and our home-trained therapists. 

Education

In the case of Monty, aged 15 with autism, he started with very personalized education and only much later, at 9 years old, did we add personalized medicine.

It is pretty clear than in cases of severe autism you need all the help you can get and so as to achieve a  relatively good life (the palm tree by the beach, in the above graphic); you need personalized education and personalized medicine.

Education of typical children

For some years I was a school governor at an international school and so I got to know many different teachers, different educational systems and curricula.

When schooling kids with autism the choice is normally between mainstream school, special school or home schooling. In some countries home schooling is illegal.

Mainstream schooling varies greatly from country to country. Most active autism parents seem to be North American and they likely do not realize how lucky they are to have a pretty easy school curriculum, which lends itself to less able learners.

In some other countries the standard of maths and science is very much higher and school is really geared up to benefit the most able. Anyone of average ability, or below, very often gets left behind.

The level of selection in schools is also important and highly variable. In some countries kids get separated at age of 10-12 into those who are expected to do well and becomes doctors/scientists/ lawyers and those who will end up with vocational training rather than a degree.

In other countries you get a genuine mix of abilities all the way up through high school.

Poor Learners

I had a visit recently from a friend of mine who runs an organisation in Austria that tries to attract top achievers from university to spend two or more years teaching in the country’s worst performing schools, before starting their intended high-flying careers. It is part of an international group doing the same thing across the world. They seem to be doing well and the schools perform much better with their energetic young teachers.

What was interesting to hear was just how bad the standards are at some of these schools.  A significant minority of 12 years old kids are functionally illiterate. One reason is that they have many immigrant children who do not speak German at home, did not speak German in Kindergarten and now sit in a class that is 80% non-native German speakers. The end result is that they cannot write a sentence in German, even though they might have lived all their life in Austria. So much for inclusion/integration.

Interestingly, my friend told me that in Austria, almost no one knows that Hans Asperger was an Austrian.  I did not mention that some Americans are worrying about whether Asperger was a Nazi.  Andreas Rett, another Viennese doctor, whose name was given to Rett syndrome by the English-speaking world 17 years after he described it in the German literature, is another forgotten Austrian. Rett actually was a Nazi, so I suppose some people will want to rename that syndrome, when they figure this out. Leo Kanner was really Austro-Hungarian, being born in Lviv. Kanner was Jewish, so definitely not a Nazi. So many Austrians connected to autism and yet nowadays the German speaking world contributes almost nothing to autism research. I will leave you to draw your own conclusions.

How Austria can restore its status as a center of autism research

Back to education.

The top performers educationally are usually Singapore, where they practice old-fashioned education and Finland, where they follow a very enlightened non-pressurizing Scandinavian approach and where school starts at 7 years old.

The maths curriculum and the workbooks from Singapore are widely used by home schoolers around the world and I bought them for my son. 

A suitable learning environment for someone with severe autism

In many developed countries education authorities believe that children with severe autism can be educated in both mainstream classrooms or in special education.

Given just how variable mainstream education is, we should not expect consistent results. For some children inclusive education will work well and for others it might be a disaster.  A lot depends on what you are being included into and you have to be “includable”.

Small classes, with up to 12 kids, that include all abilities and only one special needs learner give the best chance of success, in my opinion.

Classes with 30 kids including 2+ special needs learners are a recipe for failure for all 30 kids.

Special education varies from large groups and a single teacher in some countries to tiny groups and where each child also has their own 1:1 assistant. There is no normal or typical special school.  There are some very good special schools in the United States, but they must cost someone $100,000 a year.

Home schooling is only as effective as how good the “teacher” is.

Parents need to think long and hard about how to educate their child with severe autism and not assume the State will provide them a perfect solution.  The better the education is for typical children, the greater chance you have of good special needs provision. Not surprisingly, special education is good in Scandinavia and terrible in most poor countries.  One of Monty's assistants moved to Norway to be a special needs teacher.

Some people with severe autism will struggle to learn anything, anywhere. These people need personalized medicine or else their 15-18 years spent in “education” is just day-care and a prelude to institutionalization, perhaps with a nice name like a group home.                                      

Personalized Education combined with Personalized Medicine

At the age of 8, after 4 years of intensive ABA-inspired intervention, Monty could not grasp the simplest elements of maths; I mean single digit addition or subtraction using the number line. Language and cognitive function appeared to be immovable barriers to progress.

December 2018 marks six years after starting personalized medicine, and I just learned that Monty’s grade for Maths this term is B+. He could handle the algebra and trigonometry in the end of term test, without any prompting from his assistant.

The addition of personalized medicine has had a transformative effect on cognition.  This continues to surprise people even now. 

Equally encouraging is that Monty has taught himself to swim "properly", he has long been confident in a pool or in the sea, but now at school they go to swim in a full sized pool and get timed swimming laps. Today he was the fastest of two combined classes, that is something else that would not have been expected. 

One autism Grandad we know regards Monty as "80% fixed", but "some problems will always remain"; that is quite a nice summary. It is all relative to what you know, this Grandad only knows really severe autism.  I think many of the parents of the 1 in 40 now diagnosed in the US with "autism" would regard Monty as far from "fixed", but then their kids are fully verbal and have few challenges.  

People with severe autism inevitably plateau at a low cognitive-equivalent age, but it does not have to be like that, if you can treat the underlying biology.  

If you start by treating the biology and fine-tune brain function to the extent that is possible, then you should benefit greatly from all that costly personalized education, that you may or may not get someone else to pay for.

Conclusion

If you have a child with severe autism, life may become a huge challenge. There are all kinds of horror stories you can read about - I suggest you do not dwell on them.  Everyone has options, whether to rely entirely on what you get for free from the State, or whether to apply other methods.

In a resource unconstrained situation, the best outcome is likely to come by combining personalized medicine with personalized education. I can only say that this combination has worked well for us.  In terms of money, it has clearly cost much more than having a typical child, about twice as much. 

If money is tight, start with personalized medicine.

People tend not to put a value on time, but for many time may be the greatest cost. You typically cannot leave a person with severe autism unattended and if they have a complicated schedule, somebody always has to be there and to be able to step in when something gets cancelled, or someone is off sick. 

Until the 1970s, medicine did have a strategy for people with severe autism. It was diagnose, institutionalize as a young child and forget. The Germans added their own variant to this.  Having shut down all the big residential hospitals for mental conditions, there is now often a big gap in provision.  Where do you put adult-sized people with severe autism?  It may not be a problem for those who are docile, but what about those who are not?

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

Today’s post is all about one of the potential medical, but non-drug, interventions for autism. The others tend to involve electrical/magnetic stimulation of one kind or another.

Low level laser therapy (LLLT) was developed more than fifty years ago in Russia. Today in Western countries LLLT is often regarded as alternative medicine or just quackery.  There are some FDA approved devices.  In Russia and some East European countries LLLT is part of mainstream medicine.

Two people forwarded me a recent study that was carried out in Havana by a team from Cuba and Israel.

There are only 11 million Cubans, but there are a lot of Cuban doctors.  They have developed interesting drugs, some related to cancer, that are now being taken up by Western medicine.  Cuba actually leases out doctors to work in more than 50 developing countries around the world.

The results of the study are indeed interesting and there is a long list of possible mechanisms that may be involved.

The question we are left with is can you achieve a similar result with cheap LEDs (light emitting diodes), or do you need a genuine laser (that confusingly use a different kind of diode).  I do not know the answer, but there is definitely a difference.  

Let’s start with the background to LLLT

Low-Level Laser Therapy in Russia: History, Science and Practice

 In Russia (formerly USSR) study of biomodulation action (BMA) mechanisms of low-intensity laser irradiation (LILI) began in 1964, immediately after the development of lasers. During the period from 1965 to 1972 several dozens of scientific conferences were held, hundreds of studies were published. Generally, secondary mechanisms and results of LILI effect on patients with various diseases were studied. This data was immediately implemented into practical medicine in the fields of oncology, surgery, dermatology and dentistry, and since 1974 low level laser therapy (LLLT) is included in the standard of state medical care. For 50 years no less than 1000 books were published (monographs, collections, methodical and clinical materials), thousands of researches were carried out. Primary mechanism and patterns of interaction of LILI with acceptors within cells can be represented in the following order: absorption of photon’s energy – emergence of a local temperature gradient – release of Ca²⁺ from intracellular stores – stimulating Ca²⁺–dependent processes. Understanding of this process allowed the explanation of all known secondary effects, optimized methods and extremely increased effectiveness of LLLT. Owing to the knowledge of BMA mechanisms of LILI, numerous associated and combined LLLT techniques were developed and are widely used nowadays: locally, on the projection of internal organs, laser acupuncture, reflexology, intracavitary, transdermal and intravenous laser blood illumination, magnetic-laser therapy, laser phoresis, laser-vacuum massage, biomodulation, etc. About 400 000 laser therapeutic devices are used in Russian practical healthcare. Unique, having no analogues in the world devices, are produced – red pulsed laser diodes (wavelength 635 nm, power 5-40 W, pulse duration 100 ns, frequency 10 000 Hz) are designed specially for effective laser therapy. 

About 400 000 laser therapeutic devices are used in Russian practical healthcare; about half of them are used in professional medicine (clinics), and half of them – at patients’ home for independent use. Around the world only lasers designed for other purposes (technical) are used, which are not always effective in medicine. The peculiarity of Russian laser therapeutic apparatus is the development and production of special lasers, designed specifically for therapy. For example, unique, having no analogues in the world, devices are produced - red pulsed laser diodes (wavelength 635 nm, power 5-40 W, pulse duration 100 ns, frequency 10 000 Hz) are designed specially for effective laser therapy. ^‎

Laser therapy is widely used in almost all medicine fields: obstetrics and gynecology, gastroenterology, cardiology, dermatology and cosmetology, neurology, oncology, otolaryngology, pediatrics, pulmonology, dentistry, traumatology and orthopedics (diseases of musculoskeletal system), urology and andrology, phthisiology, etc. 

Cheap LEDS vs Expensive Lasers? This paper says you cannot cut corners.

Only lasers can be used for low level laser therapy

The question of lasers' exclusivity, as well as the degree of influence of special properties of low-intensity laser illumination (LILI), such as coherence, polarity and monochromaticity, on the effectiveness of low level laser therapy (LLLT) continues to cause arguments.

The study analyzes publications from 1973 to 2016, in which laser and conventional light sources are compared, and the following conclusions are drawn. First, there are a lot of publications with incorrect comparison or unfounded statements. Secondly, other sources of light are often meant by LILI without any justification. Thirdly, all studies, in which the comparison is carried out correctly and close parameters of the impact and the model are used, have a firm conclusion that laser light is much more effective. Fourthly, it is uniquely identified that the most important parameter that determines the efficiency of lasers is monochromaticity, i.e., a much narrower spectral width than for all other light sources.

Only laser light sources can be used for LLLT! 


Here is the Cuban study on autism using lasers:-

Effects of Low-Level Laser Therapy in Autism Spectrum Disorder

The study examined the efficacy of low-level laser therapy, a form of photobiomodulation, for the treatment of irritability associated with autistic spectrum disorder in children and adolescents aged 5–17 years. Twenty-one of the 40 participants received eight 5-min procedures administered to the base of the skull and temporal areas across a 4-week period (test, i.e., active treatment participants). All the participants were evaluated with the Aberrant Behavior Checklist (ABC), with the global scale and five subscales (irritability/agitation, lethargy/social withdrawal, stereotypic behavior, hyperactivity/noncompliance, and inappropriate speech), and the Clinical Global Impressions (CGI) Scale including a severity of-illness scale (CGI-S) and a global improvement/change scale (CGI-C). The evaluation took place at baseline, week 2 (interim), week 4 (endpoint), and week 8 (postprocedure) of the study. The adjusted mean difference in the baseline to study endpoint change in the ABC irritability subscale score between test and placebo participants was _15.17 in favor of the test procedure group. ANCOVA analysis found this difference to be statistically significant (F ¼ 99.34, p < 0.0001) compared to the baseline ABC irritability subscale score. The study found that low-level laser therapy could be an effective tool for reducing irritability and other symptoms and behaviors associated with the autistic spectrum disorder in children and adolescents, with positive changes maintained and augmented over time. 

A pulsed laser of 635 nm with a power output of 15 mW and a red 635 nm LED were used as treatment and placebo, respectively.

 A significant literature exists on the ability of low-level light therapy (LLLT) to penetrate the skull. Low-energy light passes the skull and a therapeutic effect likely exists. LLLT systems employ the so-called quantum optically induced transparency effect. This effect controls optical properties of dense media enhancing transparency contrast by a factor of five. Therefore, the skull, spine, or joints can be penetrated even with moderate intensity light reaching deep layers in muscles, connective tissue, and even bone, enabling transcranial effects of LLLT.

LLLT achieves a therapeutic effect by employing non-ionizing light, including lasers, light-emitting diodes, or broadband light in the visible red (600–700 nm) and near-infrared (780–1100 nm) spectra. LLLT is a nonthermal process occurring when a chromophore is exposed to a suitable wavelength of light. Chromophores are responsible for the color associated with biological compounds such as hemoglobin and cytochromes. With chromophore absorption of a photon of light, an electron transits to an excited state, with a physiologic effect occurring when photons dissociate the inhibitory signaling molecule nitric oxide (NO) from cytochrome-C-oxidase, increasing the electron transport, mitochondrial membrane potentials, and production of mitochondrial products such as ATP and NADH. Other effects include the production of reactive oxygen species (ROS) which activate transcription factors, leading to the cellular proliferation and migration.

Based on these complex characteristics, LLLT possesses physiologically modifying properties associated with light characteristics such as wavelength and irradiance, varied by exposure parameters, such as energy density, irradiation duration, and treatment frequency. On the basis of the above, we investigated behavioral and cognitive changes in ASD as a consequence of the delivery of red LLLT.

2.4 Procedure

All the 40 participants completed the course according to the protocol. Twenty-one of them were randomized to the test (active treatment) procedure group, and 19 were randomized to the placebo procedure group. Participants received eight 5-min laser light applications to the base of the skull and temporal areas with the Erchonia® EAL Laser (active or sham) across a 4-week period: two applications per week, 3–4 days apart at the investigator’s test site.A pulsed laser of 635 nm with a power output of 15 mW and a red 635 nm LED were used as treatment and placebo, respectively. Participants were required to maintain their regular medication schedule and treatment regimens, as reported at the baseline evaluation, to treat symptoms related to autistic disorder throughout the study time. All of them complied with this requirement.  

Twenty out of the 21 active treatment participants showed some degree of improvement in autism-related symptoms at endpoint relative to baseline. The majority (13) received ratings of “much improved”. No placebo group participant demonstrated improvement in symptoms at endpoint relative to baseline. The majority (17) demonstrated “no change”, and the remaining 2 placebo participants rated “minimally worse”. We found that the ABC global and five subscale scores decreased progressively and significantly from baseline across each of the three successive evaluation points; the decrease progressed over time, including a 4-week followup during which no further LLLT occurred. Conversely, the placebo group demonstrated no significant change across the study duration, demonstrating the effectiveness of LLLT in reducing ASD-associated symptoms.

Conclusion 

Either the researchers have cheated, which has been known to happen, or Low Level Laser Therapy (LLLT) is indeed a worthwhile therapy for much autism.  The question of safety should be carefully considered.

Judging by the drugs the participants had been taking, they were not kids with trivial autism.

According to the current FDA standards, an FDA cleared LLLT device (also called a cold laser) can be sold for 3 main issues: 

·        Pain Control

·        Inflammation Reduction

·        Increased Blood Flow  

The cheapest FDA approved laser device that would be vaguely equivalent to the device used in the trial in Cuba costs $2500 in the US.

Hopefully, one day someone will compare the effect on subjects with autism of cheap LED devices versus true laser devices.

This press release was highlighted by our reader RD:-

Erchonia Submits Data to US FDA to Support Low-Level Laser 510(k) Market Clearance for Autism

Quadruple-Blind laser study proves success in treating Autism in children and adolescents.

“The results are so strong, nobody can argue them.”

MELBOURNE, Fla. (PRWEB)September 05, 2018

Erchonia, the World Leader in Low Level Laser technology, announces today that they have submitted data to the US FDA to support a 510(k) market clearance for Autism.

The clinical trial was a quadruple-blind (Participant, Care Provider, Investigator and Outcome Assessor), randomized, placebo-controlled, and crossover clinical trial. The study was designed to treat autistic children with the 640nm Erchonia Spectrum Laser as the active device or a 640nm LED or light emitting diode as a placebo device, which had the same power output. FDA input was obtained prior to clinical trial and implemented into the protocol.

Both test and placebo patients were treated twice a week for 4 weeks. Post-treatment follow-up on both sets of patients was performed after 4 weeks, 8 weeks, and 6 months. At the end of 6 months, patients from the LED placebo group were crossed over and then given Erchonia’s Spectrum Laser treatment protocol. The results were documented and submitted to the US FDA for a 510(k) market clearance De Novo Application.

The inclusion criteria consisted of autistic children between the ages of 5 to 17 years old, and progress was measured by using the ABC or Aberrant Behavior Checklist as the primary diagnosis. The ABC 58-point symptom checklist was used to assess and classify behaviors of irritability and agitation; lethargy and social withdrawal, stereotypic behavior, hyperactivity and noncompliance, and inappropriate speech in children with developmental disorders. The ABC tests were performed at baseline, 2 weeks, and 4 weeks during the treatments phase, and 4 weeks, 8 weeks, and 6 months post-treatment in both the treated and placebo groups.

“This is a well-designed trial that shows evidence supporting the use of Low Level Laser Therapy in children and adolescents with autism,” said Dr. Morales-Quezada, Associate Research Director at Spaulding-Labushagne Neuromodulation Center. “Moreover, the technique proved to be safe and well tolerated by the study participants. The active intervention showed to be more effective than the placebo (sham) device in treating symptoms of autistic disorder, and this statistically significant treatment effect was observed for all clinical outcomes, by the end of the intervention period and after the 6 months follow-up. This evidence offers a new treatment option to be considered for children and adolescents with autism.”

Calixto Machado, MD, PhD, FAAN, President of the Cuban Society of the Clinical Neurophysiology Institute of Neurology and Neurosurgery agreed, “Results are so strong, nobody can argue them.”

Steven Shanks, President of Erchonia stated, “This study from a scientific perspective is one of the most stringent ways to perform a clinical trial. The original placebo patients have now acted as their own control group. The LED that was used as a placebo showed no results even though we used the same wavelength and power output.”

The Erchonia Spectrum Laser implemented in this clinical trial was a prototype laser and is not currently sold. While waiting for the 510(k) market clearance, Erchonia will start the development process for the new Erchonia Spectrum Laser.

Erchonia would like to thank Calixto Machado, MD, PhD, FAAN, Mauricio Chinchilla, MD, Yanin Ferrer, MD, and the University of Havana for their dedication to research and helping Erchonia with its latest achievement.

About Erchonia. Erchonia created the low-level laser category in January 2002 when the FDA granted Erchonia the very 1st 510(k) market clearance for any low-level laser. This new study further sets Erchonia apart from its competitors based on their commitment to research and numerous 510(k) market clearances obtained through blind and controlled clinical trials.

Non-verbal Autism

For people born around the year 2000, or before, and diagnosed before 4 years old, having autism very often meant being non-verbal. By my earlier estimations, about 0.3% of children are still non-verbal when their peers are already chatting away. Of that 0.3% some will spontaneously develop speech, some develop speech due to intensive intervention either by parents or therapists and some never develop speech.

Being non-verbal does not mean you cannot communicate; you can use sign language, you can write/type, you can use pictures (Picture Exchange Communication System – PECS) or you can use an augmentative communication device. Such devices used to cost a fortune, but now they are just apps you can install on a tablet computer or smartphone. These apps exist in numerous languages not just English, Spanish, German and French.

In 2007 we used PECS and started to use a special touch screen connected to a PC. Using special software, Monty could show that his vocabulary was much more extensive than we thought, even though he could not speak, read or write; it was all picture-based.

I just saw that one American study is suggesting that the incidence of DSM 5 autism is now 2.5%. I think this will inevitably mean less and less attention for those with non-verbal autism, which I suspect is still around 0.3% of three year olds.

Parents or the State?

Who should be doing something to help those who are non-verbal?

This question recently arose when I was talking to the family of an 8 year old boy with severe autism. He is non-verbal, but goes every day to a special school for autism. I asked if he is going to learn sign language, or is he going to get some other kind of means to communicate? Apparently not.  I explained about augmentative communication devices and suggested asking the school about them, or just go and buy one.  You do have to wonder what they are doing all day long in this special school.

There are many alternative methods to communicate, but they all require someone to teach them.

Whose job is it to choose a method and make sure it is implemented?

I guess this depends on where you live.

In my world, the proactive parent would start to do this by the time the child was three or four years old.  Given not all parents are proactive, you would think that at pre-school or junior/primary school “the State” would step in and take some action; apparently not, at least where we live.

So what happens to little kids who have no means of communication? They become adults who have no means of communication and, not surprisingly, they will have major behavioural issues.


Non verbal vs non conversational

Whilst on this subject, there is another important issue to highlight.  Even when some people with severe autism do start to talk, they very often do not become conversational. They can answer questions and make requests for items they want, but they do not become chatty like typical kids.

Some parents refer to their non chatty child with autism as being non-verbal, this really is not fair to those children who do not have a single spoken word.

Some children with autism can sing but do not talk. This may sound very strange but both Monty's assistants also participate in musical/theatrical group of kids with autism that puts on public performances.  They have such kids.

I think if you can sing, you can be "trained" to talk.  It is just requires a lot of effort by someone - parents, therapists or school assistants. 

Becoming more conversational is a continuing challenge in educating a child who was non-verbal. I have a big pile of books and training manuals on this subject and recently decided to re-emphasize this in Monty's daily schedule. We cut back on physical education (PE) at school and one after-school piano lesson.  We already cut out the two foreign languages at school to make time for 1:1 work with his assistants.

By encouraging longer answers to questions both spoken and written, there is also a net benefit to regular school work.  


Studying Severe Autism 

Researchers tend to avoid studying severe autism, which often also means non-verbal autism. Research is focused on what I would call Asperger's and what researchers would call level 1 autism; in DSM5 terminology there are 3 levels of severity.  Clearly it is much easier to study people who can hold a conversation and have a typical or even high IQ.  

There is an initiative, see below, to study severe autism, but for drug producers the big market is mild autism. You can see this by looking at the types of drugs currently in clinical trials.

What Can We Learn from Studying Severe Autism?

   

What, When and Where of Autism – Critical Periods and Sensitive Periods

When time is of the essence

All kinds of dysfunctions may appear in autistic brains, which in itself make it a highly complex condition. There is also the when and where aspects of these dysfunctions, which often gets overlooked, or lost in oversimplification.

This then has to fit into the concept of critical periods, that I introduced in an earlier post. 

Critical Periods in the Biology of Autism – Not to miss the Boat

Critical periods are times during the brain’s development when it is particularly vulnerable to any disturbance, for example an excitatory/inhibitory imbalance.

This then leads to another related concept which is that of sensitive periods; these are periods when the person should be responsive to particular therapy.

Sensitive periods are very important to be understood by those planning clinical trials, because a therapy may indeed be effective only when given within a specific time window. During this time the person is sensitive to the therapy, but they will not be a responder after the time window has passed.

I am pleased to say that more research is beginning to consider the when aspect and not just the what aspect of biological dysfunction in autism.

The where aspect reflects the fact that in one part of the brain there might be, say, NMDA hypofunction, while in another part the opposite is present, NMDA hyperfunction.  Since most therapies come as pills you swallow, you cannot treat one part of the brain for one problem and another part of the brain for the opposite problem. There is currently no way around this issue, you just have to do what is best for the brain overall. In practical terms it means you may make one problem better, but create a new one. 

Earlier treatment could help reverse autistic-like behavior in tuberous sclerosis.  Scientists find a sensitive period for reversing social deficits  

New research in a mouse model suggests that the drug rapamycin can reverse autism-like social deficits -- but only if given early. The study is the first to shed light on the crucial timing of therapy to improve social impairments in a condition associated with autism spectrum disorder. Its findings could help inform future clinical trials in children with tuberous sclerosis complex. 

Full Paper:

Sensitive Periods for Cerebellar-Mediated Autistic-like Behaviors

  

Mefenamic Acid

I have mentioned mefenamic acid (Ponstan) in several posts. It is the only human autism therapy currently in development that has a treatment window.  It is suggested that the sensitive period to take this drug is the second year of life, to avoid severe non-verbal autism. 

Conclusion

The good news is that we have seen time and again that it is never too late to treat autism. Clearly the earlier you do start, the more extensive the long term benefit should be. So once you realize that intervention is possible, best not to delay.

When autism  is of a single gene origin, there really should eventually be scope to make some kind of permanent fix, if you can intervene very early and so still during that intervention’s sensitive period.  This might involve something very clever like gene editing, which you cannot do at home, or it might be just some drug therapy, like Rapamycin in TSC1 as in the above study.

Sugar-coating Autism and Autism Misinformation

Do you tell it as it really is? Or sugar-coat it, to make it more appealing?

It looks like in the English-speaking world we are more and more being driven by emotional political correctness, rather than calling things out as they actually are. Now this does not really matter if you are talking about relatively trivial subjects, which is what we deal with most of the time, but is a problem when dealing with a serious subject. When it comes to autism, giving the cold truth is quite upsetting to many people.

Bryna Siegel, a Californian Psychologist working with autism for a few decades has been promoting her new book, The Politics of Autism, in various articles.

                            https://thepoliticsofautism.com/

She tells a lot of home truths that many parents and professionals do not want to hear and people often react very emotionally and quite aggressively. I have found myself on more than one occasion giving her support.

She has several key points to make.  Autism is indeed over-diagnosed and as long there is a financial incentive for this, prevalence will increase.

She is very critical of the results of inclusive education, based on what young people are actually able to achieve when they leave school. The idea of inclusion sounds great, but what actually matters is the end result, in terms of independent living skills and job prospects. She wonders if people with more severe autism are being taught the right skills, rather than just a dumbed-down version of the standard curriculum.

At times, even I think she is perhaps a bit too brutal, but I think I will buy her new book. Monty’s assistants are also keen to read it, so maybe I will also donate a copy to be shared.

I know one little boy with severe autism, who is entirely non-verbal, and has no sign language or facilitated communication device. I do not think he can read or write.  At primary/junior school he now has to learn a foreign language. 

Autism Misinformation

A good example of autism misinformation occurred recently following on from a popular UK daytime TV show, and was highlighted in the Questioning Answers blog.

"Has Daniel always been autistic?" 

The host was interviewing a mother about her son with autism and he asked the very reasonable question “has your child always been autistic?” This prompted an outcry from the public and a supposedly knowledgeable organisation called the National Autistic Society (NAS), the UK’s dominant autism organisation. The host was blasted for not knowing that apparently “autism is always present from birth” and “it is not something you can grow out of” and of course it is un-treatable.

Given this child was described by his own mother as having regressed at 18 months and lost his speech, he might well not have been born autistic. The research has shown that many things can trigger “autism” during childhood and we know that about 10% of kids diagnosed with autism do indeed later go on to lose their diagnosis, so they do pretty much grow out of their autism. But why let the scientific facts get in the way of the simple storyline?

I always found the idea of raising autism awareness to be odd; it very often is just promoting misinformation, or putting one random person forward to explain the condition to others. This just confuses other people.

It is much better to just raise public awareness of disability in general, both physical and mental and to tackle bullying at school. Kids should be aware that a small percentage of their peers have severe problems and a much larger percentage have less disadvantaging problems, that can often be mitigated with extra help and understanding during all those years spent at school.

People need to know that just as autism is a spectrum from severe to mild, so are many other conditions like ADHD or dyslexia. Some people just need a little extra help, but some others have profound problems. Sometime soon 10% of all kids will have a medical diagnosis, but only a small fraction will be disabled by it. 

You can have dyslexia and still make it through medical school, but don’t dream about it if your kid has Down Syndrome.

“Dr” Wakefield

I do think Andrew Wakefield was very unfortunate to have studied medicine in the UK and not the US; had he done so I rather doubt he would have ever lost his medical license and he would never have become so well known.  He has a right to his opinions and there are some far more cranky physicians merrily practising today in the US.

Wakefield seems to making himself a new life with Elle Macpherson.  This clearly upsets the UK tabloid media, who still portray him as the devil - how can the devil end up with a super model?  I wish them well. 

Wakefield likes to refer to autism as brain damage, which is rather brutal like Dr Siegel; but he is right in case of DSM3-type autism.

Nowadays people get upset if autism is called a disease, or a mental illness and even some researchers want to sugar-coat it and call it a condition as opposed to a disorder (Autistic Spectrum Condition).  

Giving a nice name to something disabling does not make it go away. It just makes some people without that disability feel better.

Having mentioned Wakefield, I suppose we have to touch on vaccinations.

It would also be great if it was possible to be entirely honest about what we know about vaccines and autism. It is well established that mitochondrial disease can be triggered by vaccinations and it can manifest as regressive autism. This does not mean that all regressive autism is caused by vaccines. This does not mean that people should not be vaccinated; it just means that there is a small risk of something bad happening. Left unvaccinated there is a much larger risk of something else bad happening. Public health believes lay people are too dumb to understand this, I disagree; you just need to be 100% honest and explain it.  It is fashionable to be selectively truthful, or let pass a little white lie. I think being 100% honest, brutally honest, is what is needed when dealing with such an important subject. 

Details do Matter

Whether it is an unusual medical condition like autism, or any scientific investigation, all the details in their entirety are extremely important if you want any chance of solving the problem.

I just had a medical procedure to correct a problem that I first raised 40 years ago. I had an operation 40 years ago for a Meckel’s diverticulum, but it was the wrong operation and for the wrong diverticulum. Last week I had the right operation and, what could/should have been identified and treated in childhood, got treated decades later. When I read the summary of the completed treatment, it is a very well written concise explanation, with all the diagnostic inputs.

Now when I compare this to autism, which is far more complex, I can see mainstream medicine in not yet prepared to try and treat it.

Where do you go to get a precise summary of your child’s unique variant of autism / brain damage, all in 100 words?  Perhaps this will also take another 40 years?

A first small step would be make sure what we do actually know about autism is more widely shared and that at least Autism organisations, with public funding, should be required to have a detailed understanding of what they are supposed to be advocating for. There are excellent organisations to represent other medical conditions, for example diabetes or even Rett syndrome, but not for autism.

Whilst waiting for my operation I had a visit from a curious Nephrologist who dropped by to take my photo (an ultrasound image) to show her friends. Being a liver specialist, she did naturally take a peek at that as well and asked if I knew I had some fat in my liver. Off she went, leaving me to figure out where this fat had come from. 

I am pretty sure it comes from another misdiagnosis I had recently.  I had a sudden reduction in hearing in one ear and not being able to resolve it myself, I went to an ear nose and throat clinic. The diagnosis was a simple case of wax in the ear. Unfortunately this was the wrong diagnosis; by the time I had returned from a trip abroad, quite some time had passed. The second doctor I consulted very quickly diagnosed an inner ear problem (Endolymphatic hydrops) that apparently is quite common but is often left untreated, leading to life-long problems. It leads to a degree of permanent hearing loss, tinnitus and potentially vertigo. A virus, infection or even a physical shock can cause a build-up in pressure in the fluid in the inner ear. If you begin treatment within a week, you have a good chance to avoid permanent hearing loss. My treatment started after almost one month, which was far too late, so I had ten days of injected steroids, starting at a very high dose.  

High doses of steroids can have many side effects, one of which is causing fat to get deposited in your liver. It seems the fat spotted by the curious nephrologist should gradually disappear. I hope so.

Not wanting to be left deaf in one ear and noting the doctor did not seem entirely hopeful, I did quickly engage myself and read up on the science and the medicine.  I regularly do this for my son, but did not think I really should have to do so for my own ear problem. Ménière's disease is an incurable condition, of unknown cause(s), that has major similarities to what was affecting me.  I found a study, with supporting MRI images of the inner ear, showing that the amount of fluid in the ear can be reduced by taking the diuretic acetazolamide/Diamox, at least in some people. I did take note of a Cochrane review saying there is no evidence that diuretics have any benefit, but I did check the MRI images for myself. There is plenty in the blog about Diamox and autism. In Ménière's disease, Diamox responders lose the benefit when they stop taking the diuretic and this is reflected in their MRIs.  Since my condition was hopefully not yet chronic, I thought the immune suppressing actions of the steroid were indeed the long term fix, but at this late stage only pretty immediate rather than gradual loss of inner ear fluid would avoid permanent hearing loss.

Since I have Diamox from a few years ago sitting at the back of my autism pill shelf at home, I decided to add that to my therapy for a few days.  Diamox is cheap, except in the US, and is usually very well tolerated. As a bumetanide family we have a good supply of potassium supplements and bananas, so no chance of hypokalaemia.

My hearing returned and I have no related symptoms (tinnitus, vertigo etc). I have no idea if Diamox helped, but I am certainly glad I took it.

Another side effect of high dose steroid plus acetazolamide/Diamox was a change to my eyesight, both near and distant vision. Both drugs can affect your eyesight, but I think it was the steroid, since I took Diamox once to avoid altitude sickness with no side effects.  The vision side effects gradually fade away when you stop taking the drug.

All this was a timely reminder that drugs and supplements can have unexpected effects and it is best not to get carried away with how many you give your child.  I did recently take Monty, aged 15 with ASD, to see a paediatric cardiologist for a lengthy ultrasound investigation and ECG because, rather bizarrely, his autism drugs are mainly repurposed heart drugs. Where we live it is simple to arrange such a check-up and there is open access to lab tests.  I am fully aware that in countries with universal healthcare trying to access anything unusual may not be possible, unless your GP “gatekeeper” is supportive.   One French parent told me that his doctor would not prescribe bumetanide for his son, but was willing to authorize the blood tests to monitor potassium, if he acquired the bumetanide somewhere else.

Conclusion

In a recent comment our reader David from Spain, who is trying to get his child into the large Stage 3 trial for Bumetanide, informed us that the current prediction is 2023 for commercialization of this autism therapy. That would be 11 years after my son began to benefit.  That is how long it takes to repurpose an existing drug.

This really makes me think that it is not just a case of autism needing personalized medicine, but rather parent-inspired personalized medicine. This is much easier if the parent is a doctor.

As I know to my own cost, medicine currently can struggle with even slightly unusual conditions, so we should not expect wonders from strangers, even when they finally do have approved drugs to prescribe.  

The key will remain parent-inspired personalized medicine. When you do finally get 0.5mg of bumetanide twice a day as an approved autism therapy, it will be up to parents to realize that 1mg once a day or 2mg once a day might actually be much more beneficial.

If you ever have sudden hearing loss in one ear, go to your doctor straight away and have him/her specifically rule out an inner ear problem. If you live in the UK, hopefully you will not be made to wait 2 weeks to get an initial appointment with your GP.  If you don’t live in a country with universal healthcare or don’t have insurance, I suppose some people just go deaf.