Sulfarlem / Anethole trithione (AOL) for Autism secondary to Mitochondrial Dysfunction (AMD)? Not to mention Metastasis

Sulfarlem has been used to treat dry mouths for half a century

By www.scientificanimations.com - http://www.scientificanimations.com/wiki-images/, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=77499374

Sulfarlem is a drug containing a chemical called Anethole trithione. Anethole is an organic compound used as a flavouring, it contributes a large component of the odour and flavour of anise and fennel.

Anise seed, or aniseed, contains a large amount of Anethole. The popular Greek drink Ouzo turns cloudy when diluted with water because of the Anethole. For the French it is called Pastis.   

                                                                      

Ouzo has been used to treat dry Greek mouths for seven centuries, particularly after a good meal.

For Anethole without the alcohol, a good source would include aniseed or fennel.

Aniseed

Today's post was prompted by a comment made before Christmas by our reader Claudia; she highlighted some recent French research that repurposes a drug developed by Solvay half a century ago.  The drug is Sulfarlem / Anethole trithione and it is used to treat people with a dry mouth, mainly in French speaking countries (including Canada) and in China, particularly Taiwan.

Sulfarlem appears to have secondary effects that include inhibiting oxidative stress in mitochondria which might benefit a long list of diseases, though they do not mention autism secondary to mitochondrial disease.

The other effect is a reduction in metastasis in people with cancer. This effect was written about in 2002 in the mass media.

An old medicine as a new drug to prevent mitochondrial complex I from producing oxygen radicals

Here, we demonstrate that OP2113 (5-(4-Methoxyphenyl)-3H-1,2-dithiole-3-thione, CAS 532-11-6), synthesized and used as a drug since 1696, does not act as an unspecific antioxidant molecule (i.e., as a radical scavenger) but unexpectedly decreases mitochondrial reactive oxygen species (ROS/H2O2) production by acting as a specific inhibitor of ROS production at the IQ site of complex I of the mitochondrial respiratory chain. Studies performed on isolated rat heart mitochondria also showed that OP2113 does not affect oxidative phosphorylation driven by complex I or complex II substrates. We assessed the effect of OP2113 on an infarct model of ex vivo rat heart in which mitochondrial ROS production is highly involved and showed that OP2113 protects heart tissue as well as the recovery of heart contractile activity. 

Conclusion / Significance This work represents the first demonstration of a drug authorized for use in humans that can prevent mitochondria from producing ROS/H2O2. OP2113 therefore appears to be a member of the new class of mitochondrial ROS blockers (S1QELs) and could protect mitochondrial function in numerous diseases in which ROS-induced mitochondrial dysfunction occurs. These applications include but are not limited to aging, Parkinson’s and Alzheimer’s diseases, cardiac atrial fibrillation, and ischemia-reperfusion injury.


Here is the associated patent:-

Compounds for the treatment of diseases linked to mitochondrial reactive oxygen species (rose) production

  

SUMMARY 

The present invention relates to an inhibitor of production of reactive oxygen species (ROS) for treating or for use in the treatment of free oxygen-radicals related diseases. In one embodiment, said inhibitor is anethole trithione (AOL). In one embodiment, said inhibitor inhibits mitochondrial production of ROS. In a preferred embodiment, said inhibitor inhibits mitochondrial production of ROS at site IQ of complex I of mitochondria. 

In one embodiment, said free oxygen-radicals related diseases are selected from the group comprising: age-related macular degeneration, Parkinson's disease, Alzheimer's disease, ischemic and reperfusion injury, pulmonary arterial hypertension, scleroderma, atherosclerosis, heart failure, myocardial infarction, arthritis, pulmonary toxicity, cardiopulmonary diseases, inflammatory diseases, cancer, metastasis, cardiac toxicity of anthracyclines, heart failure regardless of origin, ischemia, heart attack, stroke, thrombosis and embolism, asthma, allergic/inflammatory conditions, bronchial asthma, rheumatoid arthritis, Inflammatory Bowel Disease, Huntington's disease, cognitive disorders, Progeria, progeroid syndromes, epileptic dementia, presenile dementia, post traumatic dementia, senile dementia, vascular dementia, HIV-1-associated dementia, post-stroke dementia, Down's syndrome, motor neuron disease, amyloidosis, amyloid associated with type 11 diabetes, Creutzfelt-Jakob disease, necrotic cell death, Gerstmann-Straussler syndrome, kuru and animal scrapie, amyloid associated with longterm hemodialysis, senile cardiac amyloid and Familial Amyloidotic Polyneuropathy, cerebropathy, neurospanchnic disorders, memory loss, aluminum intoxication, reducing the level of iron in the cells of living subjects, reducing free transition metal ion levels in mammals, patients having toxic amounts of metal in the body or in certain body compartments, multiple sclerosis, amyotrophic lateral sclerosis, cataract, diabetes, cancer, liver diseases, skin ageing, transplantation, ototoxic secondary effects of aminoglycosides, neoplasms and toxicity of anti-neoplastic or immunosuppressive agents and chemicals, innate immune responses, and, Friedreich's Ataxia.

In one embodiment, said inhibitor is for preventing or for use in the prevention of metastasis.

                                                                                                   

From way back in 2002: -

Dry-Mouth Drug Joins Cancer Fight

Stephen Lam, director of the lung cancer prevention program at the British Columbia Cancer Research Center in Vancouver, British Columbia, found that one of Solvay's drugs, marketed as Sialor or Sulfarlem, also significantly reduces the spread of lung-cancer tumors.

Lam's study completed the second phase of trials necessary for the FDA's consideration. Over six months, 101 smokers and former smokers took the dry-mouth drug. It reduced the progression of their lung cancer tumors by an average of 22 percent.

To participate in the study, the smokers had to have smoked at least a pack a day for 30 years, or two packs a day for 15 years.

Those who took a placebo had 53 percent more new lesions or lesions that got worse than those who took the drug.

The billion-dollar question is, who will pay for more clinical trials? Lam's study was paid for with grants from the National Cancer Institute, and the money has run out. The final stage of clinical trials can cost hundreds of millions of dollars.

The French have recently followed up :-

Mitochondria ROS blocker OP2-113 downregulates the insulin receptor substrate-2 (IRS-2) and inhibits lung tumor growth

They go further in their patent and propose Sulfarlem as a blocker of metastasis.

A recent Chinese paper sets out the mechanism of action.

CXCR4 and PTEN are involved in the anti-metastatic regulation of anethole in DU145 prostate cancer cells

Taken together, anethole demonstrated to act as the CXCR4 antagonist and as the PTEN activator which resulted to PI3K/AKT-mediated inhibition of the metastatic prostate cancer progressions.

Regular readers will know that PTEN is both a cancer gene and an autism gene.

PTEN is best known as a tumor suppressor affecting RAS-dependent cancer, like much prostate cancer. Activating PTEN is good for slowing cancer growth. As I mentioned in a recent comment to Roger, many substances are known to activate PTEN; a good example being I3C (indole-3-carbindol) which is found in those cruciferous vegetables (broccoli, Brussels sprouts, cabbage etc) that many people choose not to eat.

Activating PTEN should also help some types of autism.

A recent Japanese study has a different take on the anti-metastatic mode of action.

Anethole Exerts Antimetastatic Activity via Inhibition of Matrix Metalloproteinase 2/9 and AKT/Mitogen-Activated Kinase/Nuclear Factor Kappa B Signaling Pathways

Anethole is known to possess anti-inflammatory and anti-tumor activities and to be a main constituent of fennel, anise, and camphor. In the present study, we evaluated anti-metastatic and apoptotic effects of anethole on highly-metastatic HT-1080 human fibrosarcoma tumor cells. Despite weak cytotoxicity against HT-1080 cells, anethole inhibited the adhesion to Matrigel and invasion of HT-1080 cells in a dose-dependent manner. Anethole was also able to down-regulate the expression of matrix metalloproteinase (MMP)-2 and -9 and up-regulate the gene expression of tissue inhibitor of metalloproteinase (TIMP)-1. The similar inhibitory effect of anethole on MMP-2 and -9 activities was confirmed by zymography assay. Furthermore, anethole significantly decreased mRNA expression of urokinase plasminogen activator (uPA), but not uPA receptor (uPAR). In addition, anethole suppressed the phosphorylation of AKT, extracellular signal-regulated kinase (ERK), p38 and nuclear transcription factor kappa B (NF-kB) in HT-1080 cells. Taken together, our findings indicate that anethole is a potent anti-metastatic drug that functions through inhibiting MMP-2/9 and AKT/mitogen-activated protein kinase (MAPK)/NF-kB signal transducers.

Metastasis

There is quite a lot in this blog about cancer, due to the overlapping signalling pathways with autism, so follows a little digression about metastasis.

Metastasis is a pathogenic agent's spread from an initial/primary site to a different/secondary site within the host's body.

Often it is the metastasis that ultimately kills people; indeed this just happened to the mother of one of Monty's friends with autism.

Metastasis involves a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the body via the bloodstream, via the lymphatic system, or by direct extension.

Source: Mikael Häggström 

If a cheap substance could reduce metastasis that would be a big deal.  Cancer is currently the second most common cause of death.  If you can take cheap/safe chemoprotective agents to reduce cancer’s occurrence and a cheap substance to reduce its spread/metastasis you would be pretty smart.

Cheap Cancer Drugs

Numerous cheap drugs have known anti-cancer properties (Metformin, Aspirin, Statins, plus many more) but absolutely no serious interest is shown to apply any of them.  Instead, some hugely expensive drugs have been developed that often extend life by a matter of months.

Sulfarlem certainly is cheap, costing 3 euros (USD 3.3) a pack in France, where it seems to be sold OTC.

It looks like the world of cancer research is as dysfunctional as the world of autism research, when it comes to translating existing knowledge into beneficial therapies.  Nobody wants a cheap cancer drug and I think nobody wants a cheap autism drug.  

Most people still believe autism cannot be treated and some even think it should not be treated. 

Conclusion

Sulfarlem has been around for 50 years and so there is plenty of safety data regarding its use.

It does look like a significant number of people with autism have a problem with Complex 1 in their mitochondria.  This subject has been covered extensively in this blog in regard to regressive autism and what Dr Kelley, from Johns Hopkins, termed autism secondary to mitochondrial disease (AMD).  Unfortunately for us, he has retired.

https://epiphanyasd.blogspot.com/p/regressive-autism.html

Dr Kelley’s mito-cocktail of antioxidants is used by many, but even he makes clear that it is far from perfect and it is not so cheap. 

Sulfarlem looks like an interesting potential add-on, or even a potential replacement.

The fact that Sulfarlem also activates PTEN means that an entirely different group with autism might see a benefit.

Who might carry out a trial of Sulfarlem in autism?  I think the one likely group are those irrepressible autism researchers in Iran, who have trialed so many off-label drugs.  Since Sulfarlem is already licensed in Canada, one of those more enlightened researchers in Toronto might like to investigate.

If you live in France you can skip your early morning expresso and go down to the pharmacy with your three euros and then make your own trial.

Sulfarlem, or just plain anethole, seems a cheap/safe way to potentially reduce metastasis once cancer has been identified. Probably not worth waiting another 20 years for any possible further clinical trials.

The Clever Ketogenic Diet for some Autism

I have covered the Ketogenic Diet (KD) in earlier posts. 

There are more and more studies being published that apply the KD to mouse models of autism.

Calling the KD a diet does rather under sell it.  The classic therapeutic ketogenic diet was developed for treatment of pediatric epilepsy in the 1920s and was widely used into the next decade, but its popularity waned with the introduction of effective epilepsy drugs.

There are various exclusion diets put forward to treat different medical conditions; some are medically accepted but most are not, but that does not mean they do not benefit at least some people.

When it comes to the ketogenic diet (KD) the situation is completely different, this diet is supposed to be started in hospital and maintained under occasional medical guidance. The KD was developed as a medical therapy to treat pediatric epilepsy.  It is very restrictive which is why it is used mainly in children, since they usually will (eventually) eat what is put in front of them.

The KD was pioneered as a medical therapy by researchers at Johns Hopkins in the 1920s, over the years they have shown that most of the benefit of the KD can be achieved by the much less restrictive Modified Atkins Diet (MAD).  The first autism mouse study below suggests something similar “Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior”.

What about the KD in Autism?

Most people with autism, but without epilepsy, will struggle to get medical help to initiate the KD.  Much research in animal models points to the potential benefit of the KD.

Ketogenic diets improve behaviors associated with autism spectrum disorder in a sex-specific manner in the EL mouse

·        Drug treatments are poorly effective against core symptoms of autism.

·        Ketogenic diets were tested in EL mice, a model of comorbid autism and epilepsy.

·        Sociability was improved and repetitive behaviors were reduced in female mice.

·        In males behavioral improvements were more limited.

·        Metabolic therapy may be especially beneficial in comorbid autism and epilepsy.

The core symptoms of autism spectrum disorder are poorly treated with current medications. Symptoms of autism spectrum disorder are frequently comorbid with a diagnosis of epilepsy and vice versa. Medically-supervised ketogenic diets are remarkably effective nonpharmacological treatments for epilepsy, even in drug-refractory cases. There is accumulating evidence that supports the efficacy of ketogenic diets in treating the core symptoms of autism spectrum disorders in animal models as well as limited reports of benefits in patients. This study tests the behavioral effects of ketogenic diet feeding in the EL mouse, a model with behavioral characteristics of autism spectrum disorder and comorbid epilepsy. Male and female EL mice were fed control diet or one of two ketogenic diet formulas ad libitum starting at 5 weeks of age. Beginning at 8 weeks of age, diet protocols continued and performance of each group on tests of sociability and repetitive behavior was assessed. A ketogenic diet improved behavioral characteristics of autism spectrum disorder in a sex- and test-specific manner; ketogenic diet never worsened relevant behaviors. Ketogenic diet feeding improved multiple measures of sociability and reduced repetitive behavior in female mice, with limited effects in males. Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior. Taken together these results add to the growing number of studies suggesting that ketogenic and related diets may provide significant relief from the core symptoms of autism spectrum disorder, and suggest that in some cases there may be increased efficacy in females.

Ketogenic diet restores aberrant cortical motor maps and excitation-to-inhibition imbalance in the BTBR mouse model of autism spectrum disorder

·        The BTBR mouse has lower movement thresholds and larger motor maps relative to control mice.

·        The high-fat low-carbohydrate ketogenic diet raised movement thresholds and reduced motor map size in BTBR mice.

·        The ketogenic diet normalizes movement thresholds and motor map size to control levels.

Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental disorder characterized by deficits in sociability and communication, and restricted and/or repetitive motor behaviors. Amongst the diverse hypotheses regarding the pathophysiology of ASD, one possibility is that there is increased neuronal excitation, leading to alterations in sensory processing, functional integration and behavior. Meanwhile, the high-fat, low-carbohydrate ketogenic diet (KD), traditionally used in the treatment of medically intractable epilepsy, has already been shown to reduce autistic behaviors in both humans and in rodent models of ASD. While the mechanisms underlying these effects remain unclear, we hypothesized that this dietary approach might shift the balance of excitation and inhibition towards more normal levels of inhibition. Using high-resolution intracortical microstimulation, we investigated basal sensorimotor excitation/inhibition in the BTBR T + Itpr^tf/J (BTBR) mouse model of ASD and tested whether the KD restores the balance of excitation/inhibition. We found that BTBR mice had lower movement thresholds and larger motor maps indicative of higher excitation/inhibition compared to C57BL/6J (B6) controls, and that the KD reversed both these abnormalities. Collectively, our results afford a greater understanding of cortical excitation/inhibition balance in ASD and may help expedite the development of therapeutic approaches aimed at improving functional outcomes in this disorder.

Ketogenic diet modifies the gut microbiota in a murine model of autism spectrum disorder

Background

Gastrointestinal dysfunction and gut microbial composition disturbances have been widely reported in autism spectrum disorder (ASD). This study examines whether gut microbiome disturbances are present in the BTBR^T + tf/j (BTBR) mouse model of ASD and if the ketogenic diet, a diet previously shown to elicit therapeutic benefit in this mouse model, is capable of altering the profile.

Findings

Juvenile male C57BL/6 (B6) and BTBR mice were fed a standard chow (CH, 13 % kcal fat) or ketogenic diet (KD, 75 % kcal fat) for 10–14 days. Following diets, fecal and cecal samples were collected for analysis. Main findings are as follows: (1) gut microbiota compositions of cecal and fecal samples were altered in BTBR compared to control mice, indicating that this model may be of utility in understanding gut-brain interactions in ASD; (2) KD consumption caused an anti-microbial-like effect by significantly decreasing total host bacterial abundance in cecal and fecal matter; (3) specific to BTBR animals, the KD counteracted the common ASD phenotype of a low Firmicutes to Bacteroidetes ratio in both sample types; and (4) the KD reversed elevated Akkermansia muciniphila content in the cecal and fecal matter of BTBR animals.

Conclusions

Results indicate that consumption of a KD likely triggers reductions in total gut microbial counts and compositional remodeling in the BTBR mouse. These findings may explain, in part, the ability of a KD to mitigate some of the neurological symptoms associated with ASD in an animal model.

Effect of a ketogenic diet on autism spectrum disorder: A systematic review

·        We evaluated, throughout a systematic review, the studies with a relationship between autism and ketogenic diet.

·        Studies points to effects of KD on behavioral symptoms in ASD through the improve score in Childhood Autism Rating Scale (CARS).

·        Reviewed studies suggest effects of KD especially in moderate and mild cases of autism.

·        KD in prenatal VPA exposed rodents, as well in BTBR and Mecp2 mice strains, caused attenuation of some autistic-like features.

Autism spectrum disorder (ASD) is primarily characterized by impaired social interaction and communication, as well as restricted repetitive behaviours and interests. The utilization of the ketogenic diet (KD) in different neurological disorders has become a valid approach over time, and recently, it has also been advocated as a potential therapeutic for ASD. A MEDLINE, Scopus and Cochrane search was performed by two independent reviewers to investigate the relationship between ASD and the KD in humans and experimental studies. Of the eighty-one potentially relevant articles, eight articles met the inclusion criteria: three studies with animals and five studies with humans. The consistency between reviewers was κ = 0.817. In humans, the studies mainly focused on the behavioural outcomes provided by this diet and reported ameliorated behavioural symptoms via an improved score in the Childhood Autism Rating Scale (CARS). The KD in prenatal valproic acid (VPA)-exposed rodents, as well as in BTBR and Mecp2 mice strains, resulted in an attenuation of some autistic-like features. The limited number of reports of improvements after treatment with the KD is insufficient to attest to the practicability of the KD as a treatment for ASD, but it is still a good indicator that this diet is a promising therapeutic option for this disorder.

Conclusion

Since very many parents do not want to use drugs to treat autism, it is surprising more people do not try the ketogenic diet (KD) or at least the KD-lite, which is the Modified Atkins Diet (MAD).

I think you have to be pretty rigid about the MAD, if you go MAD-lite you will likely achieve little; rather like thinking you have a Mediterranean diet because you buy the occasional bottle of olive oil.

Many children with epilepsy who started out on the KD continue in adulthood with the Modified Atkins Diet (MAD).

There is anecdotal evidence that people with mitochondrial disease benefit from the KD.

All in all, it is hard to argue that the KD/MAD should not be the first choice for those choosing to treat autism by diet. It really does have science and clinical study to support it.

In some people with autism it appears that when you eat is as important as what you eat.  There can be strange behaviors just after eating, presumably caused by a spike in blood sugar, or for others before breakfast. 

In regressive autism (AMD) Dr Kelley, from Johns Hopkins, wrote that:- 

Another important clinical observation is that many children with mitochondrial diseases are more symptomatic (irritability, weakness, abnormal lethargy) in the morning until they have had breakfast, although this phenomenon is not as common in AMD as it is in other mitochondrial diseases.  In some children, early morning symptoms can be a consequence of compromised mitochondrial function, whereas, in others, a normal rise in epinephrine consequent to a falling blood glucose level in the early morning hours can elicit agitation, ataxia, tremors, or difficulty waking.  In children who normally sleep more than 10 hours at night, significant mitochondrial destabilization can occur by the morning and be evident in biochemical tests, although this is less common in AMD than in other mitochondrial disorders.  When early morning signs of disease are observed or suspected, giving uncooked cornstarch (1 g/kg; 1 tbsp = 10g) at bedtime effectively shortens the overnight fasting period.  Uncooked cornstarch, usually given in cold water, juice (other than orange juice), yogurt, or pudding, provides a slowly digested source of carbohydrate that, in effect, shortens overnight fasting by 4 to 5 hours.

I still find it rather odd that none of Dr Kelley's work on treating regressive autism has been published in any scientific or medical journal.  After all, he was a leading staff member at one of the world's leading hospitals.  He is no quack.  It is extremely wasteful of knowledge and clinical insights that could help improve the lives of something greater than 0.2% of the world's young children.  That is a lot of people.

Meldonium/Mildronate for Athletic Performance, but seemingly also for Mitochondria, Neuroinflammation, Cognition and Alzheimer’s

What you see is what you get,

not what you see is what he took.

Today’s post is another very short one.

You may have seen that Maria Sharapova, the tennis player has got into trouble for taking a Latvian drug called Meldonium/Mildronate for the last decade.

Like many people, I did a quick check on this drug to see what it does and if you could innocently not know that it is performance enhancing.  Well it does lots of performance enhancing things like increasing blood flow and increasing your capacity to exercise.

What drew my attention was its effect on mitochondria, cognition and even as a potential Alzheimer’s Therapy.

I should point out that Bumetanide, the most effective Autism therapy my son uses, is also a banned substance under the World Doping Agency rules.  Bumetanide and other diuretics are used as masking agents by athletes taking performance enhancing drugs.  

Mildronate

Mildronate is a Latvian drug, widely prescribed across the former Soviet Union.

For people with autism who respond to carnitine therapy, or with a diagnosed mitochondrial disorder it looks very interesting.  There really are no approved treatments that reverse such disorders, just to stop them getting worse.

Mildronate also shows some promise for both Parkinson’s and Alzheimer’s disease in animal models.

Mildronate improves cognition and reduces amyloid-β pathology in transgenic Alzheimer's disease mice

 

Mildronate, a carnitine congener drug, previously has been shown to provide neuroprotection in an azidothymidine-induced mouse model of neurotoxicity and in a Parkinson's disease rat model. The aim of this study was to investigate the effects of mildronate treatment on cognition and pathology in Alzheimer's disease (AD) model mice (APP(SweDI)). Mildronate was administered i.p. daily at 50 or 100 mg/kg for 28 days. At the end of treatment, the animals were behaviorally and cognitively tested, and brains were assessed for AD-related pathology, inflammation, synaptic markers, and acetylcholinesterase (AChE). The data show that mildronate treatment significantly improved animal performance in water maze and social recognition tests, lowered amyloid-β deposition in the hippocampus, increased expression of the microglia marker Iba-1, and decreased AChE staining, although it did not alter expression of proteins involved in synaptic plasticity (GAP-43, synaptophysin, and GAD67). Taken together, these findings indicate mildronate's ability to improve cognition and reduce amyloid-β pathology in a mouse model of AD and its possible therapeutic utility as a disease-modifying drug in AD patients.

Mildronate and its Neuroregulatory Mechanisms: Targeting the Mitochondria, Neuroinflammation, and Protein Expression

This review for the first time summarizes the data obtained in the neuropharmacological studies of mildronate, a drug previously known as a cardioprotective agent. In different animal models of neurotoxicity and neurodegenerative diseases, we demonstrated its neuroprotecting activity. By the use of immunohistochemical methods and Western blot analysis, as well as some selected behavioral tests, the new mechanisms of mildronate have been demonstrated: a regulatory effect on mitochondrial processes and on the expression of nerve cell proteins, which are involved in cell survival, functioning, and inflammation processes. Particular attention is paid to the capability of mildronate to stimulate learning and memory and to the expression of neuronal proteins involved in synaptic plasticity and adult neurogenesis. These properties can be useful in neurological practice to protect and treat neurological disorders, particularly those associated with neurodegeneration and a decline in cognitive functions.

The obtained data give a new insight into the influence of mildronate on the central nervous system. This drug shows beneficial effects in the regulation of cell processes necessary for cell integrity and survival, particularly by targeting mitochondria and by stabilizing the expression of proteins involved in neuroinflammation and neuroregeneration. These properties can be useful in neurological practice to protect and treat neurological disorders, such as Parkinson’s disease, diabetic neuropathies, and ischemic stroke. Moreover, because mildronate improves learning and memory, one may suggest mildronate as a multitargeted neuroprotective/ neurorestorative drug with its therapeutic utility as a memory enhancer in cognitive impairment conditions, such as neurodegenerative diseases, schizophrenia, and other pathologies associated with a decline in awareness.

Neuroprotective properties of mildronate, a mitochondria-targeted small molecule.

Mildronate, a representative of the aza-butyrobetaine class of drugs with proven cardioprotective efficacy, was recently found to prevent dysfunction of complex I in rat liver mitochondria. The present study demonstrates that mildronate also acts as a neuroprotective agent. In a mouse model of azidothymidine (anti-HIV drug) neurotoxicity, mildronate reduced the azidothymidine-induced alterations in mouse brain tissue: it normalized the increase in caspase-3, cellular apoptosis susceptibility protein (CAS) and iNOS expression assessed by quantitative and semi-quantitative analysis. Mildronate also normalized the changes in cytochrome c oxidase (COX) expression, reduced the expression of glial fibrillary acidic protein (GFAP) and cellular infiltration. The present results show that the neuroprotective action of mildronate results at least partially from anti-neurodegenerative (anti-apoptotic) and anti-inflammatory mechanisms. It might be suggested that the molecular conformation of mildronate can facilitate its easy binding to mitochondria, and regulate the expression of different signal molecules, hence maintaining cellular signaling and survival.

Conclusion

If any of the Russian readers of this blog have trialed Mildronate in their child with autism secondary to mitochondrial disease (AMD), please let us know the result.

Perhaps Dr Kelley should try mildronate, it clearly falls into his area of interest.

Vienna and some selected Autism History

  

Monty aged 12 with ASD, “You have been transformed into an Australopithecus afarensis, you walked upright more than 3 million years ago. Your picture is attached. This morphing-station is a co-production between Naturhistorisches Museum Vienna, Austria and the Smithsonian Natural History Museum in Washington”

We can never know if they had autism 3 million years ago, but it certainly is not a recent phenomenon.  Today’s post, prompted by a visit to Vienna, is a collection of historical episodes that I thought I should include in this blog, before I forget them.

Austria, as well as being home to an excellent natural history museum, where you can see what your children might have looked like had they been born 3 million years ago, is the home of autism. 

Both Hans Asperger and Leo Kanner were Austrian.  Kanner was later educated in Berlin and then, being Jewish, had the foresight to emigrate in 1924 to the US. In 1930 he developed the first child psychiatry service in an American pediatric hospital at Johns Hopkins Hospital.  He published his research on autism in 1943.  His narrowly defined type of autism became known as Kanner’s autism or classic autism; however if you read his actual case histories below you will see that they include quite high functioning people as well

Autistic Disturbances of Affective Contact, by Leo Kanner 1943

                   

Kanner clearly made a valuable contribution, but he also had some odd ideas, like autism is just a childhood condition, so adults cannot have autism and that autism is extremely rare.  He thought that if a patient had epilepsy they could not be autistic. He also famously suggested that autism was caused by refrigerator mothers.

But unlike all the doctors who preceded him, at least he wrote down his findings and sought out public attention.

Hans Asperger, presumably not Jewish, eventually became chair of pediatrics at the University of Vienna.  In 1943 he published, in German, his paper on autism that focused on gifted children and what would become known as Asperger’s syndrome. 

Die„Autistischen Psychopathen“ im Kindesalter (1943)

The paper was finally rediscovered in 1991 and translated into English by Uta Frith.  Thereafter in the English speaking world, people could finally be diagnosed with Asperger’s Syndrome.  Personally I think it is a very useful/clear diagnosis: - no speech delay, no cognitive dysfunction, just the trademark differences of mild autism.

It later became known that while he may have published research on very high functioning people, he also had many patients who were low functioning.  The reason Asperger highlighted the gifted children was that during World War 2, the Nazis had a program called Aktion T4, which was set up to kill people with disabilities (unable to work).  People with Down syndrome, epilepsy, mental retardation etc. were removed from their residential institutions or homes and given a lethal injection or just carbon monoxide poisoning.  The family later received a letter that the child had sadly died of pneumonia.

At Schloss Hartheim, near Linz, two hours west on Vienna, about 30,000 people were killed, including those selected under Aktion T4.

So not surprisingly, Asperger did not write about those with autism without special gifts and talents.

Schloss Hartheim

Great Ormond Street Hospital, London 1877

Twenty years even before Johns Hopkins Hospital had been founded in Baltimore, children with epilepsy, “autism” and GI problems were being treated in London at Great Ormond Street Hospital, today of Europe's top children's hospitals.

They were using a very early drug to shift the excitatory/inhibitory balance of the neurotransmitter GABA.  It was Potassium Bromide, which is still used today in Germany to treat children with epilepsy.  Of course back in 1877 they did not know why it was effective.  Below is a link to a fascinating chapter of a book.

Dr Dickinson and his patients with “autism” in 1877

In 2015 this same hospital would tell you that autism is untreatable and that GI problems are not comorbid with autism.

At some point I will be writing a post all about Potassium Bromide and autism.

More History

For those of you who despair sometimes about the low level of knowledge and understanding regarding autism among healthcare providers and even supposed “experts”, I suggest you look back at the history.

As is often the case, history holds many of the answers.

Until relatively recently most children with disorders like Downs Syndrome or classic autism were sent from a very young age to live in so called “homes for the feeble minded”.  In recent times this occurs far less common and nobody uses terms like feeble-minded, but nonetheless difficult to control children are still put “into care”.

It really was a case of out sight being out of mind.

As we saw in the data on Down syndrome in the US, life expectancy was extremely short in these massive institutions where the kids lived in dormitories.  The average being only 10 years as recently as 1970.

As in Austria and Germany, in the US being sent to a home for the feeble minded was very often a death sentence, albeit a slower one.  The Germans even went as far as to financially justify their actions by quoting the cost of keeping a child in an institution for 10 years (the same life expectancy of Down's kids in the US, just 50 years ago).

Given this backdrop, not surprisingly everybody kept quiet about autism, almost nobody was interested in treating it and nobody would dream of using the word autism, for someone who was fully verbal and not mentally retarded.

So it is hardly surprising that there are/were very few older people with autism, or indeed Downs Syndrome.

Homes for the Feeble-Minded

There were numerous Homes for the Feeble-Minded in the US and across the world.  Here are some examples.

Vineland Training School for Feeble-Minded Girls and Boys

Maine School for the Feeble-Minded

Belchertown State School, Massachusetts

Throughout its first 40 years, Belchertown operated mostly without scrutiny from outside sources. Author Benjamin Ricci (whose son lived at the school, and who later led a class-action lawsuit protesting the conditions there) referred to the conditions as "horrific", "medieval and "barbaric". Doctors at the school had little regard for patients' mental capacity, evidenced by this quote:

His method of evaluating me consisted of looking me over during the physical exam and deciding that since I couldn't talk and apparently couldn't understand what he was saying, I must be an imbecile. [...] Since I couldn't ask him to speak up or repeat what he said, he assumed I was a moron

The horrendous conditions at Belchertown were revealed in 1971 in a newspaper article entitled "The Tragedy of Belchertown". Parents sued the school, and when the state Attorney General toured the facility, he described it as "a hell hole".

In Michigan they even gave a special mention to those with epilepsy:

Michigan Home for the Feeble Minded and Epileptic

Why feeble minded?

Going back 110 years in the United Kingdom, you can see where terms like feeble minded came from:

In 1904 a Royal Commission was appointed to consider “the existing methods of dealing with Idiots and Epileptics and with Imbeciles and Feeble-Minded not certified under the Lunacy Laws.”

They disallow the name of “Lunatic” and “Asylum” and classify the mentally defective as follows:-

·          Persons of unsound mind (who require care and control).

·          Persons mentally infirm (who are incapable of managing their own affairs)

·          Idiots. Defective in mind from birth.

·          Imbeciles. (Capable of guarding themselves against common physical dangers, but incapable of earning their own living).

·          Feeble-Minded. (Persons who may be capable of earning their own living under favourable conditions, but are incapable of competing with others or managing themselves).

·          Moral Imbeciles. (Persons who display some Mental Defect with vicious or criminal propensities on which punishment is no deterrent).

·          Epileptics.

·          Inebriates.  All of these three are considered Mentally Defective.

·          Deaf, Dumb and Blind.

Almost all such people were, in effect, locked up. In the UK at that time there were 149,628 such people deemed to be mentally defective.  That is 0.4% of the population at that time.

Modern Times

In rich western countries large “out of sight out of mind” institutions are a thing of the past.  They still exist in some other countries.

Now that at least some children with disabilities are educated in the community, or at least live at home many things began to change.  

The incentive to hide your disability was replaced by an incentive to promote it.  For each child with a diagnosis extra money is allocated to the school district (in the US) and in many countries families are entitled to weekly or monthly benefits payments.

Changes to diagnosis began to be made such that children with MR/ID were now diagnosed as having autism, boosting prevalence.

Then from the 1990s onwards came the boom in diagnosing Asperger’s in children and then later diagnosing Asperger’s in quite old adults.  

Finally, just to confuse everyone, in the US at least, Asperger’s has been merged into autism.

Once a rare condition, autism has become anything but; all over the period of 20 years. But it is not the same autism.

Even though the science is clearly indicating that within autism are numerous separate biological disorders and as many as 1,000 genes are involved, the US psychiatrists, with DSM5, have decided that it is all just “autism” and you are ranked on a scale of 1 to 3 for severity. I would have thought 1 to 300 might have been more reasonable.

The key discriminating factors like regressive or not, MR/ID or not, epilepsy or not, speech delay or not are not seen a relevant.

As a result the modern diagnosis of “autism” then just begs the question “what sort?”

Better to forget about “autism awareness”; much better to explain what autism really is and how certain types can be treated today based on existing hard science.

Dr Wakefield

Until Dr Wakefield published his paper in 1998, few people were familiar with autism, because nobody spoke about it.  Talk of the MMR vaccine and autism created fear among parents.

In the end Wakefield did a great deal of harm, even though much of what he said was actually true.  There is an unwritten rule that must not be challenged, “vaccines do no harm”.

As Martha Herbert pointed out, everything regarded as “Wakefield” became taboo, and research in those areas became un-fundable.  The link to GI problems is one area she highlighted and is still disputed by many, but not Boston Children’s Hospital, supposedly the number one Pediatric hospital in the world.   

Hannah Poling

As was shown in the legal case brought by US neurologist Dr Jon Poling, regarding his daughter Hannah, children with mitochondrial dysfunction can suffer an inflammatory response to multiple vaccines that can trigger mitochondrial damage leading to profound autism.  This doctor meticulously documented his case and was awarded compensation of $1.5 million plus $500,000 a year thereafter. 

It turns out that in the last 25 years the US government has paid out $3 billion dollars in compensation for childhood vaccinations (see table below).

It was expected that this case would act as a precedent to later cases, opening the flood gates so to speak.  It did not.

In this case Dr Poling was much more effective that Wakefield.  He made his point and kept his medical license.

But the public health interest in vaccination programs is immense.  Hundreds of millions of lives have been saved by vaccines and nothing is going to be let to get in the way of that.  Vaccines are effective once a critical mass of people have taken them, (Herd Immunity).  So in theory it would be fine for certain groups not to be vaccinated, like those with genetic mitochondrial dysfunctions.

As Dr Poling pointed out, quite a large minority of people with autism do have mitochondrial disorders; even Dr Kelley from Johns Hopkins has referred to this.

 

Herd Immunity

When a critical proportion of the population becomes immune, called the herd immunity threshold (HIT) or herd immunity level (HIL), the disease may no longer persist in the population

It should be noted that in about 2% of people vaccination may fail to provide immunity.   In the case of influenza you have to know which type of virus to protect against.

  

Here is Dr Poling’s response to the highly sceptical Dr Steven Novella, an American clinical neurologist and assistant professor at Yale University School of Medicine and a blogger. Novella is best known for his involvement in the skeptical movement. He had written about the Hannah Poling case on his blog.

Dear Dr. Novella,

Your assertion that the scientific question of Autism etiology belongs to the medical community rather than Hollywood Stars is correct.  I also agree that Hollywood opinions are more likely to be broadcast to millions because of their position in the media.  This heightened awareness is nothing but a positive thing for the million families struggling with this difficult, and all too common, disorder.  Jenny McCarthy is an Autism Mom looking for answers and rattling some cages—good for her.  Amanda Peet is a new mom who believes in the importance of vaccines to protect her baby—good for her too.  Don’t attack the moms, listen to them.   

These issues are very complex as we exchanged before and not amenable to soundbites.  Regarding your entry on Hannah’s case, your blog entry unfortunately propagates several of the mistakes from the media.

In criticizing the journalism of Mr. David Kirby, you wrote:

“He refers again to the Hannah Poling case, a girl with a mitochondrial disorder who developed a neurodegenerative disorder with “features of autism” after getting a fever from vaccines.”

Actually—Hannah has diagnoses of DSM-IV Autism (by JHU/KKI psychology) and mitochondrial disorder (by two metabolic experts).  The only ‘degeneration’ that occurred (along with 6mos of total growth failure) after 18mos of NORMAL development followed vaccination and nothing else! Of course, any ‘scientist’ can obviously point out that temporal correlation in a single case never proves causation. Rule number one of pediatrics though is “LISTEN TO THE MOM.”  Are 10s of thousands of autism moms over the last decade suffering from mass hysteria induced by Hollywood?  Not likely.

You also noted:

“This special case - which is not a case of autism being caused by toxins in vaccines - says nothing about the broader vaccine-autism debate.”

The only thing unique about my little girl’s case is the level of medical documentation—5 to 20% of patients with ASDs have mitochondrial dysfunction.  Many other cases where mitochondrial testing is WNL is because "we never looked" not because the testing would be "within normal limits."  Most mitochondrial experts will tell you that the dots of autism and mitochondrial disorders are strongly connected.

Finally, you say:

“The case was settled (not judged in Poling’s favor, but settled) because both sides realized it was a special case that could not be extrapolated to other vaccine-autism cases.”

The case was not settled, it was conceded by medical representatives of Sec HHS.  We are obviously pleased with the HHS decision to concede our case, but we had NOTHING to do with the concession.  This was a unilateral decision from HHS (recall that HHS is the respondent, rather than the vaccine maker, as manufacturers have blanket liability protection afforded by the Vaccine Injury Program established in 1986)  I will not speculate on the obvious question—why concede?   Hannah’s case was positioned to set precedent as a test case in the Omnibus Autism Proceedings for potentially thousands of other cases.

With regard to the science of Autism, I have no argument with the assertion that a single case does not prove causation of a generalized autism-vaccine link.  What the case does illustrate though is a more subtle point that many physicians cannot or do not want to comprehend (ostensibly because vaccines are too important to even question).  Autism is a heterogeneous disorder defined by behavioral criteria and having multiple causes.  Epidemiological studies which have not found a link between autism and aspects of vaccination do not consider the concept of autism subgroups.  Indeed, in a heterogeneous disorder like Autism, subgroups may indeed be ‘vaccine-injured’ but the effect is diluted out in the larger population (improperly powered study due to inability to calculate effect size with unknown susceptible subpopulation).   I think former NIH Director, Dr. Bernadine Healey explained it best in that population epidemiology studies are not “granular” enough to rule-out a susceptible subgroup. 

Furthermore, ‘science’ has not systematically studied the children who fell ill following vaccination to determine what the cause(s) for their adverse reaction was.  It would follow that if you never tried to understand why a single child developed encephalopathy following vaccination—you wouldn’t have the first clue as to what aspects of vaccination you could alter which could increase the relative risk of that adverse event (whether it be thimerosal, live virus, or ‘too many’). Could the susceptibility be a mitochondrial genetic haplogroup similar to Chloramphenicol toxicity—sure it could!  Why did a few Alzheimer’s patients die of fatal encephalitis following administration of the failed AN-1792 vaccine, but the majority had no ill effects (vaccine didn’t work though)? 

Definition:  Autism is a heterogeneous systemic disorder with primary neuropsychiatric manifestations due to complex genetic and gene-environmental interactions likely affecting synaptic plasticity early in childhood development.  This new theory of Autism is rapidly replacing the ‘old guard’ dictum that Autism is a genetically predetermined developmental brain disorder of synaptic formation/pruning that is set in motion prenatally.  By the ‘10 year rule of science,’ your time is about up! 

Until the biological basis of ASD subgroups are better understood, further epidemiological and genetic studies regarding “Autism” causation will be relatively meaningless.  We need good science to be able to address these complex issues which parallel nicely the emerging story of genetic and environmental influences in Parkinson’s disease.  Perhaps some Parkinson’s researchers want to take a crack at Autism?

Recommended SCIENCE reading for the evening:
 
Altered calcium homeostasis in autism-spectrum disorders: evidence from biochemical and genetic studies of the mitochondrial aspartate/glutamate carrier AGC1. Mol Psychiatry 2008 Jul 8.  (The discussion includes thimerosal as a potential toxin that could trigger further perturbations of calcium homeostasis leading to neuronal injury—and in a mainstream Nature publication no less)

Thank-you Dr. Novella and his band of skeptics for continuing the debate.

Dr. Jon Poling

Jon S. Poling MD PhD
Managing Partner, Athens Neurological Associates
Clinical Assistant Professor, Department of Neurology, Medical College of Georgia
Diplomate, American Association of Neuromuscular and Electrodiagnostic Medicine
ASN Certified in MRI and CT Neuroimaging

                               

In the US there is $0.75 levy on childhood vaccines to fund a compensation scheme.

National Vaccine Injury Compensation Program

Source: http://www.hrsa.gov/vaccinecompensation/vicpmonthlyaugust.pdf

By the 1980/90s almost all of the huge institutions for “feeble minded” children had been closed in the US and other Western countries.  The understanding of autism among medical practitioners did not really change.  Finally Asperger’s old papers were translated from German into English and in the 1990s large numbers of children started to get diagnosed with Asperger’s syndrome.  The stigma of such a diagnosis was no longer as it would have been a few decades before.

Conclusion

It is rather odd that many people’s points of reference regarding autism still date back to those two Austrians, Kanner and Asperger, from 1943.

Neuroscience has moved on a fair way since world war two, but in many ways autism has not.  In some ways it is now going backwards.

The main change is the surge of interest in Asperger’s, which is now, unhelpfully, being referred to simply as autism.  This does a great disservice to those with what used to be known as autism.  They generally cannot speak up for themselves and really do need customized medical treatment.

People with Asperger’s are more than capable enough to decide for themselves whether they want/need to treat their condition.

Fortunately researchers probably pay little attention to what is (mis)reported in the mass media regarding autism and the so those research papers will keep coming.

Drug firms have been struggling for decades to come up with new treatments for neurological disorders.  Apparently the disease likely to be first “overcome” is Parkinson’s.  Dr Poling did suggest in his commentary above that autism might benefit from some Parkinson’s researchers; maybe there will be some surplus ones sometime soon.

It is clear that no serious investigation of the type suggested by Dr Poling into the effect of vaccines on specific sub-types of autism will happen.  The link with mitochondrial disease and its treatment remains almost hushed up, even though the clinicians involved are at leading institutions (Johns Hopkins, Harvard etc.).  As one reader commented to me, “why is Dr Kelley’s work on mitochondrial disease and autism not published in the literature?”.

In reality, I expect that only a tiny percentage of autism can be traced back to vaccines, so there should be nothing for public health authorities to be fearful about.  Even Dr Poling remains pro-vaccines.

I am still shocked that in the US over $3 billion has already been paid out in compensation for damage caused by childhood vaccines.