Suramin in China, where things can move fast – blocking Enterovirus-71 rather than treating Autism

The new Chinese and old Colonial, side by side in central Shanghai

  

I do not speak Chinese, but fortunately Google does.

I was sent some interesting links to some articles from China about Suramin, the potential autism therapy which many autism parents are eagerly awaiting.  Prepare for a long wait, but hopefully less long in China.

My original post on Suramin for autism can be found  in the link below:-

Suramin, the Purinome and Autism

 

 

I have never had a banner appear on my computer trying to sell me a Rolls Royce until today.  This is more proof, if I needed it, of how much China has changed since my first visit there as a teenager.  Back then there were a lot of bicycles; I still remember many were Flying Pigeon brand – not a name you forget. I just looked them up and since 1950, more than 500 million Flying Pigeon bicycles have been made - that is a lot bicycles.

I even went to see a factory still producing steam locomotives in Datong in the 1980s. They gave you a personal certificate of your visit, which I still have somewhere. 

Last year I was again in China and travelled on their ultra-modern high speed trains.  These run on purpose-built tracks, often running to totally new vast railway stations.  The network is massive with 36,000 km (22,000 miles) in total length and trains running at speeds up to 220 mph / 350 km/h.  The ride is perfectly smooth and the tickets are not so expensive.   The old train lines I used many years ago still exist and you can still take the “hard sleeper” to travel long distances overnight for little money, but not quite as cheap as it once was.  

 

 Things move fast in China, hopefully so will Suramin

Suramin is an approved drug, but it is almost impossible to get hold of, unless you are in a limited number of African countries affected by African Sleeping Sickness and River Blindness.  Suramin is made by the German giant Bayer and the brand name (below) is not very original.

 

I think the clever idea is the intranasal version now being developed in the US.

But why not just put this old drug from 1916 in a metered pump dispenser, in the same way the Alzheimer’s researchers put insulin in a nasal spray?  In autism, Vasopressin and Oxytocin are just popped into nasal sprays.  A few years in this blog I mentioned Dr Jay Goldstein who was treating people with TRH intranasally (he wrote a great book called Tuning the Brain – I actually bought it).

Tuning the brain eventually got Jay Goldstein into trouble. Though long “retired”, he has just published another book on ME/CFS.  Goldstein also used Ketamine eye drops and nasal spray.

I guess if he would have been among the first put this old Suramin drug in a nasal spray and see what happens. It quite possibly would help ME/CFS, as suggested by Dr Naviaux himself.

We saw in a post in 2014 that Professor Rita Levi-Montalcini had the clever idea of using home-made NGF eye drops to stave off decline in old age.  She was the first one to discover the existence of Nerve Growth factor (NGF). She became the first Nobel laureate to reach the age of 100.  The NGF eye drops did not do her any harm.

Your eyes are part of the Central Nervous System (CNS) and so an ideal entry point to target the brain. For nasal sprays the route to the CNS is via the trigeminal nerves and not much actually gets through (see below).  Due to the blood brain barrier many drugs taken orally cannot reach the brain.

 

Nose-to-Brain Delivery

The route of transfer of compounds through the nasal respiratory epithelium to the brain is via the trigeminal nerves 

A key advantage of the nose-to-brain route is the possibility of reducing plasma exposure, as has been demonstrated thus eliminating peripheral side effects.

 Simply dissolving the drug molecule in an aqueous phase has been used to administer molecules via the nose-to-brain route. The vast majority of clinical studies, which report pharmacological effects, have involved a solution of the drug in aqueous media delivered using a nasal delivery device

Oxytocin has also been delivered to the brain via the nasal route using a solution with a C_max of 0.003% of a 10 μg dose being found in the brain. A solution of the human immunodeficiency virus replication inhibitor DB213 delivered the drug to the rat brain with a C_max that was estimated at no more than 0.007% of the administered dose.

The addition of functional excipients to these solution formulations improves brain delivery via the nasal route. 

 

It may well be that Rita and Jay got it right by choosing eye drops over a nasal spray. Suramin eye drops? Not as crazy as it may sound.  Perhaps in China?

   

Back to China

 For several years there has been research looking at treating hand foot and mouth disease using Suramin.

Hand, foot, and mouth disease is common in children under five years old, but anyone can get it.

The illness is usually not serious, but it is very contagious. It spreads quickly at schools and day care centres.

 

Hand, foot, and mouth disease is caused by viruses that belong to the Enterovirus family.

Common causes of hand, foot, and mouth disease are:

• Coxsackievirus A16 is typically the most common cause of hand, foot, and mouth disease in the United States. Other coxsackieviruses can also cause the illness.
• Coxsackievirus A6 can also cause HFMD and the symptoms may be more severe.
• Enterovirus 71 (EV-A71) has been associated with cases and outbreaks in East and Southeast Asia. Although very rare, EV-A71 has been associated with more severe diseases, such as encephalitis. 

Enterovirus 71 (EV-A71)

Suramin inhibits EV71 infection

Highlights

·        Suramin inhibits the proliferation of EV71 virus.

·        Suramin directly blocks the attachment of EV71 virion to host cell.

·        Suramin can be used as a potential clinical therapeutic against EV71 infection.

 

Abstract

Enterovirus-71 (EV71) is one of the major causative reagents for hand-foot-and-mouth disease. In particular, EV71 causes severe central nervous system infections and leads to numerous dead cases. Although several inactivated whole-virus vaccines have entered in clinical trials, no antiviral agent has been provided for clinical therapy. In the present work, we screened our compound library and identified that suramin, which has been clinically used to treat variable diseases, could inhibit EV71 proliferation with an IC50 value of 40 μM. We further revealed that suramin could block the attachment of EV71 to host cells to regulate the early stage of EV71 infection, as well as affected other steps of EV71 life cycle. Our results are helpful to understand the mechanism for EV71 life cycle and provide a potential for the usage of an approved drug, suramin, as the antiviral against EV71 infection.

 

 

The approved pediatric drug suramin identified as a clinical candidate for the treatment of EV71 infection - Suramin inhibits EV71 infection in vitro and in vivo

 Enterovirus 71 (EV71) causes severe central nervous system infections, leading to cardiopulmonary complications and death in young children. There is an urgent unmet medical need for new pharmaceutical agents to control EV71 infections. Using a multidisciplinary approach, we found that the approved pediatric antiparasitic drug suramin blocked EV71 infectivity by a novel mechanism of action that involves binding of the naphtalentrisulonic acid group of suramin to the viral capsid. Moreover, we demonstrate that when suramin is used in vivo at doses equivalent to or lower than the highest dose already used in humans, it significantly decreased mortality in mice challenged with a lethal dose of EV71 and peak viral load in adult rhesus monkeys. Thus, suramin inhibits EV71 infection by neutralizing virus particles prior to cell attachment. Consequently, these findings identify suramin as a clinical candidate for further development as a therapeutic or prophylactic treatment for severe EV71 infection.

 

 

Kangzhi Pharmaceutical has the rights to develop Suramin for hand foot and mouth disease in China and beyond. 

 

Kangzhi Pharmaceutical has developed a new indication for "Suramin Sodium" and is committed to the development of drugs for hand, foot and mouth disease 

Currently, there are no specific antiviral drugs for enteroviruses in the world, and support and symptomatic treatment are the main ones. Clinically, there is an urgent need to develop specialized drugs to treat patients with hand, foot and mouth disease who have been infected. Now that Kangzhi Pharmaceutical's suramin sodium for injection has been approved for clinical trials, it is undoubtedly a gospel for children with hand-foot-mouth disease and is expected to break the dilemma of treatment of hand-foot-mouth disease.

Kangzhi Pharmaceutical has been focusing on children's health for a long time. Under the guidance of "Children's Health Strategy" and "Excellent Strategy", the company insists on investing about 5% of its annual sales in research and development. In 2013, the company took the lead in establishing a post-doctoral scientific research station with children's drug research and development as the main direction in China, and was recognized as "Hainan Children's Drug Preparation Engineering Technology Research Center" in 2016. In order to solve the problem of no medicine for hand, foot and mouth disease, Kangzhi Pharmaceutical has invested heavily in the research and development of suramin sodium for injection.  

https://translate.googleusercontent.com/translate_c?depth=1&pto=aue&rurl=translate.google.com&sl=zh-CN&sp=nmt4&tl=en&u=https://finance.sina.com.cn/roll/2020-05-10/doc-iircuyvi2360398.shtml&usg=ALkJrhiXYaD6KShQuW26JhJlYDhdduUqyA

 For a long time, the anti-fever drug "Ruizhiqing (Nimesulide)" is Kangzhi Pharmaceutical's leading product in the children's medicine market. The company's revenue accounted for as high as 70% at one time. However, this product had previously suffered from side effects. Controversial, Kangzhi Pharmaceutical has no longer listed this product as a core competitive advantage in its financial report. Instead, it has given key exposure to another long-developed new drug for the treatment of hand, foot and mouth disease. ——Suramin Sodium for Injection.

It is understood that hand, foot and mouth disease is an infectious disease that is generally susceptible to infants and children under 5 years old. It continues to be prevalent at a fixed period every year. There is no specific medicine for targeted treatment. According to the statistics of the my country Center for Disease Control, the number of cases of hand, foot and mouth disease in China in 2018 was 2,533,310.

Obviously, if Kangzhi Pharmaceutical's new hand, foot and mouth disease drug can be successfully listed, it will become a major "cash cow" product of the company. By then, both performance and stock price will be effectively boosted. However, since this product was exposed by Kangzhi Pharmaceutical, the outside world only knows that this product will be "the world's first new medicine for the treatment of hand, foot and mouth disease", but its final market is still far away.

"The company has obtained the approval for the clinical trial of the drug, and the product has successfully completed the phase I clinical trial and will start the phase II clinical trial. If the clinical trial is successful and the marketing authorization is obtained, suramin sodium will become the world's first treatment for hand, foot and mouth. New medicine for disease.” In the 2019 financial report, Kangzhi Pharmaceutical introduced the latest development of suramin sodium.

As early as 2015, after Kangzhi Pharmaceuticals spent 18 million yuan to buy the patented technology of "Institutions and Methods for Treating Viral Diseases" of the Shanghai Pasteur Institute of the Chinese Academy of Sciences, and planned to invest 50 million yuan in suramin Subsequent research and development of sodium.

In 2018, after the application for the clinical trial of suramin sodium was submitted, it was quickly reviewed and approved according to the special review route. At that time, Hong Liping, vice chairman and vice president of Kangzhi Pharmaceuticals, said in an interview: "Suramin sodium for injection is approved for clinical trials, which is an important achievement of Kangzhi Pharmaceuticals in the development of new drugs. The company deeply feels the responsibility. With the help of the current national policy to encourage the spring breeze of clinically urgently needed therapeutic drugs, we will actively promote the development of clinical trials of the drug and promote the market of new drugs as soon as possible to help children with hand, foot and mouth disease get rid of the disease as soon as possible.

According to the company's secretary of the board of directors on the Shenzhen Stock Exchange, the clinical trial of suramin sodium is divided into 3 phases, and only phase 1 has been completed. The time of the clinical trial is uncertain.

It is reported that the new indication of suramin sodium for the treatment of hand, foot and mouth disease developed by Kangzhi Pharmaceutical has previously applied for an international invention patent through the PCT, and has successively obtained invention patent authorization in China, Japan, Singapore and the United States. The new Indonesian patent authorization will help to further leverage the advantages of independent intellectual property rights, promote the research of hand-foot-mouth disease treatment drugs, benefit the world's hand-foot-mouth disease patients, and enhance the core competitiveness of Kangzhi Pharmaceutical.

  

Conclusion 

It looks like there will eventually be at least 3 pharmaceutical companies selling Suramin.

•  Bayer (Germany)

•  Kangzhi Pharmaceutical (China)

•  Paxmedica (USA), or really which ever Big Pharma they sell out to 

This is all good news for autism and hand foot and mouth disease. 

People do not like injections, nor side effects caused by your drug needlessly going everywhere in your body.

The nasal spray, or eye drops, look a good idea for autism and ME/CFS.

Hopefully the Chinese will move fast, like their trains, and bring their Suramin to the market.

 

In 2008 Arnold Schwarzenegger signed a bill to bring high speed rail to California.  The total system length would have been approximately 800 miles (1,300 km).  Where are we 12 years later?

The British are no better with their high-speed rail, but it is a very densely populated country. China's new rail lines were not built where the old lines ran. Spain actually has really good high-speed trains, that are not so expensive and a great way to get around the country.

Where are those autism drugs, "fast-tracked" for approval by the FDA? In the same place as Arnie’s model train set (going nowhere fast).

 

 

The Role of Microglia in the Puzzle of Neuro-inflammation in Autism

Regular readers of this and similar blogs will have noticed that the human body functions in quite irrational ways.  We know why this is; we are the product of a very slow evolutionary process, rather than being a clean-sheet design like your smart phone or iPad.

As a result, nothing is ever quite as simple as it seems and at times the cleverer you are, the less likely you are to find a medical therapy effective in humans.

Such is the case with autism, inflammation and microglia.

It might seem that you can track back inflammation in autism to its “root cause”, which could appear to be those immune cells in the brain, called microglia.  We know they are “activated” in autism and we know that autism is typified by an “over-activated” immune response.

Working with the assumption that autism is a brain dysfunction, you would assume that the effective therapy should be inside the so-called blood brain barrier (BBB).

You would then just look for a potent drug that could “stabilize” the microglia/immune cells in the brain, to calm things down.  Having achieved this, you would sit back and marvel at the behavioral change and improvement in cognitive function.

This was exactly the thought process a few years ago when the US  National Institute of Mental Health (NIMH) got together with the Johns Hopkins researchers to follow up on their findings of chronic inflammation in the brains of people with autism.  Subsequent, third party, research has also confirmed that the microglial cells are “activated” in autism

Trial Description

Minocycline to Treat Childhood Regressive Autism

There is a subgroup of children with autism that appear to develop typically for a period of time, and then lose skills, or regress. A recent study by Vargas and co-workers at Johns Hopkins has demonstrated that the regressive subtype of autism is associated with chronic brain neuroinflammation as exemplified by activation of microglia and astroglia and the abnormal production of inflammatory cytokines and growth factors assayed in both tissue samples (brain banks) and CS. The authors remarked that these responses were similar to those seen in some neurodegenerative disorders such as amyotrophic lateral sclerosis, and that chronic microglia activation appears to be responsible for a sustained neuroinflammatory response that facilitates the production of multiple neurotoxic mediators. Chronic neuroglial activation could be the result of an abnormal persistence of a fetal development pattern. In this scenario neuroglial activation could play a role in initiating and in maintaining the pathology. Alternatively, neuroglial activation may only be a secondary response to the initiating causal factor(s) and not a direct effector of injury. Since neuroglial activation requires the nuclear translocation of the pro-inflammatory transcription factor NF-kappa B, and since inhibitors of NF-kappa-B with good CNS penetrance are available, the role of neuroinflammation in initiating and sustaining the autistic condition can be probed.

The antibiotic minocycline is a powerful inhibitor of microglial activation, apparently through blockade of NF-kappa-B nuclear translocation. Minocycline is neuroprotective in mouse models of amyotrophic lateral sclerosis (ALS) and Huntington's disease and has been recently shown to stabilize the course of Huntington's disease in humans over a 2-year period.

To evaluate the possibility of benefit in autistic children, we propose to conduct an open-label trial of the anti-inflammatory antibiotic minocycline, an agent that reduces inflammation by blocking the nuclear translocation of the proinflammatory transcription factor NF-kappa-B. Minocycline is Food and Drug Administration (FDA)-approved for treatment of a variety of infections and has been widely used for the treatment of adolescent acne. Minocycline is currently in phase III trials for the treatment of Huntington's disease and amyotrophic lateral sclerosis.

This proposal is for an initial 6-month, single-arm, off label, open-label study (with a 3 month extension phase offered to responders) that will evaluate dose safety and efficacy of minocycline in 10 children, ages 3 to 12 years, with a primary diagnosis of autism and a history of developmental regression. The subjects will be evaluated by a diagnostic/behavioral assessment, and the extent of neuroinflammation judged by CSF cytokine/chemokine profiles before and after the 6-month treatment. Subjects will also be given 0.6 mg/kg vitamin B6 twice a day as a prophylactic for possible minocycline induced nausea and vomiting. If the results of this feasibility study are encouraging, we expect to conduct a double-blind, placebo-controlled trial of minocycline therapy.

Nothing happens fast in the world of autism and so this six month study of 10 people (who completed the actual trial) was conceived in 2006, was actually concluded in 2013.  Here is the resulting paper:-

  

A pilot open-label trial of minocycline in patients with autism andregressive features

Conclusions

Changes in the pre- and post-treatment profiles of BDNF in CSF and blood, HGF in CSF and CXCL8 (IL-8) in serum, suggest that minocycline may have effects in the CNS by modulating the production of neurotrophic growth factors. However, in this small group of children, no clinical improvements were observed during or after the six months of minocycline administration.

Unfortunately, this study showed that a treatment, known to effectively stabilize microglial cells, had no positive effect on autism and actually seemed in some cases to make it worse.

We can conclude from this that stabilizing the microglia will not be the “holy grail” for treating autism.  Rather, the activated microglia is just one part of a complex, and only partially understood process.

Microglia as the Immunostat 

In a recent post we saw how Rodney Johnson referred to the microglia as the “immunostat” of the body.  Like the thermostat on the wall in your home central heating system.

Inflammation Leading to Cognitive Dysfunction

This is indeed an interesting analogy and might explain some of what is going on.

We saw in Johnson’s paper all the ways that the immune system outside the blood brain barrier (BBB) was able to communicate with the microglia.  We should assume that this communication works both ways; something that is usually overlooked.

In a perfectly functioning body, as in a perfectly functioning house, the immunostat/thermostat gives a good indication of the actual state/temperature, as well as the one you intended.  So if you set your room thermostat to 72 Fahrenheit / 22 Celsius  you expect the actual temperature to be 72 Fahrenheit / 22 Celsius.

However, in the real world things do not work like this.

We live in a house with very large south facing windows, a big fireplace, underfloor heating in some places and European-style hot water radiators (in the US they do have them).  So we have at least four sources of heat.  In spite of having clever German electronics to control our heating system, the thermostat in the centre of the house, by itself, is not adequate.

Something similar is happening in body and brain of people with autism, just replace temperature with inflammation.

Just as my house has multiple systems resulting in heating, the human body has numerous processes leading to “inflammation”.  Some of these inflammatory processes are interconnected and some are not.  The net result at any one time can be measured by looking at various cytokine levels, gene expression, microglial activation and numerous other things; there is no single measurable thing called “inflammation”.

There will never be a single wonder anti-inflammatory treatment.

The activated state of the microglia rather than being the ultimate target for intervention may just be a reflection of inflammation elsewhere in the body, or alternatively it may be just the result of oxidative stress in the brain.

Just like after a few years you may need to replace your wall thermostat, because it is giving false data, the clever immunostat, that may be the microglia, could have been disrupted by all that oxidative stress in the brain.  It might even be sending its proinflammatory signal in reverse, back across the BBB, to the rest of the body. Not such a crazy idea?

The future of anti-inflammatory interventions

The NIMH and Johns Hopkins would naturally be disappointed by the results of their study; but it was a study well worth doing.  Hopefully they will pursue other avenues of thought.

We already know that there are numerous ways to achieve a degree of immuno-modulatory change and that in some types of autism there can be a profound behavioral impact.

These range from simple Ibuprofen, to steroids like Prednisone; not to mention those Kv1.3 blockers and ShK-peptides.  These will likely all affect the microglia, but it is not their main mode of action.

Insights

As is often the case, there are useful insights that you can learn from a “failed” trial.

I would imagine that an autistic person with ulcerative colitis would also have activated microglia. Treating that person with minocycline should have some stabilizing influence on the microglia, but without resolving the ulcerative colitis, the pro-inflammatory signals continue to be sent around the body.

Turning down the thermostat in my house, when I have a big log fire blazing, has no effect on the temperature. 

The microglia in the brain of people with autism probably should not be activated; we really need to know why they are activated.

If you can work on the numerous processes/pathways leading to “inflammation” you would most likely also achieve some deactivation of the microglia.

Therefore we should look at things like PPAR gamma which are directly relevant to the pathology of autism, and agonists of PPAR gamma also happen to be “anti-inflammatory” and indeed, in the test tube, some can stabilize microglia.

One, far away, day they will bring those ShK-peptides to the market. 

In the meantime, my current targets are Tangeretin and Nobiletin, flavonoids found in tangerines.

For the scientists among you:-

In addition to being a PPAR gamma agonist, Tangeretin is also a known P2Y₂ receptor antagonist.  Both properties are potentially useful.

PPAR gamma has been covered in this blog already.  P2 receptors are a class of Purinergic receptor.  Within the field of purinergic signalling, these receptors have been implicated in learning and memory, locomotor and feeding behavior, and sleep. 

Suramin is used in research as a broad-spectrum antagonist of P2 receptors.

It is Suramin that Robert Naviaux, at UC San Diego, has been researching as a potent autism therapy.  He has shown it effective in mouse models, but the problem is that it is not safe for long term use in humans.  Regular readers should note that, yet again, an anti-parasite drug has been found to have an effect in autism.  Parasites do not cause autism, but understanding them better would be a potential advantage.

Why Suramin, a Century-Old, Anti-Parasitic Drug May Hold the Key to Understanding Autism

Dr. Robert Naviaux's recent finding suggests reversible metabolic syndrome could be at core of autism

The full paper is below:-

Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy

In particular, P2Y₁₁ is a regulator of immune response.  There are big gaps in the science and I have no idea if tangeretin affects P2Y_11.