Showing posts with label Jay Goldstein. Show all posts
Showing posts with label Jay Goldstein. Show all posts

Saturday 5 December 2020

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 Cmax 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 Cmax 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


·        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.



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.

 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.



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).



Sunday 9 February 2014

Who Pays the Piper? Off-Label or Polypill

It seems that autism is not the only “untreatable disease”, that does appear to be treatable.  At least twenty years ago, one apparently related condition was extensively treated off-label.  I am reading an intriguing book about the off-label treatment of Fibromyalgia in the 80s and 90s.


In medical-speak “off-label” is when a drug is use for a purpose it was never actually approved for.  If you have straight forward diseases, you would never need to use a drug “off label”.

In some countries off-label prescribing by doctors is totally discouraged, in others, it is quite common.
The problem occurs when it comes to paying for expensive drugs and, of course, who is to blame if things go wrong.
Since many drug discoveries are actually stumbled upon by chance, off-label drug use is not as crazy as it may sound.

Socialized Healthcare, Private Insurance and Lawsuits
In the developed world, healthcare is provided either via some kind of private insurance as in the US, or it is via the State, as in Europe.  If your insurer is unwilling to pay for off-label treatments, you will not get them (unless you pay yourself).  In the UK, if the treatment is not endorsed by NICE (in effect, the State), you are not going to get it.  In the old days, the doctor might have been willing to try some off-label drugs, but now they are likely to be more worried about being struck of the medical register for malpractice, or, in the US, being sued.

So, all over the world off-label prescribing is getting rarer.  Certain states in the US are more liberal, Florida I believe is one.
Your healthcare is really in the hands of big brother; in general, this is not a bad thing.  If you have some rare, “untreatable” condition, then the problems start.  Even if you know what off-label drug you want, you will struggle to get it.  You will even struggle to get any unusual blood tests done.

In some countries the system is much more liberal.  If you want to measure potassium in your blood or maybe IGF-1 or serotonin, the process is akin to having your dry cleaning done.  You pay and it gets done.

Off-Label in the US
Before insurers tightening things up in the 1980s, doctors in the US seemingly were able to prescribe pretty much what they wanted.  If you read about some of the things prescribed for severer cases of Fibromyalgia, you would be amazed at the things they used (IVIG, Baclofen, Oxytocin etc.) and how the underlying principle was one of trial and error.

Due to the unusual position of osteopathic medicine in the US, where osteopaths have the same drug prescribing rights as medical doctors, there are many “alternative” doctors practising what they call “holistic medicine”.  Then there is a small army of DAN doctors, some of whom are medical doctors and some are not.  You also have a large number of chiropractors in the US; graduates of chiropractic schools receive the degree Doctor of Chiropractic (DC), as I was told by a reader of this blog, US  Chiropractors do not prescribe drugs, but they do treat kids with autism (I am not sure how).
So it looks like, while the golden days are over, off-label drug prescribing is alive and well in the US.

From Off-Label to On-Label
You would think that once an off-label therapy gets established, it would be able to transition to on-label, and become an accepted mainstream therapy.  This does not happen very often.  The doctors using off-label widely, are seen as quacks by some established doctors and by much of the public.  If they are treating unusual, hard to define conditions, it is hard to carry out controlled clinical trials, and nobody has an interest to pay for them anyway.

So, off-label tends to stay off-label and for most people, untreatable conditions remain untreatable.

I am wary of my ideas being seen as risky, off-label, quack nonsense.  They certainly are off-label uses.

I think you should be able to transition from off-label to on-label.  If the disease is just a cluster of symptoms and pathologies, it will be hard to identify the sub-type for which the therapy is effective.  This applies to both autism and indeed fibromyalgia.
To move away from the very unscientific, and indeed wasteful, trial and error approach, you have to be able to use reliable biomarkers or diagnostic tests.  You would have to prove to a very cynical public, that you are not spouting nonsense.

Then faced with a therapy which can be shown effective consistently, albeit for a rare, very well defined, condition (based on blood tests etc.), there is no good reason why the therapy should not go on-label.
The question now with the Polypill is to be able to identify with >75% certainly for whom it will be effective.  I also need to understand, and indeed predict, when it might stop working.  This may sound very strange, but can happen.

Predicting when it might stop working, as well as suggesting what to do should that occur, makes things tricky. To do it perfectly you would really need the old school off-label doctor, and a vast amount of consultation time, that will not be available.
I live in a country where access to lab tests is very open and they are inexpensive, so I have come up with a testing strategy to accompany the Polypill, using tests that are inexpensive.

The idea of the tests is twofold; to identify the sub-group of children who will benefit from the Polypill therapy and to establish a baseline of markers to later understand any cases, should the Polypill “stop working”

Blood tests
·        IGF-1

·        Serotonin

·        Free T3

·        Cholesterol LDL & HDL

·        Histamine

·        Inflammatory markers CRP and   IL-6

·        Potassium

I would also use the TRH stimulation test, except it is not available where I live and requires several blood draws.  It shows central hypothyroidism to be common in autism (as it is, interestingly, in fibromyalgia).
I am expecting any loss in efficacy of the Polypill to be accompanied by a surge in histamine and/or the easy to measure inflammatory markers, C - reactive protein (CRP) and Interleukin-6.

The trials would take place in winter (no pollen) and would exclude people with food allergies, digestive disorders, IBD, IBS, pancreatic enzyme deficiency etc.  The trial would be exclusively for early onset autism, no regression.
People with seizures would be very welcome and might form a separate subgroup within the test; I expect the incidence of seizure and epilepsy to be reduced by the Polypill.

Having created a trial based on children with elevated IGF-1, Serotonin, Free T3 and Cholesterol, I would then continue to measure all the above indicators on a monthly basis.

Assessing Success
Since the Polypill has several active ingredients, I would expect a marked reduction in autistic behaviours, based on any established autism rating scale.  I would expect parents, teachers and therapists to be really impressed by the effect.

Using the above screening biomarkers to select the trial group, I would hope to achieve a successful outcome in a great majority of cases.  This success rate has to be measured.  Perhaps the screening exclusions and biomarkers are too restrictive, or not restrictive enough.  If it was 100% effective, they should be relaxed; if it was 50% they should be tightened.
What intrigues me are the cases where the Polypill may stop working after a period of success.  If this is understood, it will be another step in understanding the dynamic nature of autism.  If the loss in effect can be correlated to an increase in histamine, in some cases, I will know what to do.  If in some cases CRP and IL-6 rise but histamine and serotonin do not, we would know that the immune system had been activated, but mast cells have not degranulated.  In these cases it would require the, currently under development, “Autism Toolkit”, to provide some immuno-modulatory therapy.

Just as abruptly as the Polypill might stop working in a child, I expect it will start working again, when the external stimulation (whatever it might be) has been withdrawn.
In children who have a permanent state of over-activation of their immune system, they should have sky high CRP and IL-6 and the Polypill will never start to work in the first place.  High inflammatory markers are seen in regressive autism, according to Ashwood, who is on my Dean’s List.

Having rationalised my objectives, I am finalizing my initial submission to the European Medicines Agency, to see whether the Polypill should remain Peter’s off-label curiosity, or become an Orphan Drug, to share with others.