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).

 

 

Spring in Beijing

The Great Wall of China, two hours north of Beijing

Monty, now aged 15 with ASD, continued his travels recently with an Easter visit to China. Long haul travel can be much more demanding than shorter trips because of the change in time zone and simply the fact that you are stuck on the plane for such a long time.

Many people with autism, and indeed Asperger’s, have problems with air travel, while some other people even with severe autism have no issues whatsoever.  Some people with severe autism never go on holiday, travel being such a problem.  Some people repeat the same holiday every year.  It does not really follow any pattern.

One issue I came across at the recent conference in London was that some people cannot even consider a far-away medical specialist or enroll in a clinical trial, due the travel required.  But what to do if the autism doctor does not make house calls? Some people do take their child thousands of miles to see a specialist, but many cannot.

Monty has been flying since he was a baby, but he did have his share of problems from time to time.  For the last few years, with autism under control with his Polypill, travel has not been difficult. The only issue remaining is not really an autism issue, it is an ear popping issue. Some people’s ears just do not seem to pop after changes in air pressure and it does not matter what tricks you use, it can take a few hours for ears to go back to their normal state.

Random enhanced airport security checks very often seem to select Monty; even that is no longer an issue.  China has automated fingerprinting and facial scanning/recognition at the airport, so you have to follow the instructions carefully.

The only issue Monty had with the plane was not being willing to lock himself in the toilet. He expects something larger and with a proper door, not one that folds in the middle. No bumetanide the day of a long flight.

In-flight entertainment was fully appreciated along with all the food you get in nice little packages when you travel long haul.  For kids it is like a 10 hour party, full of surprises, like the unexpected ice cream and chocolate bars.

On arrival in Beijing we found that four people with three bags was too much for the local taxis.  Soon this became four bags and we became a two taxi family.  In Shanghai, which is much more market-driven, we all fitted in a single taxi, as we do everywhere else in the world.

Trains and the metro/underground/subway are excellent in China. The high speed trains run at 330 km/h (200mph) and within big cities the public transport is excellent. All the motorbikes/scooters are electric and the bicycles that were omnipresent when I first visited Beijing have pretty much disappeared.

I was asked how I manage Monty’s Polypill while traveling. It mainly remains the same, I just omit one or two things for practical reasons. For example, I took the Ketoforce liquid BHB, but omitted C8 caprylic acid. Next trip I will bring the C8 as well.

On our trip to Israel where they rummage through all your checked baggage before your departing flight looking for explosives, it was clear they had looked in detail at Monty’s supplies, but it was no issue.

Food in China is different and Chinese food in China is not quite like the Chinese food outside China.  The Chinese do like fried chicken and KFC is everywhere. That was appreciated by Monty and his big brother.

Monty likes noodles, rice and all kinds of soup, so eating was not a problem.

China blocks many Western internet sites like Google and Facebook, so if you are a fan of YouTube like Monty, you need to use a VPN (Virtual Private Network); but we knew about this in advance.

There are plenty of interesting things to do and see in China and independent travel really is very easy, as long as you do not expect people to speak English. In big cities many of the signs are in Chinese and English.

Monty’s big brother is a fan of military history, so we paid a visit to Beijing’s military museum. It is vast and even though it is packed with exhibits, it feels very spacious. They have a U2 spy plane that they reassembled after shooting it down over China, and a photo of it lined up with three others they shot down and reassembled. That was something new to me, I only knew about Gary Powers, the US pilot of a U2 shot down over Russia.  

The U2s were operated for the Americans by the Taiwanese in the Black Cat squadron. In the early 1960s they were flying over mainland China and the Chinese shot several down.  The pilots who survived had to wait till 1982 to go home.  China still wants to get Taiwan back.

The indigenous population of Taiwan were not Chinese. After a period of rule by the Dutch, came rule by China and mass immigration in the 17th century. Today only 2% of the population are indigenous.

China lost Taiwan to Japan in 1895. After being a Japanese colony for 50 years, when world war two ended the Chinese took back control of the island.   At the end of the 20 year civil war in China in 1949 the Communist Party of China (CPC)  held the mainland and the Kuomintang (KMT)-led government of the Republic of China (ROC) fled to Taiwan. China regards Taiwan as a renegade province that must be reunited with the Mainland.

Taiwan’s tallest mountain, Yu Shan, was renamed by the Japanese as Mount Niitake (meaning “New High Mountain”) because it was taller than Mount Fuji, back in Japan proper.

"Climb Mount Niitaka" was the coded order for the Japanese to attack Pearl Harbour in 1941.

I think most foreigners are not aware of Japan’s role in China, particularly in the 1930s and up to 1945. Some pretty evil things went on under the Japanese occupation of Manchuria in 1931 and later when they invaded much of the rest of China, killing tens of millions of civilians, but it does not stop today’s Chinese wearing Japanese branded fashion or driving a Toyota.

I was surprised to see quite so many luxury German cars, they seemed to be much more prevalent in Beijing than Berlin; and many were the stretched versions, to give the rear passenger more space.

There really are a lot of counterfeit products, ranging for full-sized lookalike copies of Porsche and Audi cars, to fake Lego Starwars toys. In central Shanghai the western people are constantly targeted by people selling fake Rolex watches and copies of branded handbags.  It looks like the Chinese are buying the real thing, while the younger foreigners are buying their $50 “Rolex”.  There are still relatively few foreigners in China, so in most places you are a curiosity. At the summer palace in Beijing, some teenage girls wanted Monty’s big brother to pose for a photo with them and some parents did encourage their young children to come for a close up view of the gweilo (westerners).

On my last visit to China it was the vast open spaces of Tibet in the West of China that were most impressive. During that trip in the late 1980s, which was rather more adventurous, the Chinese were still making steam locomotives and I still have a certificate from the steam engine factory in Datong that I rode in the cab. Now China has 18,000 miles (29,000 km) of high speed train lines, with more added every day. Back then for $60 I took the train from Beijing to Berlin, via Siberia. I expect it costs rather more these days.

This visit to China I was sitting with Monty on the train getting him to practice his geometry schoolwork while looking out the window at long rows of 30 storey/story  apartment buildings in cities I had never heard of.  

This time we did not make it to Hong Kong, but it is well worth a visit, because it was shaped by its colonial history and also most people do not need a visa.  Foreigners also like it because many people speak English. 

Compared to the huge mega cities in mainland China, Hong Kong has a mere 7 million inhabitants.  Being an island just across the mainland definitely adds to its charm, like Istanbul and the Bosphorus.

More speech

Speech is often a limiting factor in people with autism and very likely needs some help from biology. This is not a simple process, there is no magic supplement to trigger fluent speech.

My current effort is boosting the effect of bumetanide to lower chloride within neurons. Potassium Bromide does do this, but does produce acne spots, which has long been known to be the main side effect.

I am hopeful that another diuretic, Azosemide, will be more potent than Bumetanide at blocking NKCC1 transporters in the brain. It seems to cause minimal diuresis, which is the main side effect of Bumetanide. I found giving Bumetanide was most effective with a larger single daily dose, which is given on waking due to the diuresis caused.  Adding an evening dose of Bumetanide did not seem to have much/any additional effect and causes a second round of diuresis.  An evening dose of Azosemide does seem to produce an incremental cognitive effect and without diuresis.  It is still early days in my investigation.

Some of yesterday’s unprompted speech:

“Monty went to China and came back on the big plane from Beijing. Monty was swimming in the swimming pool and his ears popped !”

The first thing Monty did after returning from the airport was to jump in the swimming pool. That's one way to unblock your ears.

Delayed ear popping clearly is a subject currently on Monty’s mind. The reason turned out to be his upcoming school trip to the mountains; he wanted reassurance that there would be no ear popping involved. The trip is by bus and the mountains are not so high, so no danger of ears popping.

More opinions

As was discussed in a comment with our reader Maja, one effect of a low dose of clemastine, an old OTC antihistamine that also improves myelination, is the emergence of opinions. This is very noticeable. Today “I want scrambled eggs for breakfast”. The previous day he both asks and answers the question:  “what do want for breakfast? … Pancakes”

Rather than repetition, rituals, or just repeating the last part of the question as his answer, now we have opinions. No longer the docile/passive child, he now acts like a teenager with opinions and his own requests.

Conclusions

You may not have to stay close to home if you have a child with Classic Autism.

I think it pays to start travelling early. Nobody is too bothered about a screaming 3 year old, autistic or not; they may not like it and may make comments about bad parenting, but that is all.  It is soon forgotten.

A screaming teenager might get you thrown off the plane, or worse.  So best to start young. Travelling by plane is just another skill to master, like having a haircut or going to the dentist.

If you can reduce biological causes of anxiety, with targeted pharmacotherapy, traveling gets much easier. Once you have figured it out, you just need to carry a little pill box in your pocket to ensure a smooth journey.