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The German hospital treating Russian politician Alexei Navalny, Charité-Universitätsmedizin in Berlin, have released a statement that Mr Navalny may have been poisoned with a substance from the group of cholinesterase inhibitors.
Prof Andy Smith, MRC Toxicology Unit and Honorary Professor at the University of Leicester, said:
“Cholinesterase inhibitors are a large variety of chemicals, particularly organophosphates or carbamates, which have been used as pesticides and in industry over the last 80 years and although many uses have been highly restricted or abandoned, they are still of value. Unfortunately, much more powerful agents have been developed for nefarious purposes by some institutions despite international regulation as we have seen in recent years.
“Acute clinical symptoms of poisoning are associated with inhibition of nerve action at the synapses in the brain and in neuromuscular junctions. Individual chemicals may vary in their specific actions and symptoms in animals and humans and whether inhaled, absorbed through the skin or swallowed. The action of cholinesterase inhibitors can be detected by measuring low activity of the enzyme in blood.
“The apparent possible poisoning of Alexei Nalvany and treatment with atropine suggests that low enzyme levels have been detected in addition to the clinical symptoms. Detection of the agent itself, or breakdown products, may prove more challenging after a few days but modern analytical chemistry is so powerful that this should be feasible. Although physicians in Omsk maintain that there were no signs of cholinesterase inhibitors, it is unclear what tests were performed. We need to wait for further information before the picture becomes more clear.
“Although a patient may recover outwardly with the use of atropine and other drugs from the acute phase, cholinesterase inhibition by these agents can be associated with long term neurodegeneration and neuropsychiatric disorders. Perhaps this may be the objective and warning in deliberate poisonings.”
Dr David Caldicott, Senior Clinical Lecturer in Medicine at the Australian National University, and Emergency Consultant at Calvary Hospital in Canberra, with a specialist interest in the Medical Response to Terrorism, said:
“‘Cholinesterase inhibitors’ or ‘anticholinesterases’ as they are also called, are a broad group of chemical agents that include many of the insecticides we use every day, as well as the much more exotic weapons-grade chemicals we have sadly come to know such as such as sarin, and the putative Salisbury agent, novichok. They can be effective through simple contact or inhalation.
“The weapons-grade chemicals, which were developed by Germany in the lead-up to WWII, are several orders of magnitude more potent than everyday organophosphate insecticides.
All these chemicals have roughly the same effect on the human body – they inhibit an enzyme called acetylcholinesterase at the nerve junction (synapse).
“Under normal circumstances, acetylcholinesterase regulates the amount of the neurotransmitter acetylcholine crossing nerve synapses — so it effectively works as an off-switch.
“Acetylcholine acts mainly on the body’s autonomic nervous system — the body’s involuntary nervous system — which controls things such as heart rate, respiratory rate, salivation, digestion, pupil dilation, and urination. One could therefore predict what would happen if you block one of the major ‘off-switches’ of the body, and are left with all the lights turned ‘on’ all of the time – the body runs into trouble. With an extremely rapid build-up of acetylcholine in the synapse, things like secretions, respiratory problems, and muscular dysfuntion can go on unattenuated. Death usually occurs via respiratory failure.
“It IS possible to detect whether or not someone has been exposed to organophosphate chemicals by taking urine and blood samples.
“Following the exposure to a military organophosphate you may well see the breakdown products of metabolism in the urine early on, but after it’s been secreted in the urine, it’s very difficult to detect. A delay in medical investigation can mean that such products are no longer detectable in the urine.
“Fortunately, the effects of a cholinesterase inhibitor last longer and are detectable, long after the agent causing the toxicity has cleared the body. If someone has got very low levels of functioning acetylcholinesterase in their blood, then they’ve probably been exposed to an organophosphate, because the poison has bound to it and inactivated it.
“Depending on the toxicity of the agent used, how much was involved, how long patients were exposed and how they were exposed, enzyme levels can start to return to normal levels from several days to several weeks post-exposure.
“The identity of an agent can be inferred, and in the case of war crimes, can occasionally be confirmed later by weapons inspectors, although perpetrators of previous mass poisonings have gone to some lengths to hide their crimes. It is very unlikely that the specific agent used in this case will ever be proven, although few actors would have the expertise and access to the sort of agents required to ensure a single victim was the outcome of the use of such dangerous agents.”
Dr Richard Parsons, Senior Lecturer in Biochemical Toxicology, King’s College London, said:
“The use of cholinesterase inhibitors to poison people is not new. Another name for them is organophosphates. We encounter them in everyday life as pesticides, for example sheep dips and fly sprays contain containing malathion. They are a weapon that have been used since World War One, and have been used in many atrocities by people such as Saddam Hussain (for example the Halabja Massacre) and was the class of compounds used to poison the Skripals in Salisbury.
“It can be difficult to diagnose cholinesterase inhibitor poisoning and it is difficult to treat. They prevent the breakdown of acetylcholine, a chemical messenger used in the central nervous system to control many functions required for life. They do this by binding irreversibly to the enzyme that breaks it down, called cholinesterase, increasing the amount of acetylcholine in the brain and thus overstimulating the nerves. This could be responsible for the intense pain that Mr Navalny experienced and his subsequent coma. Atropine is the antidote because it prevents the acetylcholine from binding to the nerves and activating them. However, for Mr Navalny to recover, his doctors will have to wait until his body breaks down the cholinesterase enzyme and then make more to replace it. Only then will the poison stop having its effect and he will be able to recover. This can take several weeks. During this time, his doctors will have to give him life support as necessary and maintain a constant dosing of atropine.
“Cholinesterase inhibitor poisons can be given in many ways, they can be transported in many forms, and are very potent. This is why they are a favoured method of poisoning people.”
Dr Michelle Carlin, Senior lecturer in forensic & analytical chemistry, Northumbria University, said:
“Cholinesterase inhibitors are a type of substance that stop the body breaking down a compound called acetylcholine. This substance, if not broken down by the body, can cause effects such as abdominal pain and cramps, breathing problems, increased sweating and salivation. Cholinesterase inhibitor compounds can be used in legitimate medical treatment for diseases such as Parkinson’s and Alzheimer’s. However, cholinesterase inhibitor compounds have also been used as nerve agents.”
Prof Rob Chilcott, Professor of Toxicology, University of Hertfordshire, said:
“Inhibition of cholinesterase would be consistent with exposure to a nerve agent such as novichok or VX, but there are also a number of naturally occurring toxins which may cause a similar biochemical effect. In the absence of a more detailed clinical picture and focussed laboratory investigations, it would be prudent not to draw any conclusions at this stage.”
Prof Atholl Johnston, Professor of Clinical Pharmacology, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, said:
What are cholinesterase inhibitors?
“The most commonly encountered cholinesterase inhibitors are organophosphorous pesticides. But in warfare and terrorism they are nerve gases and nerve agents such as Sarin, Vx, and Novichok.
How can doctors conclude that cholinesterase inhibitors have been responsible for someone’s ill health?
“Measure plasma for blood cholinesterase activity.
Are cholinesterase inhibitors known poisons?
“Yes.
How are cholinesterase inhibitors usually administered?
“By accident in the case of pesticides but deliberately as in the case of nerve gases and nerve agents such as Sarin, Vx, and Novichok.
Do cholinesterase inhibitors appear to fit with the information we have had so far about the incident and symptoms?
“I don’t have enough information on Mr Navalny’s symptoms.
When will doctors likely be able to know for certain which substance was responsible?
“They may never know. But the antidote / treatment is the same for all of the anticholinesterase inhibitors.
Is it too soon to know what has happened?
“Yes.
Any other comments?
“Salisbury all over again? But if it was a cholinesterase inhibitor administration in tea would be a strange choice.”
Dr Wayne Carter, Associate Professor, University of Nottingham, said:
“Cholinesterase inhibitors are a broad group of chemicals that include pesticides and nerve agents. By binding to and inhibiting the action of acetylcholinesterase they can cause paralysis, and this can be fatal. An example being the Novichok nerve agent used in the Salisbury poisonings in 2018. If a cholinesterase inhibitor was used to poison Alexei Navalny it would leave a chemical signature that can be detected and confirmed. The administration of an antidote can result in recovery, but not always, and long-term nerve damage may occur.”
Prof Vicki Stone, Professor of Toxicology, Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot-Watt University, said:
What are cholinesterase inhibitors?
“Cholinesterase inhibitors have been used as pesticides (organophosphates). When one nerve is activated it releases a chemical (e.g. acetyl choline) which then stimulates a second nerve allowing messages to be sent from one nerve cell to another. The chemical signal needs to be broken down. The cholinesterase inhibitor stops the chemical signal being broken down and so the nerves become over stimulated so that they no longer function appropriately.
How can doctors conclude that cholinesterase inhibitors have been responsible for someone’s ill health?
“There are a list of classic symptoms associated with such poisonings.
Are cholinesterase inhibitors known poisons?
“Yes, there are many examples of farm worker poisonings and use for chemical warfare (Kurds were poisoned by Saddam Hussein’s troops).
How are cholinesterase inhibitors usually administered?
“They are sprayed onto crops and so can be accidentally inhaled of absorbed through the skin, but they could also be ingested.”
Prof Alastair Hay, Professor (Emeritus) of Environmental Toxicology, University of Leeds, said:
Why is this case considered to be caused by cholinesterase inhibitors?
“Signs and symptoms almost certainly, but probably because tests were carried out on blood showing inhibition of the cholinesterase enzymes.
What are cholinesterase inhibitors?
“Cholinesterase inhibitors block a crucial enzyme which regulates messages from nerves to muscles. The enzyme is called acetylcholinesterase. Inhibition of the enzyme interferes with nerve to muscle messaging and muscles are no longer able to contract and relax. They go into a sort of spasm. All muscles are affected with the most crucial being those which affect breathing. As breathing is inhibited individuals may become unconscious. There are also direct effects of cholinesterase inhibitors on the brain. Organophosphate compounds and carbamate compounds are cholinesterase inhibitors. Both organophosphates and carbamate families of chemicals are used as insecticides. But they have a crucial difference in how they function. Organophosphates generally inhibit acetylcholinesterase in an irreversible manner whereas carbamates are reversible inhibitors of the enzyme. The temporary inhibition of acetylcholinesterase by carbamates has even been exploited as a sort of prophylactic against organophosphate poisoning. Nerve gases and the so called Novichoks are cholinesterase inhibitors.
What impact do they have on the body?
“The route of administration affects appearance of symptoms. If it is by ingestion there is colicky pain together with nausea, vomiting, diarrhoea and involuntary defecation. As the chemicals are absorbed they get distributed throughout the body and will interfere with nerve to muscle message transmission. As a result individuals become weak, cannot stand, have difficulty breathing and seeing, will sweat profusely and have increased secretions from nose and lungs. Speech will be slurred if still conscious. If the dose is sufficient victims become unconscious. This may be as a result of poor oxygenation through diminished diaphragm movement or direct effects of cholinesterase inhibitors on the brain.
How difficult is this to treat?
“It can be very difficult and delays add to complications. Witness the treatment of the Scripals and Charlie Rowley and death of Dawn Sturgess. Specific treatment is with atropine and an oxime. Atropine blocks some of the effects of the cholinesterase inhibitor. If it is an organophosphate compound which caused the poisoning, the oxime helps to remove the inhibitor from the enzyme. No single oxime works with all organophosphates. And oximes work best when given early after exposure to organophosphates but are worth trying in all events.
“You need to be in intensive care with all the support that provides. Organophosphates cause fitting and so individuals are often put into an induced coma until the chemical is cleared from the body. The clearance can take quite some time, days, and even weeks, depending on the chemical half life.
Any other comments?
“I wish Mr Navalny well.”
Prof Andrea Sella, Professor of Inorganic Chemistry, UCL, said:
“Acetylcholine is the key neurotransmitter in parts of the nervous system. It is released in the synapse, the gap between nerve cells, to transit a signal from one nerve to the next. The enzyme acetylcholinesterase snips the neurotransmitter after it has done it’s job allowing the nerves to reset before the next signal. An AChE inhibitor is a molecule that attaches itself to the active site of the enzyme and prevents it from snipping the neurotransmitter. The results can be catastrophic.
“There are numerous such AChE inhibitors many of which are widely used as insecticides. The carbamates and the organophosphates are the most famous of these, and among them are the nerve agents such as Sarin and Novichok, but because there are numerous insecticides that fall in this category there is a pretty wide spectrum of compounds to ‘choose’ from and the analytical chemists will be hunting for fragments of the initial poison in order to determine what exactly Mr Navalny has been exposed to. There a numerous possibilities for how Mr Navalny might have come into contact with this material. These compounds are typically liquids and can be absorbed trhough the skin or mucous membranes, or it might have been inhaled as an aerosol, though it is harder to understand how that would be restricted to single person.
“It is straightforward to assay for AChE activity and it is surprising that this was not done in Omsk. In addition to life support treatment will involve atropine and drugs such as pralidoxime which are designed to reverse the effect of the inhibitor.”
Declared interests
Prof Andy Smith: “I have no conflicts as far as I am aware.”
Dr Michelle Carlin: “Nothing interfering with me making comment.”
Prof Rob Chilcott: “No conflict of interest to declare.”
Prof Andrea Sella: “No conflict of interest of which I’m aware.”
None others received.