Carbon Monoxide Poisoning: Finally An Antidote

7. March 2017
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CO poisoning is the worldwide leading cause of fatal poisoning. Despite this, there is no effective antidote. Pulmonologists have now developed a protein that represents an alternative to treatment using oxygen. It binds the poisonous gas within seconds.

After inhalation carbon monoxide finds its way through the lungs into the blood. There it binds to haemoglobin. Normally these red blood pigments take up inhaled oxygen in the lungs and transport this to the body organs. Should carbon monoxide however also make its way into the lungs through the breath, it displaces this life-giving oxygen from haemoglobin. This is because the respiratory poison possesses – compared to oxygen – an approximately 300 times higher affinity to haemoglobin.

The more carbon monoxide is thus inhaled, the more binding sites are occupied by carbon monoxide, and the less oxygen can bind to the remaining places on haemoglobin. All the less oxygen consequently arrives at the organs. The first symptoms such as headache and dizziness already occur at an “occupation rate” of 25 percent; at a share of 50 per cent sufferers become unconscious; at more than 60 percent coma may occur, and eventually death by internal asphyxiation. A proportion of only 1.28 percent carbon monoxide in the air is sufficient to cause death within a few minutes.

Carbon monoxide is formed through imperfect combustion

This respiratory poison is produced when carbon-containing substances, such as gas, oil or coal, are burned in the presence of insufficient oxygen supply, or when technical defects of furnaces, heating systems or exhaust pipes are present.

Potential hazards include:
• devices defectively installed
• poor maintenance of gas water heaters or heating systems
• inadequate supply of fresh air
• barbecues/grilling (including charcoal heated griddles) in enclosed spaces (eg. garages, flats)
• operating gasoline powered hand tools (eg. lawnmowers) in confined spaces
• poorly drawing fireplaces or clogged chimneys (eg. due to birds’ nests)

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Grilling is all the rage! In closed spaces however, a particularly large volume of poisonous carbon monoxide is created. © Gabriel Saldana, flickr

No antidote available worldwide

Until now, treatment has consisted of immediate administration of pure oxygen, whereby the carbon monoxide is indeed displaced slightly faster, but in real terms still very slowly from the binding sites: With pure oxygen the elimination half-life is shortened from about five hours to about 80 minutes. The process is faster only when using so-called hyperbaric oxygen treatment, wherein oxygen is administered to the patient in a hyperbaric chamber: in just 20 minutes half of the carbon monoxide in the blood is removed – a period which often for patients is still far too long. In addition, not every hospital has a hyperbaric oxygen pressure chamber. What’s more, transport there takes time!

“Although carbon monoxide poisoning is the most common cause of poisoning worldwide, we have to date no effective antidote”, says Mark Gladwin from the University of Pittsburgh in a press release. He and his team have developed a protein that could provide an alternative to the current treatment using pure oxygen: In a very short time it frees haemoglobin from carbon monoxide. “Our protein is extraordinarily effective in capturing carbon monoxide from the blood”, adds Mark Gladwin.

The relatives of haemoglobin

The protein developed by the US researchers belongs to the neuroglobin group, the relatives of haemoglobin. Neuroglobin also transports oxygen. It protects cells from death following ischaemia or reperfusion injury – such as after a heart attack or accidental injuries. The protein, first discovered in 2000, is produced in the brain and in the retina of humans and mice. For the US researchers it was of interest because it binds oxygen significantly more strongly in comparison to haemoglobin. In addition, it has an increased affinity for carbon monoxide.

For their studies [Paywall] the researchers decided to work with a slightly altered neuroglobin named “Ngb-H64Q”. “Ngb” stands for neuroglobin and “H64Q” expresses the fact that the distal histidine radical (H64), which binds the haem iron, has been replaced by a glutamine unit. This change in molecular structure causes the Ngb H64Q to be less susceptible to binding oxygen (autooxidation) and to also be able to bind to it more stabily.

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Senior author Mark Gladwin from the University of Pittsburgh © UPMC

In order to prevent the aggregation (oligomerisation) of the protein at high protein concentrations, and to improve its solubility, the researchers led by Mark Gladwin in a further step replaced three cysteine units on the surface of the protein with less reactive amino acids. The research team named the resulting molecule “Ngb-H64Q-CCC”. As subsequent laboratory experiments demonstrated, the affinity of the Ngb-H64Q-CCC to carbon monoxide was higher by a factor of 500 than that of haemoglobin to the same respiratory poison. This aspect was important so that neuroglobin could snatch the carbon monoxide bound to the haemoglobin. Through Ngb-H64Q-CCC administration, the elimination half-life of carbon monoxide decreased in cell-free liquid and in erythrocytes from over 500 minutes (atmospheric oxygen) to 0.11 minutes and 0.41 minutes respectively.

Nearly all mice survived

For the subsequent animal experiments, the research team placed mice for 50 minutes in a carbon monoxide-air mixture, so that about 60 percent of the oxygen binding sites of haemoglobin were occupied by the poisonous gas. None of the animals died. Subsequently Mark Gladwin and colleagues administered neuroglobin to some of the mice. Already 30 seconds later the number of occupied haemoglobin binding sites had dropped by 30 percent – in the control group this figure was only 13 percent and in the animals that had been ventilated with 100-percent oxygen it was 27 percent. Another advantage is its rapid clearance: 60 minutes after administration, about 90 percent of neuroglobin was in the bladder of the animals.

But can neuroglobin really protect animals or humans from death by poisoning? To answer this question, the scientists first administered a normally lethal dose of carbon monoxide. The result: only a maximum of 10 percent of ten or seven control mice survived the experiment. In the neuroglobin group things looked rather different. These animals after being exposed to carbon monoxide had received Ngb-H64Q-CCC. Of this group, 90 percent of eight rodents survived.

Further safety and efficacy studies necessary

Up until now, Ngb-H64Q-CCC has only been tested on mice. Before it can therefore be used in humans, more comprehensive safety and efficacy studies in animals are necessary. The study, according to the scientists led by Mark Gladwin, appears to show that neuroglobin seems at least to have no serious side effects. Researchers sought in vain 48 hours after injection to find changes in the blood and the kidneys of the animals.

Moreover Ngb-H64Q-CCC was not detectable at this time either in the liver, kidney, heart, brain or lung tissue. Mark Gladwin at least is convinced of his creation and has, along with another study author, registered for a patent on the use of neuroglobin-mutants for carbon monoxide poisoning. The first clinical trials are likely to start within the next five years.

Phototherapy, hydroxocobalamine, supramolecular complex

There are alongside Ngb-H64Q-CCC other developments in the treatment of carbon monoxide poisoning in the pipeline. Phototherapy using light between 530 and 690 nm for example is supposed to increase carbon monoxide release from the haemoglobin, and hydroxocobalamin increased the metabolisation of carbon monoxide to carbon dioxide in rats [Paywall].

Japanese researchers [Paywall] already developed a water-soluble supramolecular complex in 2010 which removed carbon monoxide from the bodies in rats. However, these developments are still at an early stage.

Even if Ngb-H64Q-CCC or other developments should prove safe and effective in animal experiments, it could take several more years for approval. Until such time, installing carbon monoxide detectors in apartments and avoiding potential carbon monoxide sources are our only help.

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1 comment:

Professor Surendra Singh
Professor Surendra Singh

An interesting article. Results in mice very, very encouraging.

0.41 min for CO removal from RBCs ! Wow.

Can it be produced in large enough quantity to to stock with first responders ?

What would be the cost of providing in all the units of 1st responders ?

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