First Antidote For Carbon Monoxide Poisoning 'Cleans' Blood In Minutes (newatlas.com) 37
An anonymous reader New Atlas: An engineered protein that acts like a molecular sponge has the potential to change how carbon monoxide poisoning is treated, chasing down CO molecules in the bloodstream and helping the body flush them out in just minutes, without the risk of short- or long-term health issues that come with the current frontline treatment, pure oxygen. Researchers at the University of Maryland School of Medicine (UMSOM) were focused on a natural protein known as RcoM, found in the bacterium Paraburkholderia xenovorans. In bacteria, RcoM detects trace amounts of CO in the environment, so the engineers believed this could be harnessed to scavenge for CO molecules attached to red blood cells instead.
The re-engineered protein is the basis of the therapy they call RcoM-HBD-CCC. While it's not exactly a catchy name, it possesses somewhat of a superpower when it comes to cleaning out CO. It selectively binds tightly to the poisonous CO molecules, while ignoring oxygen (O2) and other critical chemical compounds, such as blood-pressure-regulating nitric oxide (NO), in the body. [...] In mouse models, RcoM-HBD-CCC therapy was able to clear CO from the blood in minutes, with it safely flushed out of the body through urine. The engineered antidote acts like a sponge, seeking out and soaking up CO attached to red blood cells. In mice, half the CO in the bloodstream was cleared out in less than a minute, freeing the hemoglobin on the cells to once again start carrying O2.
Importantly, other experimental scavenger hemoproteins haven't been able to selectively target CO, and as a result also bind to NO – so infusions of such hemoproteins can lead to a reduction of NO in the blood, tightening blood vessels and spiking blood pressure. In the study, RcoM-HBD-CCC showed it didn't have this affinity with the vital molecule. "Unlike other protein-based treatments, we found the compound caused only minimal changes in blood pressure, which was an exciting finding and raised the potential for this new molecule to have clinical applications," said study corresponding author Dr Mark T. Gladwin, Dean of UMSOM. "This has the potential to become a rapid, intravenous antidote for carbon monoxide that could be given in the emergency department or even in the field by first-responders." The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).
The re-engineered protein is the basis of the therapy they call RcoM-HBD-CCC. While it's not exactly a catchy name, it possesses somewhat of a superpower when it comes to cleaning out CO. It selectively binds tightly to the poisonous CO molecules, while ignoring oxygen (O2) and other critical chemical compounds, such as blood-pressure-regulating nitric oxide (NO), in the body. [...] In mouse models, RcoM-HBD-CCC therapy was able to clear CO from the blood in minutes, with it safely flushed out of the body through urine. The engineered antidote acts like a sponge, seeking out and soaking up CO attached to red blood cells. In mice, half the CO in the bloodstream was cleared out in less than a minute, freeing the hemoglobin on the cells to once again start carrying O2.
Importantly, other experimental scavenger hemoproteins haven't been able to selectively target CO, and as a result also bind to NO – so infusions of such hemoproteins can lead to a reduction of NO in the blood, tightening blood vessels and spiking blood pressure. In the study, RcoM-HBD-CCC showed it didn't have this affinity with the vital molecule. "Unlike other protein-based treatments, we found the compound caused only minimal changes in blood pressure, which was an exciting finding and raised the potential for this new molecule to have clinical applications," said study corresponding author Dr Mark T. Gladwin, Dean of UMSOM. "This has the potential to become a rapid, intravenous antidote for carbon monoxide that could be given in the emergency department or even in the field by first-responders." The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).
Cleans blood in minutes? (Score:1)
Yeah, well, mice don't have a lot of blood. How long does it take to do an elephant?
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In the study, RcoM-HBD-CCC showed it didn't have this affinity with the vital molecule.
I think you missed the very next line.
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Yeah, well, mice don't have a lot of blood. How long does it take to do an elephant?
Are you training elephants to fight forest fires?
I mean seriously..that question.
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1. After the protein molecule reaches a red blood cell, it probably works equally fast for mice, humans and elephants.
2. For humans, it takes about 20-60 seconds for blood to complete a full circuit of the body. 1-2 cycles should be enough to mix the antidote with the blood quite well.
3. We need one more cycle because CO-free red cells need to reach lungs to get O2 and then reach the brain.
How would this be used? (Score:1, Interesting)
I'm curious on how anyone intends for this CO poisoning antidote to be used.
I can understand the value in something that can clear the blood of CO in a hurry. But how would this be administered to a patient? I assume it would be injected in the blood. Could it be an inhaler?
If this is injected then would there be auto-injectors like an Epipen given out to first responders? That kind of makes sense. But then maybe there's something complicated here and it should only be used by a physician.
How safe is t
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This, presumably, will increase their survival odds.
For the folks who never make it to the hospital- I suspect most of them didn't understand the danger of the situation they were in, because they were sleeping, or misjudged the toxicity of CO, and weren't going to use any kind of treatment, period.
Of course there is certainly some fraction of the population that knows they've been poisoned with CO, still has the faculties to understand the gr
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Probably most who make it to the hospital are found by someone else.
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It could, potentially, remove or reduce the need for these systems, which are expensive, rare, and in some cases old.
This isnt just a case of someone suffering from an old house leak, but also divers around the world and other situations that I cant think of right now.
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Ambient pressure oxygen is already available in every ambulance. And it's very effective. If a patient has such intense CO poisoning that their respiration centre is packing up, then the likelihood of survival, let alone survival with their brain, mind, memories and personality is very rapidly tending towards zero.
Steel "pots", yes.
Inflatable plastic "pots" have been available for diving expeditions, which are light enough to helicopter a casu
Re:How would this be used? (Score:5, Informative)
They said in right in the summary. Given by the emergency department (ER) or used by first responders (paramedics).
Since clearing the CO is extremely urgent, I assume IV push would be preferred. Since it's a protein, I doubt inhaling it would be effective.
I doubt it would be over the counter just because of needing to give it by IV.
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The phrase "intravenous antidote" is also in the summary.
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I'm curious on how anyone intends for this CO poisoning antidote to be used.
My guess is that you eat the mouse.
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In America, the new CO-pen will be sold only to first responders. It will be made by one company. Using it will charge your insurance company $17,000 every time it’s needed in an emergency. Which of course will be deemed medically unnecessary and not covered by insurance.
Hey, you said it yourself when you mentioned EpiPen. As if they haven’t paved the damn road for Greed. We can only hope I’m dead wrong.
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What about people committing suicide by using the charcoal grill in a small room?
Do they have to get an additional tattoo to the "Do not resuscitate" one, saying "Do not use Paraburkholderia xenovorans"?
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Do they have to get an additional tattoo to the "Do not resuscitate" one, saying "Do not use Paraburkholderia xenovorans"?
DNR tattoos are meaningless. They carry no legal weight whatsoever. If you want to not be resuscitated, have the DNR on your person. And not just one you drew up yourself, it needs to be a real one, and signed and dated. Further, medics are supposed to look for your DNR if it's convenient, but they're not going to dig through your stuff, so you really need to put it where they can find it easily.
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The Tattoo makes them LOOK for it, since they don't want to get sued.
Re: How would this be used? (Score:3)
They already look for it because they don't want to get sued, so again, the tattoo does nothing. They are not required to go through your file cabinets whether they think you have a DNR or not. I've been trained on this, what's the basis for your statement?
Doping (Score:3)
Obvious medical emergencies aside, what about doping for sporting events?
I have zero clue if this would be any benefit in that realm, but it sure sounds like it could be advantageous to clear most of the CO from your blood right before a race (or during, if possible).
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If you have more than a few percent of CO-hæmoglobin amongst your oxy-hæmoglobin, you already have a problem.
You probably do have that much though, if you live in an urban environment ; you get exposure form traffic fumes, second-hand smoke, general combustion pollution (industrial, domestic), and there are a variety of other environmental sources that contribute to background CO-hæmoglobin saturations.
When did Paracelsus say the "the dose makes the poison"?
16th century?
Still true.
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You probably do have that much though, if you live in an urban environment
Interesting point! Maybe one day, something like this could be taken every morning/night?
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How safe is this?
It probably is safer than CO (that is really unsafe).
But how would this be administered to a patient?
I think it could be used by paramedics (or by anybody who can make an intravenous injection).
Could it be an inhaler?
No. You need to infect quite much of antidote into the blood stream. Intramuscular injections (like epipen) also won't work.
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Good question. I'm decidedly dubious too, from the point of view of being a diver who has personally suffered a carbon monoxide hit from an incautiously-set-up portable compressor. (Insufficiently-cautious - the wind changed direction between starting and finishing the filling session.)
Let's see - human air consumption is highly variable with stress etc, but when planning shallow depth (but h
Some estimates (Score:5, Interesting)
As is too often the case, the article is paywalled, and crucial information allowing for real understanding is hidden.
But, based on info given, some back-of-the-napkin calculations can be done. These are done with the intent to estimate doses, and thereby answer questions brought up in some of the comments here.
One obvious detail is that this will be intravenous infusion, something that can be started in the field with emt's and paramedics, or expeditiously in the ER.
Basics - CO poisoning is common, from vehicle and marine exhaust, faulty lamps-furnaces-camping equipment, faulty home heating, house fires, et al. Normally, hemoglobin (hgb) shuttles oxygen around. Hemoglobin is protein red blood cells, each hemoglobin protein carrying four heme groups each holding one iron atom. That iron atom wants to "rust" and bind with oxygen. Oxygen is picked up by hgb as blood goes through the lungs. In the periphery where O2 is needed, local chemistry based on CO2 and acid-base levels allow hgb to release the oxygen. It is one of nature's brilliant systems, and key is that Hgb can easily bind and unbind.
But, CO has very high affinity for hemoglobin, and once iron bound, it blocks oxygen binding. Once locked in, it does not dislodge, so the body loses that oxygen carrying capacity. All red cells eventually die and are replaced, so the situation is self correcting for low levels of carboxyhemoglobin, as you might have after sitting around a campfire or commonly in smokers. Generally, up to 10% carboxyhemoglobin is tolerated with no or minimum symptoms. On the other hand, 50% carboxyhemoglobin (instead of hemoglobin or oxyhemoglobin) is highly toxic and needs icu care, often fatal, and 70% COHg is uniformly fatal. Anything that can dislodge CO and thereby bring current red cells back "on line" is the goal.
Current best rx is oxygen, hyperbaric oxygen, and blood replacement in more extreme case, but these all take time to implement. This new RcoM peptide sounds promising for very rapid effects, in minutes.
Now, here is the estimated stoichiometry:
There is published info about RcoM which is a peptide with about 250 residues (amino acids), and this paper intro implies they modified the natural protein, presumably making a smaller peptide having the same CO binding affinity.
Each red cell has about 250 million hgb molecules, meaning 1 billion iron atoms = 10^9.
Red blood cell (rbc) counts in normal healthy people are about 5 million cells per cubic mm = 5 x 10^6.
A liter has one million cubic mm per liter = 10^6.
Normal adult blood volume is about 5 liters.
So : (10^9 iron atoms per rbc) x (5 x 10^6 rbc / cu.mm) x (10^6 cu.mm / liter) x (5 liters)
= 25 x 10^21 = 2.5 x 10^22, round off to 10^22 iron atoms per circulating blood (other rbc's are sequestered in bone marrow and spleen, but we can ignore for this calculation).
Avogadro's number is about 6 x 10^23. Rounding off :
(10^22 iron atoms / blood volume) / (10^23 atoms / mole) = 10^-1 moles/ blood volume.
In CO poisoning, each iron binds on CO, so there is 1:1 molar equivalency.
What I can infer from the article stub is that the RcoM peptide they made has high and tight CO binding, and once joined, the complex is excreted by the kidneys. It also sounds like one peptide of RcoM binds one molecule CO, so the molar stoichiometry is 1:1.
That means that 0.1 moles of their RcoM-HBD is need to suck up 0.1 moles of CO. That would be needed in a patient who has 100% carboxyhemoglobin, but they would be dead already, so we are talking about 0.05 moles for someone with 50% COHg.
Next question is - how many grams is 1 mole of RcoM-HBD?
The kidney is a giant filter. Pressurized blood in renal capillaries (going through a structure called the glomerulus) is filtered through a membrane into the urine space. Small molecules are forced across the membrane - water, electrolytes (inorganics), and small organics. The downstream renal tubules reabsorb the water and ash as they cannot otherwise be conserved (new such molecules must come from diet). Small organics are mainly waste that needed to be eliminated, or some small bioactive chemicals that the body easily regenerates. The healthy kidney has such a fine mesh "sieve" that larger molecules like proteins cannot pass through. Proteinuria is a key marker of renal disease as the membrane gets too porous. However, some peptides, too small to be officially classified as proteins, can get through. What is the limit on size of chemicals that normally get through the sieve or are blocked?
Peptides 10-12 kDa (kilodaltons, molecular weight units) filter freely. Proteins 50-70 kDA are blocked. In between, filtration drops off according to some curve. It is safe to assume from the paper that RcoM-HBD, freely and easily eliminated in the urine, is down there around 10-12 kDa.
How many residues (individual chained AA amino acids) are in a peptide weighing 10,000 - 12,000 daltons?
Average amino acid weight is about 110 da. So, (11,000 DA per RcoM-HBD) / (110 Da per AA) = 100 aa's.
Native RcoM has about 250 residues, so RcoM-HBD / RcoM = 100 / 250 = 0.4 which is also the relative molecular weight.
That number is not needed for further calculations, but it implies that these guys re-engineered RcoM to eliminate 60% of its weight, and that sounds quite plausible trying to derive a pharmaceutical from a natural source.
So -
In a patient with 50% COHg, we need 0.05 moles of therapeutic RcoM-HBD.
Molar weight is the molecular weight in grams, so if RcoM-HBD has molar weight 11,000, then
(11,000 gm / mole) x (0.05 moles) = 550 GM.
And - believe it or not, that is a reasonable number.
An analogous drug (in terms of bulk biological chemistry) is mannitol, a 6-carbon polyol (a sugar alcohol, basically a sugar molecule that stays straight instead of chasing its tail into a ring). It is a vital drug for treating brain edema, pulmonary edema, renal failure, trauma resuscitation, etc. Depending on the clinical situation, it is given IV "push", or IV drip, or both, push then drip. Push doses are typically 25-100 Gm.
So, a drug like this could plausibly given as, let's say, 50 Gm at once, then a continuous drip until a total of 550 Gm is administered. A comparable dose, 50 Gm, maybe every 10-15 minutes, would see a full course of rx administered in 2-3 hours.
Depending on the pharmacokinetics and clinical pharmacy, which would have to be studied in detail for approval and clinical use, might reveal higher lower limits or tolerances, and actual care adjusted accordingly.
I can foresee something like this being combined with mannitol infusion perhaps, to augment renal blood flow and glomerular clearance (if the RcoM is not inherently osmotic, probably not at 11 kDA), plus short term 100% oxygen but only for 2-3 hours until CO is cleared enough.
This stuff is pretty brilliant, and important, and life saving. Many of these estimates might be right or wrong, and many of these details might already be worked out by them - but behind a paywall - you all know about that.
But this "Fermi problem" estimation comes up with clinically and biologically realistic numbers.
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Shelf life is also essential, it's a rather niche medicine to have sitting around in the ambulance. Ideally firefighters would have it too, but I don't think they generally have IV training.
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Ideally firefighters would have it too, but I don't think they generally have IV training.
Right. Until recently I've been taking medical first responder classes with our local VFD (I am too busy now, got some health problems in the household to deal with, but I did it for about a year) and they leave that to the ambulance crews.
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Ambulances also (universally?) carry oxygen, and are trained to administer it. So this product will be in direct competition with it's most obvious, well-tested, alternative treatment.
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The article is paywalled, but you're not supposed to read media articles claiming to characterize research anyway.
The PNAS link does give the abstract.
One obvious detail is that this will be intravenous infusion, something that can be started in the field with emt's and paramedics
The first problem with your analysis is right here: "this will be."
Not at all. This is a mouse model study. As with the vast majority of mouse model studies, it will either not work in humans or not be safe in humans.
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See also the estimates that by az-saguaro (1231754) and I have posted up-thread, where we estimate (using different methods) the necessary amount of drug to get into the blood stream to be in the hundreds of grammes.
That's the drug. Not the solution containing the drug.
See also "In Mice". I forget who was promoting the idea, and it hasn't taken hold ; but the idea of requiring all such reports to have flashing neon signs which emphasise the "In Mice" bit of the report does have some good points.
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I looked at the question form a different basis (diving physiology), but got to fairly similar answers.
I don't like topics like this. They strike too close to home. I'm a diver (amateur). And I've worked with "sour" hydrocarbons on more than a few occasions. And this sort of topic leads me to finding really unsettling papers like this [dhmjournal.com]. Yeuch.