Pa. college develops potential carbon monoxide antidote
The antidote cut CO blood levels by half in only 25 seconds in mice and in laboratory testing
By David Templeton
PITTSBURGH — Carbon-monoxide poisoning kills about 430 people nationwide each year and that doesn’t even include CO fatalities from fires or suicides.
The gas, commonly described as the “invisible killer,” has no odor, color nor taste. It also has no antidote, with 100-percent oxygen therapy inside a hyperbaric tube or chamber representing the only treatment, requiring 20 minutes to several hours to work.
Now there’s a potential game-changer.
A study based at the University of Pittsburgh and published today in Science Translational Medicine describes a mutated brain protein the research team developed that served successfully as a fast-acting antidote for CO-poisoned mice.
The antidote actually cut CO blood levels by half in only 25 seconds in mice and in laboratory testing.
If it’s effective in humans, then paramedics could provide the antidote on the spot and quickly revive people sickened or unconscious from household exposures, fires or even attempted suicides.
“You want to lower levels immediately to improve oxygen delivery to the body,” said study leader Mark T. Gladwin, director of the Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute in the University of Pittsburgh School of Medicine. “I think if you can lower CO levels 15 to 25 percent, you help most people.”
For now, carbon monoxide deaths are equally divided between unintentional exposures, fires and suicides. Accidents typically involve faulty furnaces, poorly positioned grills or generators, or vehicles left running in garages, among other rogue sources of the vapor.
“Our vision would be for people involved in fire rescue to carry the antidote,” Dr. Gladwin said. “You can do a finger pulse oximeter test to see what the CO levels are in the blood then give a dose in the field intravenously.”
It takes 320 minutes (5 hours, 20 minutes) for half the carbon monoxide in the blood to clear the human body naturally. Oxygen therapy can reduce that time to 74 minutes and hospital-based hyperbaric oxygen therapy to 20 minutes, but one must consider and add transport time to the treatment center.
The discovery of the potential antidote happened serendipitously as the research team tried figuring out what role neuroglobin, a protein in neuron cells, plays in human biology.
To test its function, the team made mutations of the protein to see if it resulted in changes in brain cell function and signal it’s biologically function. Soon, however, the team realized the mutated proteins were binding tightly with CO and could serve as an antidote.
Hemoglobin, a key constituent in the blood, transports oxygen throughout the body by loosely binding with oxygen in the lungs. That oxygen easily releases itself from the hemoglobin at oxygen-deficient points throughout the body. In that sense, hemoglobin serves as the body’s oxygen delivery system.
So consider hemoglobin to be a San Francisco trolley with oxygen hopping on and filling all trolley spaces and quickly departing at different destinations.
But carbon monoxide binds more firmly with hemoglobin and fills all the spaces on the trolley more quickly than oxygen can. Then when the carbon monoxide is released, new molecules of CO fill the open spaces before oxygen can, leading to rising CO concentrations.
The Merck Manual of Diagnosis and Therapy says headache and nausea occur at blood concentrations of 10 percent to 20 percent with higher levels causing dizziness, weakness, problems with concentration and impaired judgment. At 30 percent CO concentrations cause labored breathing, chest pain and confusion, with yet higher levels leading to loss of consciousness and seizures. Depending on the person’s health, death can occur at various stages of CO concentration.
“CO is always releasing from the hemoglobin and rebinding with it, but it releases slower than oxygen and recombines with it faster than oxygen, so it is always out-competing oxygen” for space on the hemoglobin molecule, Dr. Gladwin said.
In the mouse study, the mutated neuroglobin (Nrg-H64Q-CCC) that the team developed bound with CO 500 times more strongly than CO binds with hemoglobin. Reducing CO blood-concentration levels by half — the so-called half-life of the poison — took 25 seconds.
The antidote quickly restored heart rate and blood pressure in the mice, with increased survival levels and rapid elimination of the protein-bound CO through the urine, showing the “mutant” proteins to be “potential antidotes for CO poisoning by virtue of their ability to bind and eliminate it,” the study says.
One of the mice was revived, despite CO concentrations of 60 percent, Dr. Gladwin said.
The next step, he said, is testing in larger mammals, with no signs of toxicity in the mouse study. All the mutant protein’s receptors — or available spaces — were bound with CO, which means the molecule is capped. That generally means it’s biochemically inactive in the body, leading to easier elimination in the urine.
Because it works so quickly, smaller doses could be used to reduce CO levels more gradually, if the person’s life isn’t in immediate danger. Even if the antidote has some toxic impact on the kidneys, Dr. Gladwin said, saving a person’s life at some risk to kidney function might be a reasonable trade off.
If mammal testing proves successful with U.S. Food and Drug Administration oversight, he said, the procedure could advance quickly to fast-track testing in humans due to the lack of an alternative antidote.
Copyright 2016 the Pittsburgh Post-Gazette