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Oxygen insufficiency is a major hazard for all tissues in your body, but the heart is particularly sensitive to such hypoxic conditions, which can lead to long-term tissue damage, or even death. heart attack.
New studies have been conducted. At UC San Francisco, a new therapeutic treatment for releasing oxygen has restored the function of oxygen – free cardiac tissue in an animal model of global hypoxia. Unlike its experimental predecessors, the new drug does not appear to cause systemic side effects or excessively correct with excessive oxygenation of the blood, which may itself be toxic. The new drug only delivers its precious cargo of oxygen to the tissues that need it the most.
"Any tissue whose blood flow is compromised, whether due to trauma, stroke or heart disease, could potentially be targeted by treatment such as this," said Emin Maltepe , MD, PhD, Associate Professor of Pediatrics at UCSF and co-lead author of the paper.
The new drug, called OMX-CV, was developed by Omniox, Inc., a biopharmaceutical company developing Therapeutic Oxygen Therapy for the treatment of cancer, cardiovascular disease, trauma and stroke. Other conditions in which low levels of oxygen or hypoxia have a negative impact on the outcome of the disease.
Omniox, which was one of the first start-up biotechnology companies to embark on the QB3 "Garage Incubator" on UCSF's Mission Bay Campus, in 2010, was one of the world's largest incubators. is badociated with Maltepe and other UCSF researchers to test the treatment, and published its results on October 18, 2018 in the journal PLOS Biology .
] Hypo xia during heart disease – an uncontrolled clinical threat
Cardiovascular diseases such as coronary artery disease can starve the heart of oxygen, causing cardiac dysfunction or heart attack in the home. Adult, but cardiac hypoxia is also a problem in children.According to the Centers for Disease Control and Prevention (CDC), about 10,000 children are born each year with a critical conbad heart defect. many of these infants s need to undergo heart surgery during their first year of life, during which time blood may be temporarily removed from the heart, thus leaving the organ deprived of oxygen.
Under normal conditions, the heart consumes more oxygen by weight than any other organ. and when oxygen levels are low, demand increases even more. The hypoxic heart pumps harder to deliver oxygen to the rest of the body and, paradoxically, needs more and more oxygen itself to maintain its function. A drug that releases oxygen, such as OMX-CV, could alleviate the physical stress badociated with hypoxia and improve recovery after a heart attack or open-heart operation in adults and children.
Scientists have attempted to devise a way to fight hypoxia by providing oxygen through the back. hemoglobin, the protein that allows red blood cells to carry oxygen throughout the body and also produces their scarlet color. But these treatments also carry a lot of luggage.
Hemoglobin-based drugs have proved too effective in their work: they tend to flood the blood with excess oxygen that can itself cause serious tissue damage. In addition, when it is outside of red blood cells, hemoglobin can attach to nitric oxide, a natural muscle relaxant found in blood vessels. Vessels depleted of nitric oxide contract, causing a rise in blood pressure, increasing the risk of heart attack and reducing blood flow to organs as important as the kidneys.
OMX-CV eliminates these problems by using a bacterial protein known as H-NOX. as a base, rather than hemoglobin. H-NOX proteins contain a "co-factor" called hemic group – the same co-factor that gives its name to hemoglobin – which allows the protein to bind not only to oxygen, but also to nitric oxide. By altering the chemical structure of H-NOX proteins, Omniox scientists have modified their design to keep them under oxygen, while leaving nitric oxide alone.
The researchers also showed that the modified proteins fixed the oxygen so tightly that they only gave up their grip
"Unlike hemoglobin-based oxygen transporters, OMX-CV is designed to release oxygen only under pathological conditions, "said Ana Krtolica, PhD, vice president of research at Omniox and co-senior. author of the article. "Relatively low doses of the drug transform the heart's ability to cope with severe hypoxia."
Targeted Administration in Oxygen-deficient Tissues
The authors firstly consider OMX-CV being used to treat many conditions affected by hypoxia in adults, but the new study was also designed for the purpose of pediatric applications. The research was conducted as part of the Initiative for the Development of Pediatric Drugs and Instruments, or iPD3, a collaboration between UCSF and the University of Maryland, Baltimore. The goal is to design and test therapies specifically for pediatric care, rather than "pbad on" therapies designed for adults.
"Children change so much by growing up – their drug metabolism changes dramatically from year to year," Maltepe said. "Once medications are established in adults, pediatricians must essentially experiment with children to understand the toxicity profiles of the treatments and the appropriate dosage for different age groups." By initially designing and testing drugs while thinking about children, and taking action such as using disease models in juvenile animals, researchers hope to bypbad this tedious approximation.
During their experiments, scientists tested the effects of OMX-CV in acute toxins. the researchers examined the ability of the drug to deliver oxygen to juvenile animal hearts, which share important anatomical and physiological features with the hearts of human infants.
The researchers found that OMX -CV provided oxygen to stressed hearts but not to tissues with a sufficient oxygen supply. The perfusion of OMX-CV improved the ability of hearts to contract almost twice as well as their own initial values under conditions of hypoxia, without the toxic effects of hemoglobin-based treatments. In contrast, the cardiac function of untreated animals has significantly deteriorated during the study of one hour.
These impressive results were obtained with a relatively low dose of OMX-CV: each animal was treated with a dose equivalent to only 2% of the blood oxygen transport capacity of hemoglobin. in natural circulation.
Studies underway at UCSF, funded by the National Institutes of Health, using similar juvenile animal models, were designed to test whether OMX-CV can be developed to protect the heart of infants subjected to cardiac bypbad. surgery.
A myriad of applications s
More preclinical research is needed before OMX-CV reaches clinical trials on humans. Researchers expect separate clinical trials for the various applications of the drug.
"Given the general need for oxygen in tissues and organs, hypoxia is badociated with a number of pathological conditions," said Krtolica. Omniox develops preclinical programs focused on oxygen delivery in ischemic stroke, which compromises blood flow to the brain, as well as in cancer.
"This treatment targets a fundamental problem in medicine – in intensive care, for example" We are still struggling to make tissues do not become hypoxic, "said Maltepe, adding that the technology could one day form the basis for the treatment. a more general blood substitute, long considered a "holy grail" of the drug.
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