New drug improves heart function by removing free radicals

April 28, 2001

WINSTON-SALEM, N.C. - A new drug being studied at Wake Forest University Baptist Medical Center has been shown to improve heart function following a heart attack, according to researchers speaking at the American Academy of Pediatrics in Baltimore.

The drug, called M40403, removes free radicals from injured tissues, which can cause extensive damage to the heart following a heart attack. M40403 administered after a heart attack, but prior to re-opening the blood vessels in the heart, appears to protect the heart cells from further damage. In laboratory rats, the drug has been shown to be highly protective against injury from free radicals, according to R. Mark Payne, M.D. associate professor of pediatric cardiology at Wake Forest University School of Medicine and principal investigator of the study.

"The applications of this research are enormous," Payne said. "The early animal studies are very positive. More animal studies need to be completed before we can move to Phase I clinical trials, but I am optimistic. These data support our hypothesis that tissue can be protected during a heart attack, with potentially improved cardiac functioning."

When a person has a heart attack, blood flow to the heart and other organs is stopped. Doctors must quickly reestablish blood flow by opening up the damaged blood vessels, providing needed blood to the heart and other organs in the body. When the blood flow is reestablished, those tissues, which have a fresh inflow of blood, produce a large excess of dangerous free radicals, which damage proteins and DNA in the cell, causing the tissue to die.

Dead tissue later results in scar tissue in the heart, according to Payne. If the drug is administered before the blood vessels in the heart have been reopened - the period in which most of the cardiac damage occurs - then cardiac tissue may be saved with a better long-term outlook for the patient. "Normally these cells have coping mechanisms to deal with free radicals that are generated within the cells in low amounts," he said. "But when the heart has suffered an attack, the cells become overwhelmed and cannot cope with the enormous burst of free radicals that are produced when blood flow is reestablished to the injured regions of the heart. As a result, the cells die and are replaced by scar tissue, which does not function as normal heart muscle."

The drug, of which M40403 is the prototype, protects the cells in the heart from free radical damage, limiting the amount of injury and scar tissue.

"This synthetic drug is much smaller in size than naturally occurring proteins that usually remove free radicals," Payne said. "The small size is very important because it allows the drug to penetrate into tissues, such as the brain and the heart, that larger synthetic drugs and proteins cannot easily penetrate. In other studies, this drug has been shown effective in decreasing stroke injury in laboratory animals, when administered prior to the onset of the stroke. These data are exciting because they suggest a role for these drugs in the early treatment of stroke."

Free radicals have been talked about frequently in the last few years, Payne said. "Many people take doses of vitamins A, C, and E, which can bind to free radicals in the body and remove them," he said. "The unique thing about this drug is that it removes the free radicals from the body, but stays behind to neutralize more."

More studies need to be conducted to study the efficacy of the drug if it were administered after the opening of the blood vessels, instead of prior to opening them up.

Researchers studied M40403 in rats over a period of about one year. Half the rats were given the drug and half were used as a control group. The half who were administered the drug showed less damage to the heart than the control group.

If the studies continue to remain positive, Phase I clinical trails on the drug could begin in about a year, according to Payne.
MetaPhore Pharmaceuticals, based in St. Louis, M.O., manufactures M40403. In addition to Payne, Daniela Salvemini, Ph.D., with MetaPhore Pharmaceuticals, participated in the study. The National Institutes of Health and the Brenner Center for Child and Adolescent Health funded the study.

Media Contact: Rae Beasley, 336-716-6878.

Wake Forest Baptist Medical Center

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