Anticoagulant-Antidote Pairing Passes 1st Human Safety Test

Medication system could prove a significant advance for heart-disease patients

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By Amanda Gardner
HealthDay Reporter

MONDAY, Nov. 13, 2006 (HealthDay News) -- A novel medication "system" for heart patients, which first administers an anti-clotting drug and then adds an antidote to neutralize the effect, has passed an initial safety test in humans, researchers announced Monday.

The system, called REG1, may one day be used in patients who have had heart attacks or who are undergoing angioplasty, according to the findings, which were presented at the American Heart Association meeting in Chicago and published online early by the journal Circulation.

The pairing of an anticoagulant and its antidote would allow the fine-tuning of anti-coagulants given during various procedures, including heart-bypass surgery, angioplasty and even kidney dialysis.

"It can control the amount of treatment, i.e. the amount of anticoagulation, with the antidote," explained Dr. Richard C. Becker, the study's co-author and director of the Cardiovascular Thrombosis Center at Duke University Medical Center in Durham, N.C. "There are some circumstances where three hours may be perfect and other instances where 30 hours may be preferable."

Anticoagulants are generally used to prevent blood clots in heart patients. Many current drugs cause excessive bleeding, and Heparin, a widely used anticoagulant, can, in some instances, cause blood clots. If a "bleeding event" does occur, doctors usually have to wait for the drugs to exit the body, which can be a life-threatening delay.

That's what gives this new research such potential.

"The issue of adjusting anti-coagulant drugs is an important one for clinical practice, because many of the dugs have a fairly narrow therapeutic range before they have adverse bleeding, and we have recognized that we need to pay more attention to bleeding," said Dr. Ray Gibbons, AHA president and co-director of the Nuclear Cardiology Lab at the Mayo Clinic in Rochester, Minn. "The development of newer approaches that are going to permit closer modulation are very important."

The system is, however, only in its infancy, he added.

"This is a very first step. Other anticoagulants have been developed that have encountered safety problems later," Gibbons said. "This is a first trial and it's in healthy people. It's promising."

He added, "The next step is to test it in people who need it. Safety issues generally require larger numbers of patients over time because we've got to allow for the possibility that 2 percent of the population reacts adversely."

In a trial sponsored by Regado Bioscences Inc., which developed REG1, Becker and his colleagues studied the drug-antidote pair in 85 healthy individuals, whose average age was 32. About two-thirds of the participants were men.

The anticoagulant is a single-stranded nucleic acid called an aptamer (Latin meaning "to fit"). The aptamer's shape fits into a protein called human coagulation factor IXa, which is involved in blood clotting.

The antidote fits into the REG1 aptamer much like a lock-and-key, unlocking the factor IXa inhibition.

"When the shape change occurs, it immediately loses its activity," Becker said.

The drug took about 15 minutes to work and the antidote took one minute to five minutes.

In this Phase I trial, the anticoagulant thinned the blood as expected and the antidote reversed this process, also as expected.

"The key is, we have a means to control the level of anticoagulant and that is something we have been lacking," Becker added.

"REG1 could be viewed as a potential replacement for unfractionated heparin," he said.

The researchers are now examining the effect of the dual drugs in 50 patients with stable heart disease who are taking aspirin and/or clopidogrel to prevent clotting.

"Our intention is to develop this particular molecule in individuals with heart disease, perhaps who have sustained a heart attack or who are undergoing angioplasty," Becker said.

One day, however, such systems could be used to treat a wide variety of conditions, including cancer, infectious diseases and rheumatologic disorder.

"It's a platform that could be used in many different disease states," Becker said.

More information

Visit the American Heart Association for more on anticoagulants.

SOURCES: Richard C. Becker, M.D., professor of medicine, and director, Cardiovascular Thrombosis Center, Duke University Medical Center, Durham, N.C.; Raymond Gibbons, M.D., president, American Heart Association, and professor of medicine and co-director, Nuclear Cardiology Lab, Mayo Clinic, Rochester, Minn.; Circulation

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