Duke Researchers Develop Method to Make Safer Drugs
DURHAM, N.C. -- Using blood thinners as a model, researchers at Duke University Medical Center believe they have found a way to safely turn on and off the effects of drugs, or in this case, reverse the blood-thinning process.
Researchers believe they have developed a method to create a class of drugs with the intent of creating a matching antidote that could neutralize, or counteract, the effects of the initial drug when needed. An antidote would be used in cases when patients experience complications from a drug or when physicians think a change in the course of treatment is needed and they cannot wait for the effects of the drug to wear off naturally.
"We asked Duke clinicians what they needed in terms of therapeutics and they described a need to have a blood thinner whose activities could be controlled by an antidote. Now we believe we have a workable solution to designing antidote drugs," said Chris P. Rusconi, Ph.D., director of Duke's Research Program in Combinatorial Therapeutics and lead author of the study that appears in the Sept. 5, 2002 issue of Nature.
The study was funded by grants from the American Heart Association and the National Institutes of Health.
Researchers used as their model the drug heparin, a potent anti-clotting drug, which is used to prevent blood clots from completely closing off coronary arteries. When patients undergo cardiac surgical procedures, such as angioplasty or coronary artery bypass graft surgery, blood thinners such as heparin are commonly administered prior to the procedure to prevent blood clots. Blood tends to clot when subjected to foreign instruments, such as a bypass machine or balloons used in angioplasty.
Heparin is sometimes also administered after a sudden cardiac arrest to ensure blood flow through the heart. It's been proven to be a lifesaver, but during and after surgical procedures use of blood thinners can put a patient at risk of hemorrhaging, other complications and sometimes death.
Having the ability to control the medication with an antidote would give surgeons more control over bleeding in patients during and after surgical procedures, said Bruce A. Sullenger, M.D., vice chair of surgery at Duke University Medical Center and senior author of the study.
"While heparin's blood thinning activity can usually be controlled with an existing antidote called protamine, it doesn't always work. It is difficult to administer and is associated with its own set of toxicities," Sullenger said. (Protamine was not designed specifically as an antidote. Its antidote properties were inadvertently discovered.)
To develop drugs and matching antidotes, researchers focused their efforts on a class of drugs called aptamers. Aptamers are compounds made of nucleic acid (in this case RNA) that bind directly to a target protein and inhibit the protein's activity. Researchers expect that aptamers have the potential to be the key to developing a new class of drugs.
"We theorized we could neutralize the aptamer by using small nucleic acids that could be paired with the aptamer, much like the DNA in our cells forms paired strands. We developed an aptamer that inhibits a protein required for blood clotting to make a new anticoagulant (blood thinner). We then made an antidote specifically paired to the aptamer to reverse the blood-thinning process," Rusconi said.
Using plasma samples from six patients who cannot tolerate heparin, researchers showed the newly created anticoagulant worked and that the antidote could reverse the blood-thinning effect of heparin.
"Our study shows that once you've administered the blood thinner and then add an antidote, within 10 minutes you can totally reverse the activity of that anticoagulant (blood thinner)," Sullenger said.
Duke researchers hope to test the drug-antidote combination in animal models and, within the next several years, test the drug combination in clinical trials. There is a possibility the technology will prove to have other applications, he said.
"In principle, now you can make a drug in this class and target any protein, and design an antidote for that drug. So the potential to make an inhibitor and a safety switch for that inhibitor exists. There could be other applications ranging from anesthesiology to oncology," Sullenger said.
Co-authors of the study include Elizabeth Scardino, Julianna Layzer, George A. Pitoc and Thomas L. Ortel, M.D., all of Duke University Medical Center. Dougald Monroe, Ph.D., of the University of North Carolina School of Medicine, is also a co-author.