Mice who were not given the antidote experienced significant bleeding in response to this surgical challenge, whereas mice given the antidote after the tail clipping experienced no increased blood loss. Mice were treated with high doses of the anticoagulant and the ends of their tails were clipped off. The drug effectively prevented arterial thrombosis in murine thrombosis models, and the additional safety of the drug conferred by the antidote was demonstrated in murine surgical challenge models. In studies conducted by colleagues from the University of Michigan, the aptamer drug-antidote pair was successful in mouse models. "The antidote neutralized more than 95 percent of the anticoagulant effects of the drug within 10 minutes, and continued to neutralize the anticoagulant activity more than an hour later," Sullenger said. Then, once the blood was anticoagulated, they injected the antidote into the treated pigs. In their current experiments, the researchers first demonstrated that the factor IXa inhibitor was an effective anticoagulant in pigs. The Duke researchers previously described the discovery and design of this anti-factor IXa aptamer-antidote pair and demonstrated the blood-thinning activity of the drug and the neutralization activity of the antidote in the test tube in a paper published in Nature (Sept. "Once we determined the identity of our drug, we were able to design an antidote that would bind to the drug at a specific site, causing a conformational change, which rapidly and durably neutralizes the activity of the drug." "As soon as the drug is developed, the antidote comes relatively easily," Sullenger said. The first drug from this new class of therapeutics, Eyetech's Macugen, recently demonstrated high efficacy for the treatment of age-related macular degeneration in Phase III clinical trials. Aptamers are single-stranded nucleic acids (RNA or DNA) that bind to specific protein targets with high affinity and specificity. The researchers discovered anticoagulant aptamers that target factor IXa. Past studies have shown an association between elevated levels of factor IXa and the onset of acute coronary syndrome. Their target was human coagulation factor IXa, a pivotal clotting factor in the complex cascade of biochemical events that ultimately leads to the formation of a blood clot. The researchers took the challenge, and decided to create a drug-antidote pair from scratch. If this new approach works out, it should give us much greater control in so many situations where a drug is long-lasting but has potential side effects." "We can't easily stop or reverse the action of these drugs quickly. "One of the biggest problems we face as cardiologists is that one of the major side effects of drugs we use to 'thin the blood' is bleeding," said cardiologist Robert Califf, M.D., director of the Duke Clinical Research Institute. Patients who have received anticoagulants and who then must undergo emergency surgery can also face life-threatening delays, said Sullenger. When bleeding events occur, cardiologists have little recourse except to wait for the drug to be cleared from the body naturally, a potentially time-consuming process. Sullenger, and his colleague Chris Rusconi, Ph.D., were inspired by Duke cardiologists who said they needed a reliable blood-thinning agent that they could give to patients without the accompanying risks of bleeding. "These findings have the possibility to significantly change how we care for heart patients," said Bruce Sullenger, Ph.D., vice chairman of research for Duke's surgery department and senior member of the research team. The study was supported by the National Institutes of Health (NIH), the American Heart Association, and Duke's Department of Surgery. 17, 2004, as an Advance Online Publication of the journal Nature Biotechnology. The results of the Duke experiments were published Oct. Instead of developing agents to treat the side effects of existing drugs, researchers could develop matched drug-antidote pairs at the beginning of the drug development process to enable the control of drug activity in patients. The finding could open up a new approach to the development of medications. Using this combination pharmaceutical on-off switch, whose unique properties were demonstrated in animal models, researchers could quickly and effectively neutralize the effects of the drug. – In a discovery that could give physicians more control over the actions of medications, researchers at Duke University Medical Center have developed a novel drug pair – a potent anti-coagulant with a matched "antidote."
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |