Feb. 18, 2000 GAINESVILLE, Fla. --- University of Florida researchers have used gene therapy techniques to develop a new heart drug that safely lowers high blood pressure in rats for up to a month with a single dose.
That's significant, doctors say, because the medications most frequently prescribed to treat hypertension must be taken daily and are linked to such substantial side effects that many patients won't take them. High blood pressure raises the risk of stroke, heart attack, and heart and kidney failure for some 50 million Americans; experts estimate that as many as half are not receiving treatment and of those who are, only one in every two is receiving proper medical care.
The new, patent-pending medication, part of an emerging class of drugs that treat disease by manipulating the essential building blocks of life, represents a marked departure from standard drug design. The drug, described in the January issue of the journal Hypertension and in this week's issue of Circulation, regulates high blood pressure by rewriting the genetic instructions that normally tell the body to create the sites, or "receptors," where harmful hormones act in the heart and kidneys.
To do so, scientists reordered the chemical units in a fragment of DNA known to be responsible for receptor production. The new material is then known as antisense because it is a reversal of the DNA message, which scientists sometimes refer to as "sense." They then packaged the antisense into a solution that could be injected into the bloodstream.
"The results look promising for a new way to treat hypertension with a drug that is so specific it will have few side effects, and so long-lasting that it would control blood pressure very well, without the need for daily medication," said Dr. M. Ian Phillips, chairman of the department of physiology at UF's College of Medicine and the study's principal investigator."This is going to be a new type of medicine, part of a completely new class of medicines called antisense." Phillips worked with UF graduate student Y. Clare Zhang on the study.
Blood pressure typically rises as a normal response to stress and physical activity. However, a person with the disorder known as hypertension has high blood pressure at rest.
Since the 1960s, beta-blockers have ranked among the most widely used drugs for the treatment of high blood pressure, but they have to be taken daily and patients often stop using them because of side effects, including dizziness, fatigue, cough and impotence. The drugs fight the condition by blocking the action of certain hormones, slowing heart rate and decreasing the force with which the heart muscle contracts.
The idea of developing antisense medicines is increasingly attractive to scientists who have been scrutinizing the approach in the laboratory. The first such drug hit the market last year, when the Food and Drug Administration approved Vitravene for the prevention of blindness in AIDS patients.
UF researchers found that their drug, which they have termed a beta1 antisense oligodeoxynucleotide, doesn't affect heart rate or cross into the brain. As a result, the treatment isn't expected to cause the side effects associated with standard beta-blockers, Phillips said.
The next step is to test the antisense treatment in patients to ensure its safety and effectiveness, said Phillips, who is seeking to ally with a pharmaceutical company for the next research phase.
Dr. Victor Dzau, a professor of medicine at Harvard Medical School and chairman of the department of medicine at Brigham and Women's Hospital, called the study an exciting proof of concept, but noted that additional investigation is required to more fully understand how the beta1 antisense works and how it affects the rest of the body aside from the cardiovascular system.
"This research is introducing a new paradigm, a new therapeutic approach to treating high blood pressure, and if it's proven to be useful in humans this obviously is extremely important and it's ground-breaking," Dzau said. "But these are animal studies, and it requires very careful and extensive human studies to prove efficacy and safety."
While a medicine that could provide long-lasting protection against high blood pressure is desirable, scientists also need to assess whether such a persistent effect could eventually pose problems, Dzau added.
"Like all medication, when we begin to think about a sustained effect we have to wonder what happens if you block the receptors (with the antisense) for too long - are there downsides to it? For example, what happens if you need the receptors to kick in under certain conditions?" Dzau said. "That being said, we know that every day patients are taking beta-blockers and calcium channel blockers and angiotensin receptor blockers, so clearly the body has a way to get around this."
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