Selective Estrogen Receptor Modulator Raloxifene
SAN FRANCISCO--For the first time, raloxifene, one of the new class of drugs known as selective estrogen receptor modulators (SERMs), has been shown to exert a protective effect on blood vessels. An animal study that mimicks the development of atherosclerosis in women who have undergone menopause showed that raloxifene prevented an increase in intimal hyer-plasia in the aorta. Animals in this model typically have more than twice the amount of aortic intimal hyperplasia than usual. However, when raloxifene was given to the subjects, levels of aortic intimal hyperplasia fell to near-normal range. The study was reported at the 1999 Clinical Congress of the American College of Surgeons.
Results from the study also indicated that the action of raloxifene was not affected by cir- culating lipids. According to Craig H. Selzman, MD, first author of the study findings, raloxifene has beneficially modified lipid profiles in clinical trials. The drug has decreased over-all blood cholesterol levels as well as low-density lipoprotein (so-called bad cholesterol) concentrations, and it has increased good high-density lipoprotein cholesterol. "Until now, no one has known that raloxifene can act in some way on the blood vessel wall rather than the modification of serum lipids," he said.
This information may help Dr. Selzman and his research associates at the University of Colorado, Denver, learn why estrogens decrease morbidity and mortality from cardiovascular events. "Premenopausal women don't have the same morbidity and mortality from cardiovascu-lar disease as their age-contemporary males. When women go into menopause, unless they take hormone replacement therapy, they have a higher incidence of cardiovascular disease. We are trying to figure out how estrogens work to be cardioprotective," he said.
While Dr. Selzman is interested in raloxifene as a drug for postmenopausal women, he also foresees raloxifene and other SERMs as a means for discovering what estrogen hormones do to the blood vessel wall. "We are looking at the biology of what is going on in the blood vessel wall that allows an agent like raloxifene to have a beneficial effect. We are looking at female hormone vascular biology because females don't die of cardiovascular disease like men do. So maybe we can find a biological pathway in female hormones that can be used to protect the blood vessel wall in men and women," he said.
Raloxifene and other similar SERM drugs may be able to ferret out information about how a blood vessel responds to a noxious stimulus. "Our blood vessels are continuously exposed to injurious stimuli. Since SERMs appear to decrease the response to vascular injury, we may be able to use these compounds to interrogate the inner workings of the blood vessel wall. Ultimately, such studies will help us to learn what molecular mechanisms or structural elements determine if the blood vessel grows thicker and becomes filled with a clot, or stays nice and free-flowing," he said.
Dr. Selzman and his colleagues are studying the relationship between estrogens and other substances, such as growth factors and cytokines. "We are heading inside the blood vessel wall to see if there is something that can be used to prevent atherosclerosis in the population at large," he concluded.
Joining Dr. Selzman in this research were Stephanie A. Miller, MD; Jamie S. Gaynor, DVM; Thomas A. Whitehill, MD, FACS; Alden H. Harken, MD, FACS; and A.S. Turner, BVsc.
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