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RESEARCH BRIEFS
Drug Targets Resistant HIV, Awaits FDA ApprovalA clinical study appearing in the Dec. 22 Journal of the American Medical Association has found that adefovir, a new anti-retroviral drug, substantially reduces human immunodeficiency virus (HIV) levels in the blood of infected patients. Importantly, the drug is active in individuals failing standard treatment regimens. Some undesirable side effects were reported, including kidney damage, but the researchers believe these are clinically manageable, especially since they were reversible after drug discontinuation. The study, involving 442 patients from 33 HIV treatment centers in the U.S., was the collaborative effort of researchers from the Harvard School of Public Health and several institutions in California. Its lead authors are James Kahn, associate professor of medicine at the University of California, San Francisco, and Stephen Lagakos, the Henry Walcott professor of biostatistics and chair of that department at HSPH. Current HIV drugs have been beneficial in reducing viral loads and improving patient survival. However, new drugs are needed in order to increase the effectiveness of current therapies and to battle HIV strains resistant to these treatments. Adefovir is the first in a new class of nucleotide analogs. These drugs interrupt the life cycle of retroviruses like HIV by substituting for normal DNA nucleotides as the virus converts itself from RNA to DNA. The substitution inhibits the enzyme that catalyzes this process, reverse transcriptase, and DNA synthesis comes to a halt. Although other nucleotide analog drugs are available, structural differences in the new class may render them more effective. In spite of the drug's promise, an advisory committee recommended against FDA approval on Nov. 1, 1999. The FDA decision is discussed in an editorial accompanying the JAMA paper. Clinical studies are now under way to determine whether lower doses of adefovir will be both effective and non-toxic. More than 20 other drugs against resistant HIV strains are also undergoing clinical trials.
Meta-Study Shows Alcohol Cuts Heart Disease RiskAfter analyzing more than three decades of research, investigators at the Harvard School of Public Health estimate that moderate alcohol intake—two drinks a day in the form of wine, beer, or spirits—lowers the risk of coronary heart disease (CHD) by 25 percent. They attribute the protective benefits to elevations in high density lipoprotein (HDL) cholesterol and reductions in fibrinogen, a blood-clotting factor. They believe other unknown effects of alcohol are probably involved as well. Eric Rimm, associate professor of epidemiology and nutrition, is the first author of the study, published in the Dec. 11 British Medical Journal. The researchers predicted CHD risk by relating findings in clinical studies to epidemiological studies. Numerous clinical studies have examined alcohol's effect on certain lipids and blood clotting factors. Though epidemiological studies have provided information about associations between these factors and CHD risk, only a few have looked at this relationship specifically. Using standard meta-analysis methods, the researchers identified biomarkers consistently altered by alcohol in over 40 clinical studies—HDL cholesterol, triglycerides (which may indirectly raise HDL cholesterol levels) and fibrinogen. They then estimated the CHD risk associated with these changes based on epidemiological studies that related these biomarkers to disease risk. New Angiogenesis Inhibitor IdentifiedAdding to the arsenal of potential anticancer agents, researchers at Massachusetts General Hospital report the discovery of a new inhibitor of angiogenesis and tumor growth. The protein, thrombospondin-2 (TSP-2), is known for its role in regulating the proliferation, adhesion, and migration of several cell types. Scientists had long suspected an anti-angiogenic function for TSP-2. Mice missing the gene have significantly more blood vessels throughout their bodies. Also, a close TSP-2 family member, TSP-1, is a known angiogenesis inhibitor. Researchers Michael Detmar, associate professor of dermatology, Michael Streit, research fellow in dermatology, and colleagues tested TSP-2's ability to inhibit angiogenesis and, therefore, tumor growth in mice. They inserted the gene into human squamous cancer cells and then injected these cells into the skin of mice. To compare effects of TSP-2 with TSP-1, they injected other mice with cells containing TSP-1, or both TSP-1 and TSP-2. As expected, mice injected with cancerous cells containing neither gene rapidly developed tumors. However, tumor growth was inhibited by 90 percent in mice with TSP-2–containing cells and was associated with a marked reduction of tumor microvessels. TSP-2's effect was greater than that of its relative, TSP-1, which inhibited growth by only 40 to 50 percent. Interestingly, tumor formation was completely inhibited in cells expressing both genes. In their paper in the Dec. 21 Proceedings of the National Academy of Sciences, the researchers state that combination therapies such as these, just like combined angiostatin and endostatin therapy, may be more effective than the use of single agents. Cytokine Block Prevents Post-Injury Immune SuppressionResearchers at Brigham and Women's Hospital have discovered that blocking the activity of interleukin-10 (IL-10), an immunosuppressive cytokine, helps burn-injured mice overcome infections. Many studies have reported immune system imbalances in these traumas, which likely play a key role in susceptibility. Associated changes include decreased T-helper cell function and enhanced IL-10 secretion. In this study, led by James Lederer, assistant professor of surgery (immunology), the researchers hypothesized that since IL-10 suppresses immune function, early IL-10 antagonism might restore immunity after injury and improve the chance of surviving a major infection. To study the effects of blocking IL-10, they injected one group of burn-injured mice with antibodies against this cytokine one day after injury. All mice were exposed to a mixture of microorganisms 10 days later. Most burn-injured mice not receiving IL-10 antibodies died within three days of polymicrobial exposure. However, mortality was significantly reduced in mice injected with the antibody. In two separate studies, 50 and 70 percent of these mice survived, compared to 0 and 20 percent in untreated mice. The researchers attributed survival to restored T-helper cell function, which they assessed both in vivo and in vitro. Blocking the inhibitory function of IL-10 may prove to be a useful intervention to preserve immune function and help prevent infection in patients with burns and other serious injuries. Yet the researchers concede that "more extensive analysis of the mechanisms involved and the universality of its effects in other injury models are needed." The study appears in the December Archives of Surgery. Its first author is Ann Lyons, previously a research fellow in the Department of Surgery and currently at a surgical post in Germany. —Briefs by Lorene Leiter |
