St. Louis, June 7, 1999 -- A pilot study suggests that doxycycline, an inexpensive and safe antibiotic, might help patients with abdominal aortic aneurysms, which kill at least 15,000 Americans each year. These aneurysms are weak areas in the wall of the body's main artery. At present, only surgery can prevent them from growing to the size where they rupture and cause sudden death.
"If we had a drug therapy that could inhibit the enlargement of abdominal aortic aneurysms, we could shift the management of this condition to screening and aggressive treatment early on," says Robert W. Thompson, M.D., associate professor of surgery, radiology and cell biology and physiology at Washington University School of Medicine in St. Louis.
Thompson and postdoctoral fellow John A. Curci, M.D., present their findings today at the annual meeting of the Society for Vascular Surgery in Washington, D.C.
Abdominal aortic aneurysms (AAAs) develop in 6 percent to 9 percent of people over age 65. Smoking is a major risk factor, and men are three to five times more likely to develop the condition than women. Ninety-five percent of patients with ruptured AAAs die, including 50 percent to 70 percent of those who have emergency surgery. Preventive surgery can save patients whose aneurysms happen to be detected earlier, though it is reserved for defects that have grown to a particularly large size. So a drug treatment that could prevent small aneurysms from enlarging could prevent thousands of operations and deaths each year. "If this approach is successful, it could put us vascular surgeons out of business for this particular problem," Thompson says.
The U.S. Census Bureau projects that 79 million Americans will be 65 or older by 2050 -- up from 35 million in 2000. "So we'd like to have a preventive treatment long before that," Thompson says.
AAAs arise in the large artery that carries blood from the heart to the abdomen. A weak area in the wall tends to enlarge and eventually to balloon out, like a rupturing inner tube. Blood then courses into the abdomen, killing within hours or even minutes.
For the past seven years, Thompson's group has explored the relationship between enzymes called matrix metalloproteinases (MMPs) and abdominal aortic aneurysms. These protein-destroying enzymes are secreted by white cells called macrophages, which fight infection but also can harm host tissues. Two MMPs -- MMP-2 and MMP-9 -- are under suspicion because they are much more abundant in aneurysm tissue than in healthy artery wall. They also attack elastin, a protein that helps strengthen the wall, enabling it to withstand the force of the heart's pumping. "It is believed that the breakdown of elastin and another key protein, collagen, allows an abdominal aortic aneurysm to form and then to grow," Thompson says.
He thought doxycycline might be a useful drug because this chemical cousin of tetracycline was known to inhibit MMPs -- it now is being tested in clinical trials for patients with gingivitis, osteoarthritis and rheumatoid arthritis, three connective tissue diseases. "We were interested because our group operates on 150 to 200 patients with abdominal aortic aneurysms each year, and the number is growing," Thompson says. "So we see a great need for a preventive treatment other than surgery."
Encouraged by their years of laboratory studies, the researchers gave a one-week course of doxycycline to eight patients who were about to undergo preventive surgery for AAAs. The patients took 100 mg of the drug each morning and 100 mg each evening. After the operations, Curci analyzed aneurysm tissue that had been removed. He also looked at similar specimens from seven AAA patients who did not take doxycycline.
The results revealed that doxycycline has several potentially therapeutic effects on aneurysm tissue in addition to its ability to inhibit the activity of MMPs. The aneurysm samples from the patients who had not taken the drug contained two and one-half times as much MMP-9 protein as those from the doxycycline-treated patients. And they contained five and one-half times as much messenger RNA for MMP-9. This messenger carries the blueprint for MMP-9 from the gene to the cellular machinery that makes the enzyme. "So doxycycline decreases MMP-9 production," Curci says.
He also showed that the drug decreased the ability of cultured white cells to produce MMP-9 messenger RNA and MMP-9 protein.
Doxycycline had a different effect on MMP-2. Instead of decreasing its production, it inhibited its activation -- protein-degrading enzymes come with a safety cap that is removed only after they leave the cell. Curci determined that the aneurysm samples from the patients who had not taken doxycycline contained nearly one and one-half times as much of the active form of MMP-2 as the samples from the doxycycline-treated patients. "So in the body, doxycycline affects MMPs by a complex mixture of mechanisms," Curci says.
The drug's effect on the two MMPs resembles a military campaign involving ground troops as well as air attacks. "So doxycycline may have a distinct advantage over drugs that act simply as MMP inhibitors. The idea of using a drug that employs several mechanisms in concert is very attractive," Thompson says.
A pilot study at the School of Medicine and four other Midwest institutions now is testing the effects of a six-month course of doxycycline on the growth of AAAs. With those data, the researchers hope to persuade the National Institutes of Health to fund a clinical trial involving several hundred patients. "The remaining question is whether doxycycline therapy can reduce aneurysm growth in patients over a period of years," Thompson says. "If that proves to be the case, I would like to see everyone over 65 get an abdominal ultrasound so that those with abdominal aortic aneurysms can receive drug therapy instead of needing surgery or dying unexpectedly from a ruptured aneurysm."
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Health System.