Aortic Aneurysms - Doxycycline

The New Mexico Channel - Enzyme Battles Aneurysms

Dr. Barry Ramo

Bulging Blood Vessels a Threat

Each year, about 1,500 people die of a ruptured aortic aneurysm, a condition in which an artery wall bulges and weakens. The problem can start small, but if it grows and isn't treated, the result can be fatal.

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"When a blood vessel the size of the aorta ruptures and bleeds internally, you can essentially bleed to death," said Dr. Robert Thompson, a vascular surgeon at Washington University School of Medicine in St. Louis. An enzyme called MMP can slowly eat proteins that provide strength for blood-vessel walls. A bulge grows and weakens the wall. "After about four or five years, they reach a size where the risk of rupture becomes concerning," Thompson said. "At that time, repair is usually recommended." An antibiotic called Doxycycline may stop the growth (testimony). In a small study, Thompson found that it reduces the destructive enzyme 80 percent. "That may mean not needing an aneurysm operation at all, or maybe postponing the need for it for many, many years," Thompson said.

Healthbeat with Dr. Barry Ramo airs weekdays on Action 7 News.

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Title: SVC MEETING: Doxycycline Effective For Abdominal Aortic Aneurysms
URL: http://www.pslgroup.com/dg/104BFE.htm
Doctor's Guide
June 7, 1999

ST. LOUIS, MO -- 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," said Robert 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 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 six percent to nine 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 said.

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 said.

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 explained.

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 said. "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 analysed 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. 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 said.

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 said.

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 explained.

1. Boyle et al. Doxycycline inhibits elastin degradation and MMP activation in elastase-infusion AAA model.

2. Curci et al. Preoperative treatment of AAA with doxycycline decreases MMP activity in tissue.

3. Petrinec D, et al: Doxycycline inhibition of AAA in animals.

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Researchers identify key enzyme in aneurysm development:
http://record.wustl.edu/archive/2000/06-15-00/articles/aneurysm1.html