Michael Terrin, MDCM, MPH Scientist, Masters of Public Health, Physician trained in Pulmonary Medicine, Professor of Epidemiology and Public Health, University of Maryland School of Medicine talks about whether or not doxycycline and other antibiotics are beneficial for AAA patients.
What made you and your colleagues look at this particular topic about abdominal aortic aneurysms?
TERRIN: The problem with abdominal aortic aneurysms is important because it affects a substantial percentage of older Americans. About ten percent of older males who smoke, maybe more. It’s a disease that advances for most people, and as it advances, it eventually reaches a point where the aneurysm ruptures. A ruptured aneurysm is fatal most of the time. If we can prevent it from advancing to its end stages, we could save lives.
When you hear aneurysm, you think of an aortic aneurysm or an aneurysm that will affect the brain. What is the difference?
TERRIN: It is the aorta, which is the main artery of the body. There are two different kinds of aortic aneurysm, the ones that occur in the thorax and the ones that occur in the abdomen. There are also aneurysms that occur in the circulation of the brain. They are called cerebral aneurysms. Cerebral aneurysms are different from thoracic aorta aneurysms, which in turn are different from abdominal aortic aneurysms.
Are antibiotics a common treatment, or common part of treatment, for aneurysms?
TERRIN: Doxicycline is an antibiotic that’s been around and used for a long time. It turns out it has other properties. Among the most interesting of its other properties is it inhibits an enzyme called matrix metalloproteinase 9 (MMP 9). There are many metalloproteinases in the matrix of the blood vessels. This is one that came up number nine. Doxycycline appears to be involved in both the suppression of the transcription of that enzyme, its production, and in the function of that enzyme. That enzyme is the main enzyme involved in the destruction of the aorta wall in an abdominal aortic aneurysm. There was a time, 30 to 40 years ago, when there was a theory that aneurysms were due to infections. Then, Doxycycline was tried based on that theory in one small pilot study where the investigators gave up because they decided it wasn’t doing what they wanted it to do. But in retrospect, it looked like those aneurysms may have been slowed down in their growth. The course given was not long-term. Instead the course given was one necessary to eradicate a microorganism. That and the knowledge that Doxycycline suppresses MMP 9 led to a large series of bench studies, many of them performed by my colleagues in this study, that showed MMP 9 could prevent the growth of aneurysms in mice and rats that had been treated with enzymes or chemicals to induce aneurysms. It’s an important disease in humans and the physiological and biochemical effect of Doxy-icycline other than its antibiotic effect was reasonably well worked out in animals, in the mice and rats.
Was the study that your colleagues just did primarily in animal models or human models?
TERRIN: We randomized 261 patients and were able to get follow up CT scans on 254. We had CT scans at baseline on every single patient and blood specimens for the determination of MMP 9 levels and other important biochemistry. We kept track of our patients for two years with repeated CT scans and with enquiries about how they were feeling and what their symptoms were. We followed them for as long as we could up until the time they had surgery.
What were the findings, and what does they suggest?
TERRIN: There was no difference in the growth of aneurysms between the patients treated with placebo and the patients assigned to Doxycycline. The study gives a definitive answer because in addition to the one earlier small study, there was a more recent study comparable in size to our study that suggested Doxycycline might accelerate the growth of aneurysms. Our study gives a very definitive answer that at the doses we gave, 100 milligrams twice a day, there was no affect at all on the growth of the aneurysms. The effect on MMP 9 at a systemic level was not appreciable either. That tells us that there’s something very different between the animal models and the humans. We did observe that Doxycycline reduced the level of a protein often associated with inflammation, C reactive protein. That gave us further confidence in the results because we saw one of the effects that other medical literature would have led us to expect. We’re pretty sure Doxycycline was doing something. We just know whatever it was doing, it was not reducing the growth of aneurysms.
So then, does this suggest a change in treatment or how we think about aneurysms down the road?
TERRIN: Yes, there were surgeons who were hopeful for high-risk patients that Doxycycline might buy them some more time. But, we’re quite sure that it won’t. This is a disappointment. There is efficacious treatment for aneurysms in the form of endovascular repair or open surgical repair. There’s no place as far as we can see for Doxycycline in this treatment.
Is there harm in continuing to prescribe Doxycycline if it’s not doing anything?
TERRIN: Yes, we are concerned on two grounds. One is Doxycycline is an important antibiotic. If it’s used widely in a large percentage of the population every day, that’s an invitation to the development of antibiotic resistance in the pathogens that are out there. Another concern is that Doxy-icycline has bad side effects in some people and the dangers are manifest. There are sunburns due to drug induced photosensitivity, which enhances sunburn, which affected a few of our patients who then decided that because they couldn’t stay out of the sun for their work, they just couldn’t take the medicine. It causes gastrointestinal upset in others. Its side effects are, for the most part, not life-threatening, but bad enough that the general rule should be if you don’t have a very high expectation that a medicine is going to do a patient some good, you should steer clear of it.
Is an additional study needed?
TERRIN: We have concluded our follow-up with only two years of observation, and it would be important to know for our patients whether there was any effect that would be observed after two years since we know that there was an effect on the general background of inflammation. We have other very interesting findings on the growth of aneurysm in our study. It turns out to be slower than expected, which could be of great importance to physicians and surgeons taking care of patients, so they don’t have to rush to surgery. And, we found that growth tended to have more predictable patterns than older literature has suggested. We were very grateful to the National Institutes of Health, especially the National Institute on Aging of the National Institutes of Health, for their generous support of this study. We think the implications are important enough that we are going to go back and ask for more opportunity to cement the information on our older independent Americans.
You had mentioned there are other effective treatments for aneurysms? Can you explain?
TERRIN: The current effective treatments are surgical. They’re the placement of an endovascular device or an open surgery. Another avenue that our findings should promote is the renewed search for non-surgical interventions for aneurysms. The old models don’t work. New models and new treatments should be sought at the bench.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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University Of Maryland School Of Medicine
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