Doxycycline for Stabilization of Abdominal Aortic Aneurysms

An abdominal aortic aneurysm (AAA) affects 5-7% of people over 60, and is
responsible for more than 15.000 deaths annually in the US alone. For unknown
reasons, the incidence has been steadily increasing over the last two decades,
and a further increase is anticipated. Current approaches towards AAA are
surveillance, and preventive surgical elimination ('repair') of AAA over 5.5
cm. Unfortunately, traditional (open) elective AAA repair is associated with a
relatively high morbidity and mortality. Although short-term results of
endovascular repair appear more favourable, mid- and long-term mortality is
similar to that of conventional repair. Moreover, the high incidence of
endograft failure repair requires life-long follow-up. According to the
available studies, including a Dutch randomized trial, endovascular repair is
currently not cost-effective. Hence availability of medical therapy, inhibiting
aneurysmal growth and reducing the need for invasive treatment, could have
major advances both from patients' as well as from socio-economical perspective.
Increased activities of the matrix metalloproteinases, in particular MMP-9, are
considered a key-factor in AAA development and growth. The tetracycline
analogue doxycycline attenuates both MMP expression and activity. It was thus
hypothesised that doxycycline may prevent AAA growth. Indeed, doxycycline has
been shown to prevent aneurysm formation in animal models of the disease.
Results from two small clinical studies suggest that doxycycline treatment may
also arrest AAA growth in patients with medium sized aneurysm.
We evaluated the effect of pre-operative doxycycline treatment in patients
undergoing conventional AAA repair (NHS 2000B165), and confirmed the effects of
doxycycline on expression of the gelatinase MMP-9. Our results also revealed
remarkable suppression of MMP-8 (neutrophil collagenase) protein expression.
These findings are new and remarkable. MMP-8 is a stored secondary granule
protein that is only expressed during the late myeloid maturation pathway of
neutrophils, but not in mature, infiltrating neutrophils. This suggests that
the effect of doxycycline on aneurysm growth may extend beyond the effect on
MMP expression and involves attenuation of neutrophil influx. We confirmed the
effect on neutrophil influx by immunohistochemical analysis and explored the
mechanism underlying reduced neutrophil influx. This analysis showed that that
doxycycline, via its effects on the transcription factors AP-1 and C/EBP,
profoundly reduces IL-6 and IL-8 hyperexpression in AAA. This not only results
in reduced neutrophil influx, but also in attenuation of cytotoxic T-cell
activation.
Doxycycline has a well-established safety record, is generally well tolerated
and is inexpensive. Doxycycline should thus be considered a promising
lead-candidate for the pharmaceutical stabilization of AAA.

To test whether 100 mg doxycycline inhibits aneurysm growth

a prospective, randomized placebo controlled trial of standard dose doxycycline
or placebo

doxycyline 100 mg

Minimal, doxycyline is an established drug with an excellent safety profile