Prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms: report of a prospective (Phase II) multicenter study.

BACKGROUND: The primary purpose of this study was to evaluate compliance, side effects, and safety associated with prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms (AAAs). A secondary goal was to determine how treatment with doxycycline influences circulating levels of matrix metalloproteinase-9 (MMP-9) in this patient population. METHODS: Thirty-six patients with AAAs (30 men and 6 women; mean age, 69 +/- 1 years) were enrolled into a 6-month phase II study to evaluate treatment with doxycycline (100 mg orally twice a day). Aneurysm size was measured before and after treatment, and compliance and side effects were monitored. Plasma levels of doxycycline were measured midway through the study, and plasma MMP-9 concentrations were measured at baseline, 3 months, and 6 months. RESULTS: Thirty-three of the 36 patients (92%) completed 6 months of doxycycline treatment. Significant treatment-related side effects occurred in five patients (13.9%), including three with cutaneous photosensitivity reactions (8.3%), one with tooth discoloration (2.8%), and one with yeast infection (2.8%). A high rate of compliance with treatment was seen, despite minor but frequent side effects, including nonspecific gastrointestinal symptoms (25%), easily managed episodes of photosensitivity (22.2%), and reversible tooth discoloration (5.5%). The mean plasma doxycycline level after 3 months was 4.62 +/- 0.68 ug/mL (median, 3.64 microg/mL; range, 1.31 to 14.39 microg/mL; n = 23 patients). No significant change was seen in AAA diameter (42.7 +/- 1.3 mm at 6 months versus 41.0 +/- 0.9 mm at baseline), and the overall rate of AAA expansion was 0.63% +/- 0.25% per month. The mean plasma MMP-9 level (n = 19 patients) was elevated at baseline (118.9 +/- 37.9 ng/mL; upper limit of normal, 85 ng/mL) but subsequently decreased to 83.8 +/- 32.9 ng/mL at 3 months (not significant versus baseline) and to 66.4 +/- 24.2 ng/mL at 6 months (P =.022 versus baseline). Only 21% of patients had an elevated level of plasma MMP-9 after 6 months of treatment compared with 47% at baseline (P <.05). CONCLUSION: Prolonged administration of doxycycline is safe and well tolerated by patients with small asymptomatic AAAs and is associated with a gradual reduction in plasma MMP-9 levels. Further studies are needed to evaluate the long-term effects of doxycycline on the rate and extent of aneurysm growth and the potential use of plasma MMP-9 levels as a biomarker of aneurysm disease progression.

Doxycycline in patients with abdominal aortic aneurysms and in mice: comparison of serum levels and effect on aneurysm growth in mice.

OBJECTIVE: Doxycycline has been shown to inhibit aneurysm formation in a rodent model of abdominal aortic aneurysm (AAA). The doses necessary for this inhibition (6 mg/kg) are much higher than the standard antibiotic doses (1 to 1.5 mg/kg) used in humans. Because the side effects associated with doxycycline are dose related, whether patients would tolerate doses that are four to six times higher than normal is unclear. Also unclear is whether the serum levels necessary in these animal models can be safely achieved in patients. The purposes of this study were to determine the serum concentrations necessary to inhibit aneurysm formation in a mouse model of AAA and to compare them with the plasma concentrations in patients with AAA with a standard dose of doxycycline. METHODS: Four groups of 10 mice of C57BL/6 strain were given doxycycline (0, 10, 50, and 100 mg/kg) beginning at 7 weeks of age. At 8 weeks of age, the mice underwent AAA induction through bathing periadventitial aortic tissue with 0.25 mol/L CaCl(2). Blood samples were taken 10 weeks after surgery to assess the levels of doxycycline. Aortic size was measured at AAA induction and at death with a videomicrometer. Fourteen patients with diagnosed AAA were given 100 mg of doxycycline twice a day for at least 3 months. Blood samples to determine the plasma levels of the drug were taken at 3 or 6 months. The circulating levels of doxycycline for mice and humans were assessed with high-performance liquid chromatography. RESULTS: The changes in aortic size and circulating levels of doxycycline in the AAA murine model are reported. Doses of 10, 50, and 100 mg/kg accounted for a 33%, 44%, and 66% reduction of the aneurysmal growth in the mice, respectively. In patients, the circulating doxycycline levels ranged from 1.8 to 9.42 microg/mL (mean, 4.14 +/- 0.557), values similar to those obtained in mice. CONCLUSION: The circulating doxycycline levels of the patients are comparable with those achieved in mice. Doxycycline accounts for an inhibition of 33% to 66% of the aortic growth. The findings suggest that standard doxycycline doses could inhibit AAA growth in humans.