期刊
ANNALS OF VASCULAR SURGERY
卷 20, 期 2, 页码 228-236出版社
ELSEVIER SCIENCE INC
DOI: 10.1007/s10016-006-9017-z
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资金
- NHLBI NIH HHS [HL64333, HL64332] Funding Source: Medline
Treatment with doxycycline suppresses the development of abdominal aortic aneurysms (AAAs) in experimental animal models, but its use in humans can be accompanied by dose-related side effects. We sought to determine if localized administration of doxycycline can achieve inhibition of AAAs equivalent to that achieved by systemic treatment. C57BL/6 mice underwent transient elastase perfusion of the abdominal aorta to induce the development of AAAs. After 14 days, the mean increase in aortic diameter was reduced from 167.2 +/- 7.8% in untreated mice to only 129.7 +/- 13.8% in mice treated with 100 mg/kg/day oral doxycycline (p < 0.05). Using osmotic minipumps to provide continuous periaortic infusion of doxycycline, localized infusion at rates of 0.75 to 1.0 mg/kg/day suppressed AAAs to an equivalent or even greater extent than systemic treatment [mean increase in aortic diameter 131.5 +/- 14.4% at 0.75 mg/kg/day, p < 0.05; 103.2 +/- 13.5% at 1.0 mg/kg/day, p < 0.01). Mean plasma doxycycline levels reached 332 +/- 62 ng/mL during oral administration, but the drug was undetectable in the circulation during localized infusion. The doxycycline concentration in aortic tissue extracts was 22 +/- 6 ng/mL during systemic treatment compared to only 5.6 +/- 2.2 ng/mL [at 0.75 mg/kg/day] and 7.8 +/- 4.0 ng/mL [at 1.0 mg/kg/day] during localized infusion (p < 0.05). Localized administration of doxycycline can effectively suppress experimental AAAs with undetectable plasma drug levels, even at doses 100-fold lower than those used during oral drug administration. Localized delivery of doxycycline holds promise as a novel strategy to inhibit the progressive expansion of aortic aneurysms, perhaps as a pharmacological adjunct to endovascular (stent graft) treatment.
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