Abstract
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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References
UK Small Aneurysm Trial Participants. Mortality results for randomised controlled trial of early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. Lancet 1998;352:1649–1655
Lederle FA, Wilson SE, Johnson GR, et al. Immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med 2002;346:1437–1444
Powell JT, Brady AR. Detection, management, and prospects for the medical treatment of small abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 2004;24:241–245
Koch AE, Haines GK, Rizzo RJ, et al. Human abdominal aortic aneurysms. Immunophenotypic analysis suggesting an immune-mediated response. Am J Pathol 1990;137:1199–1213
Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT. Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 1995;15:1145–1151
Pyo R, Lee JK, Shipley JM, et al. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms. J Clin Invest 2000;105:1641–1649
Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 2002;110:625–632
Thompson RW, Baxter BT. MMP inhibition in abdominal aortic aneurysms: rationale for a prospective randomized clinical trial. Ann NY Acad Sci 1999;878:159–178
Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 1998;12:12–26
Petrinec D, Liao S, Holmes DR, Reilly JM, Parks WC, Thompson RW. Doxycycline inhibition of aneurysmal degeneration in an elastase-induced rat model of abdominal aortic aneurysm: preservation of aortic elastin associated with suppressed production of 92 kD gelatinase. J Vasc Surg 1996;23:336–346
Prall AK, Longo GM, Mayhan WG, et al. Doxycycline in patients with abdominal aortic aneurysms and in mice: comparison of serum levels and effect on aneurysm growth in mice. J Vasc Surg 2002;35:923–929
Kaito K, Urayama H, Watanabe G. Doxycycline treatment in a model of early abdominal aortic aneurysm. Surg Today 2003;33:426–433
Manning MW, Cassis LA, Daugherty A. Differential effects of doxycycline, a broad-spectrum matrix metalloproteinase inhibitor, on angiotensin II-induced atherosclerosis and abdominal aortic aneurysms. Arterioscler. Thromb Vasc Biol 2003;23:483–488
Curci JA, Mao D, Bohner DG, et al. Preoperative treatment with doxycycline reduces aortic wall expression and activation of matrix metalloproteinases in patients with abdominal aortic aneurysms. J Vasc Surg 2000;31:325–342
Baxter BT, Pearce WH, Waltke EA, et al. Prolonged administration of doxycycline in patients with small asymptomatic abdominal aortic aneurysms: report of a prospective (phase II) multicenter study. J Vasc Surg 2002;36:1–12
Mosorin M, Juvonen J, Biancari F, et al. Use of doxycycline to decrease the growth rate of abdominal aortic aneurysms: a randomized, double-blind, placebo-controlled pilot study. J Vasc Surg 2001;34:606–610
Steinmetz EF, Buckley C, Shames ML, et al. Treatment with simvastatin suppresses the development of experimental abdominal aortic aneurysms in normal and hypercholesterolemic mice. Ann Surg 2005;241:92–101
Sho E, Chu J, Sho M, et al. Continuous periaortic infusion improves doxycycline efficacy in experimental aortic aneurysms. J Vasc Surg 2004;39:1312–1321
Franklin IJ, Harley SL, Greenhalgh RM, Powell JT. Uptake of tetracycline by aortic aneurysm wall and its effect on inflammation and proteolysis. Br J Surg 1999;86:771–775
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Portions of this work were initially presented at the Lifeline Foundation Research Forum of the Society for Vacular Surgery, June 3-6, 2004, Anaheim, CA.
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Bartoli, M.A., Parodi, F.E., Chu, J. et al. Localized Administration of Doxycycline Suppresses Aortic Dilatation in an Experimental Mouse Model of Abdominal Aortic Aneurysm. Ann Vasc Surg 20, 228–236 (2006). https://doi.org/10.1007/s10016-006-9017-z
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DOI: https://doi.org/10.1007/s10016-006-9017-z