Localized administration of doxycycline suppresses aortic dilatation in an experimental mouse model of abdominal aortic aneurysm.
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.
Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Michel A
MA
Bartoli
Federico E
FE
Parodi
Jack
J
Chu
Monica B
MB
Pagano
Dongli
D
Mao
B Timothy
BT
Baxter
Celine
C
Buckley
Terri L
TL
Ennis
Robert W
RW
Thompson
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004108:Dilatation, Pathologic; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015918:Infusion Pumps, Implantable; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase
D000900:Anti-Bacterial Agents; D010196:Pancreatic Elastase; D004318:Doxycycline