Localized administration of doxycycline suppresses aortic dilatation in an experimental mouse model of abdominal aortic aneurysm

Michel A. Bartoli, Federico E. Parodi, Jack Chu, Monica B. Pagano, Dongli Mao, Bernard Timothy Baxter, Celine Buckley, Terri L. Ennis, Robert W. Thompson

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)228-236
Number of pages9
JournalAnnals of Vascular Surgery
Volume20
Issue number2
DOIs
StatePublished - Jan 1 2006

Fingerprint

Doxycycline
Abdominal Aortic Aneurysm
Dilatation
Theoretical Models
Oral Administration
Therapeutics
Tissue Extracts
Aortic Aneurysm
Pancreatic Elastase
Abdominal Aorta
Inbred C57BL Mouse
Stents
Animal Models
Perfusion
Pharmacology
Transplants
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Surgery
  • Cardiology and Cardiovascular Medicine

Cite this

Localized administration of doxycycline suppresses aortic dilatation in an experimental mouse model of abdominal aortic aneurysm. / Bartoli, Michel A.; Parodi, Federico E.; Chu, Jack; Pagano, Monica B.; Mao, Dongli; Baxter, Bernard Timothy; Buckley, Celine; Ennis, Terri L.; Thompson, Robert W.

In: Annals of Vascular Surgery, Vol. 20, No. 2, 01.01.2006, p. 228-236.

Research output: Contribution to journalArticle

Bartoli, Michel A. ; Parodi, Federico E. ; Chu, Jack ; Pagano, Monica B. ; Mao, Dongli ; Baxter, Bernard Timothy ; Buckley, Celine ; Ennis, Terri L. ; Thompson, Robert W. / Localized administration of doxycycline suppresses aortic dilatation in an experimental mouse model of abdominal aortic aneurysm. In: Annals of Vascular Surgery. 2006 ; Vol. 20, No. 2. pp. 228-236.
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