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.


CONCLUSIONS
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.
Prall
Amy K
AK
Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68114, USA.
Longo
G Matthew
GM
Mayhan
William G
WG
Waltke
Eugene A
EA
Fleckten
Beverly
B
Thompson
Robert W
RW
Baxter
B Timothy
BT
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use*; D001012:Aorta, Abdominal / Q000187:drug effects / Q000503:physiopathology; D017544:Aortic Aneurysm, Abdominal / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010865:Pilot Projects
D000900:Anti-Bacterial Agents; D004318:Doxycycline