Doxycycline in patients with abdominal aortic aneurysms and in mice: Comparison of serum levels and effect on aneurysm growth in mice
Doxycycline in patients with abdominal aortic aneurysms and in mice: Comparison of serum levels and effect on aneurysm growth in mice
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DOI：
10.1067/mva.2002.123757
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发表时间：
2002-05-01
影响因子：
4.3
通讯作者：
Baxter, BT
中科院分区：
文献类型：
--
作者：
Prall, AK;Longo, GM;Baxter, BT
目的：多西环素在啮齿动物腹主动脉瘤（AAA）模型中显示出抑制动脉瘤形成的作用。这种抑制所需的剂量（6毫克/公斤）远远高于人类使用的标准抗生素剂量（1至1.5毫克/公斤）。由于强力霉素的副作用与剂量有关，患者是否能耐受比正常剂量高4至6倍的剂量尚不清楚。同样不清楚的是，这些动物模型所需的血清水平是否可以安全地在患者身上达到。本研究的目的是确定抑制AAA小鼠模型动脉瘤形成所需的血清浓度，并将其与给予标准剂量强力霉素的AAA患者血浆浓度进行比较。C57BL/6系小鼠4组10只，于7周龄开始给予强力霉素（0、10、50、100 mg/kg）。在8周龄时，用0.25 mol/L CaCl2浸泡主动脉瓣周围组织进行AAA诱导。术后10周采集血液样本评估强力霉素水平。在AAA诱导和死亡时用可视千分尺测量主动脉大小。14例确诊为AAA的患者给予100 mg强力霉素，每天两次，持续至少3个月。在3或6个月时采集血液样本以确定药物的血浆水平。采用高效液相色谱法测定了多西环素在小鼠和人体内的循环水平。本文报道了AAA模型小鼠主动脉大小和多西环素循环水平的变化。10、50和100 mg/kg的剂量分别使小鼠的动脉瘤生长减少33%、44%和66%。在患者中，循环多西环素水平范围为1.8至9.42马克杯/毫升（平均4.14+/-0.557），数值与小鼠相似。结论：患者体内循环多西环素水平与小鼠相当。强力霉素可以抑制33%到66%的主动脉生长。研究结果表明，标准剂量的强力霉素可以抑制人体内AAA的生长。
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 CaCl2. 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 mug/mL (mean, 4.14+/-0.557), values similar to those obtained in mice.Conclusion: 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.