MEDICAL THERAPY FOR NON-OPERATIVE CANDIDATES WITH ABDOMINAL AORTIC ANEURYSMS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。腹主动脉瘤（AAA）与年龄、动脉粥样硬化和主动脉壁的退行性重塑有关。AAAs在老年人群中发现，在高加索男性中最常见。这种疾病的第一个表现往往是致命的破裂。一个AAA患者亚组存在混杂合并症，无法进行择期手术修复。最近的实验室研究指出，基质金属蛋白酶（MMPs）作为AAA发展，生长和破裂的主要调节剂。动物研究表明，包括四环素类在内的一组抗生素是有效的MMP抑制剂。四环素类药物有效地渗透并抑制退行性人AAA组织环境中的MMPs。多西环素是一种四环素，其特征对于AAA患者MMP抑制的临床研究具有吸引力：从胃肠道吸收一致，半衰期长，通过肾脏和肝脏双重代谢，良好的安全性特征，并且没有已知的心血管副作用。本研究针对任何年龄和任何种族的患有肾下AAA（> 5 cm）且不适合手术的成人患者。将排除雌性动物，因为认为雌激素在AAA调节中起保护作用。该研究将是一项双盲随机对照试验，在30名患者中观察强力霉素减少AAA生长的疗效。20名患者将被给予强力霉素，10名患者将被给予一种看起来像药物的非活性药丸。受试者和研究者都不知道哪例患者被分配了活性药物或非活性化合物。在获得知情同意书并分配研究编号以保持机密性后，患者将接受基线多普勒超声扫描（以获得AAA尺寸），然后每4个月进行一次，持续1年。受试者将每月在GCRC诊所进行随访，以获得研究药物并回答调查。此外，患者将在基线访视时采集血液样本，然后每4个月采集一次，检测MMP水平。关注的主要终点将是一年内动脉瘤大小的变化和MMP水平的变化。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Abdominal aortic aneurysms (AAAs) are associated with aging, atherosclerosis and degenerative remodeling of the aortic wall. AAAs are found in older populations and are most common in caucasian males. The first presentation of this disease is often a fatal rupture. A subgroup of patients with AAAs have confounding comorbidities which prohibit elective operative repair. Recent laboratory investigations have pointed toward matrix metalloproteinases (MMPs) as primary modulators in AAA development, growth, and rupture. Animal studies have shown a group of antibiotics, including the tetracyclines, to be potent MMP inhibitors. Tetracyclines effectively penetrate and suppress MMPs in the tissue environment of degenerative human AAAs. Doxycycline is a tetracycline which has features attractive for clinical studies of MMP inhibition in patients with AAAs: consistent absorption from the GI tract, a long half-life, dual metabolism via the kidneys and the liver, an excellent safety profile, and no known cardiovascular side effects. This study is directed at adult patients of any age and any ethnicity with infra-renal AAAs (>5cm) who are not operative candidates. Females will be excluded as estrogens are thought to play a protective role in AAA modulation. The study will be a double blind randomized control trial of doxycycline's efficacy in reducing AAA growth in 30 patients. Twenty patients will be given doxycycline and 10 will be given an inactive pill which looks like the drug. Neither the subjects nor the investigators will know which patient has been assigned active drug or the inactive compound. After obtaining informed consent, and assigning a research number in order to maintain confidentiality, the patients will undergo a baseline duplex ultrasound scan (to obtain AAA size), then every 4 months thereafter for 1 year. Subjects will follow-up in the GCRC clinic monthly to obtain study medications and respond to a survey. Additionally, patients will have blood samples drawn at the baseline visit, then every 4 months which will be tested for MMP levels. The main endpoints of interest will be change in the size of aneurysm and change in MMP levels over a one year period.