新型有限谱 MMP 抑制剂 XL784 在腹主动脉瘤中的作用。

Effect of novel limited-spectrum MMP inhibitor XL784 in abdominal aortic aneurysms.

机构信息

Department of Surgery, Section of Vascular Surgery, Washington University School of Medicine, St Louis, MO, USA.

出版信息

J Cardiovasc Pharmacol Ther. 2012 Dec;17(4):417-26. doi: 10.1177/1074248412455695. Epub 2012 Aug 15.

DOI:10.1177/1074248412455695

PMID:22894883

Abstract

BACKGROUND

Inhibiting the growth of small abdominal aortic aneurysms (AAAs) is a clinically valuable goal and fills an important therapeutic void. Based on studies in animals and humans, inhibition of the activity of elastolytic matrix metalloproteinases (MMPs) has the potential to slow AAA expansion and limit morbidity and the need for surgery. Previous attempts to make use of the synthetic MMP inhibitors in the treatment of chronic conditions have been limited by intolerable side effects. The limited-spectrum synthetic MMP inhibitor, XL784, was well tolerated and devoid of side-effects associated with other nonspecific MMP inhibitors in phase I studies. We hypothesized that clinically relevant doses of XL784 would be effective at inhibiting aneurysm development in a mouse model.

METHODS

The 14-day elastase-perfusion model of AAA in mice was used. An initial screening study of XL784 (50 [n = 17], 125 [n = 17], and 250 mg/kg [n = 18]) administered via gavage daily until harvest. Controls received diluent alone (n = 18) or doxycycline in drinking water (n = 19). Aortic diameter was measured pre-perfusion (AD(pre)) and at harvest (AD(har)). A second study used XL784 (250 [n = 9]; 375 [n = 9], and 500 mg/kg [n = 14]) and diluent alone (n = 9) administered via gavage. The percentage dilatation [%ΔAD = [(AD(har) - AD(pre))/AD(pre)] ×100] was calculated and elastin and inflammatory content was scored.

RESULTS

All mice tolerated the treatments similarly. Control mice all developed aneurysms with a mean %ΔAD of 158.5% ± 4.3%. Treatment with all doses of XL784 and doxycycline were effective in inhibiting aortic dilatation. There was a clear dose-response relationship between XL784 and reductions in aortic dilatation at harvest (50 mg/kg 140.4% ± 3.2%; 125 mg/kg 129.3% ± 5.1%; 250 mg/kg 119.2% ± 3.5%; all Ps < .01 compared to control). This continued with the higher doses (375 mg/kg 88.6% ± 4.4%; 500 mg/kg 76.0% ± 3.5%). The highest 2 doses of XL784 tested were more effective than doxycycline (112.2% ± 2.0%, P < .05) in inhibiting maximal dilatation of the aorta after elastase perfusion.

摘要

背景

抑制小型腹主动脉瘤（AAA）的生长是一个具有临床价值的目标，填补了重要的治疗空白。基于动物和人类的研究，抑制弹性蛋白酶基质金属蛋白酶（MMPs）的活性有可能减缓 AAA 的扩张，限制发病率和手术需求。以前利用合成 MMP 抑制剂治疗慢性疾病的尝试因不可耐受的副作用而受到限制。有限谱合成 MMP 抑制剂 XL784 在 I 期研究中具有良好的耐受性，并且没有与其他非特异性 MMP 抑制剂相关的副作用。我们假设临床相关剂量的 XL784 可有效抑制小鼠模型中的动脉瘤形成。

方法

使用小鼠弹性蛋白酶灌注 AAA 的 14 天模型。对 XL784（50 [n = 17]、125 [n = 17]和 250 mg/kg [n = 18]）进行了初步筛选研究，通过灌胃每天给药直至收获。对照组接受单独的稀释剂（n = 18）或饮用水中的强力霉素（n = 19）。在灌注前（AD（pre））和收获时（AD（har））测量主动脉直径。第二项研究使用 XL784（250 [n = 9]；375 [n = 9]和 500 mg/kg [n = 14]）和单独的稀释剂（n = 9）通过灌胃给药。计算 [%ΔAD = [(AD（har）- AD（pre））/AD（pre）]×100] 的扩张百分比，并对弹性蛋白和炎症含量进行评分。

结果

所有小鼠的治疗耐受性相似。所有对照小鼠均形成动脉瘤，平均 %ΔAD 为 158.5%±4.3%。所有剂量的 XL784 和强力霉素治疗均有效抑制主动脉扩张。XL784 与收获时主动脉扩张的减少之间存在明显的剂量反应关系（50 mg/kg 140.4%±3.2%；125 mg/kg 129.3%±5.1%；250 mg/kg 119.2%±3.5%；所有 P<.01 与对照组相比）。随着剂量的增加，这种情况仍在继续（375 mg/kg 88.6%±4.4%；500 mg/kg 76.0%±3.5%）。测试的最高 2 个 XL784 剂量比强力霉素（112.2%±2.0%，P<.05）更有效抑制弹性蛋白酶灌注后主动脉的最大扩张。