Lenhard Diana C, May Ekkehard, Morgenroth Christine, Jost Gregor, Haider Wolfram, Pietsch Hubertus
From the *Institute for Vegetative Physiology, Charité-Universitätsmedizin; †Indication Expansion, and ‡MR and CT Contrast Media Research, Bayer Healthcare AG; and §Institute for Animal Pathology, Berlin, Germany.
Invest Radiol. 2014 Dec;49(12):779-87. doi: 10.1097/RLI.0000000000000084.
The aim of this preclinical study on healthy Sprague-Dawley rats was to determine whether differences exist in the induction of adverse skin reactions after the intravenous administration of a monomeric and 2 dimeric iodinated nonionic contrast agents.
After intravenous injection of iopromide (monomeric), iodixanol (dimeric), and iotrolan (dimeric) at a dose of 4 g iodine/kg of body weight, mechanical ear volume measurements (10 minute after injection) and intravital microscopy (baseline, 5 minutes after injection) of the ear with the near-infrared dye indocyanine green were performed to determine the volume change and plasma extravasation. Histopathological analysis (20 minutes, 1 hour, and 3 hours after injection) was performed to diagnose alterations in the skin. Blood plasma was analyzed to identify elevated levels of histamine (5 minutes after injection) and inflammatory markers (a multianalyte profile of 58 markers; 1 hour and 3 hours after injection).
Only iodixanol induced immediate angioedema formation, with a 100% incidence rate and with slight mast cell infiltration in the ear, muzzle, and paws. The ear showed a 53% volume increase and strong extravasation of plasma proteins into the interstitium, which correlated with highly (11-fold) increased plasma histamine levels 5 minutes after injection. Elevated levels of tumor necrosis factor-α (7.1-fold), macrophage inflammatory protein (MIP)-1α (3.2-fold), and MIP-2 (7.7-fold) were identified 1 hour after the iodixanol injection. Increased levels (fold-change) of MIP-1β (14; 6.3), monocyte chemotactic protein-1 (3.3; 3.7), monocyte chemotactic protein-3 (2.4; 3.0), stem cell factor (1.7; 2), vascular endothelial growth factor (2; 2.1), and interferon gamma-induced protein-10 (4.1; 39.1) were identified 1 hour and 3 hours after the iodixanol administration, respectively. The level of these molecules remained unchanged after the iopromide and iotrolan injections (except for stem cell factor).
A reversible anaphylactoid-like reaction in healthy Sprague-Dawley rats was observed after the iodixanol administration but not after the monomeric iopromide or dimeric iotrolan injections. Therefore, we conclude that the induction of adverse skin reactions is not per se because of a class effect of dimeric contrast agent.
本项针对健康的斯普拉格 - 道利大鼠的临床前研究旨在确定静脉注射单体及两种二聚体碘化非离子型造影剂后，在诱发不良皮肤反应方面是否存在差异。
以4克碘/千克体重的剂量静脉注射碘普罗胺（单体）、碘克沙醇（二聚体）和碘曲仑（二聚体）后，进行机械性耳容积测量（注射后10分钟）以及使用近红外染料吲哚菁绿对耳部进行活体显微镜检查（基线、注射后5分钟），以确定容积变化和血浆外渗情况。进行组织病理学分析（注射后20分钟、1小时和3小时）以诊断皮肤改变。分析血浆以确定组胺水平升高情况（注射后5分钟）以及炎症标志物水平（58种标志物的多分析物谱；注射后1小时和3小时）。
仅碘克沙醇诱发了即刻血管性水肿形成，发生率为100%，耳部、口鼻部和爪子有轻微肥大细胞浸润。耳部容积增加53%，血浆蛋白大量渗入间质，这与注射后5分钟血浆组胺水平高度升高（11倍）相关。碘克沙醇注射后1小时，肿瘤坏死因子 -α水平升高（7.1倍）、巨噬细胞炎性蛋白（MIP）-1α水平升高（3.2倍）以及MIP -2水平升高（7.7倍）。碘克沙醇给药后1小时和3小时，分别检测到MIP -1β水平升高（倍数变化：14；6.3）、单核细胞趋化蛋白 -1水平升高（3.3；3.7）、单核细胞趋化蛋白 -3水平升高（2.4；3.0）、干细胞因子水平升高（1.7；2）、血管内皮生长因子水平升高（2；2.1）以及γ干扰素诱导蛋白 -10水平升高（4.1；39.1）。碘普罗胺和碘曲仑注射后，这些分子的水平保持不变（干细胞因子除外）。
碘克沙醇给药后在健康的斯普拉格 - 道利大鼠中观察到了可逆的类过敏样反应，但单体碘普罗胺或二聚体碘曲仑注射后未观察到。因此，我们得出结论，不良皮肤反应的诱发本身并非由于二聚体造影剂的类别效应。
