Repeated Injection of High Doses of Hemoglobin-Encapsulated Liposomes (Hemoglobin Vesicles) Induces Accelerated Blood Clearance in a Hemorrhagic Shock Rat Model
Repeated Injection of High Doses of Hemoglobin-Encapsulated Liposomes (Hemoglobin Vesicles) Induces Accelerated Blood Clearance in a Hemorrhagic Shock Rat Model
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DOI：
10.1124/dmd.110.036913
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发表时间：
2011-03
影响因子：
3.9
通讯作者：
K. Taguchi;Y. Iwao;Hiroshi Watanabe;D. Kadowaki;H. Sakai;Koichi Kobayashi;H. Horinouchi;T. Maruyama;M. Otagiri
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文献类型：
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作者：
K. Taguchi;Y. Iwao;Hiroshi Watanabe;D. Kadowaki;H. Sakai;Koichi Kobayashi;H. Horinouchi;T. Maruyama;M. Otagiri
血红蛋白囊泡（HbV）是一种人工氧载体，其中浓缩的血红蛋白溶液被封装在脂质体中。为了在临床中应用脂质体制剂，重要的是考虑加速血液清除现象（ABC现象），其涉及在重复施用至相同动物后长循环半衰期的损失。本研究的目的是确定ABC现象是否是在失血性休克条件下重复注射HbV诱导的。本研究建立了大鼠失血性休克模型，并应用~（125）I标记HbV内的Hb进行了药代动力学研究。用未标记的HbV（1400 mg Hb/kg）复苏失血性休克大鼠后第4和7天，第二次剂量的125 I-HbV（1400 mg Hb/kg）与正常大鼠相比迅速从循环中清除。有趣的是，抗HbV的IgM在第一次注射HbV后4天产生，但在第7天降低。此外，第一次注射乙型肝炎病毒后4天和7天，吞噬细胞活性均增加。这些结果表明，在失血性休克条件下，以1400 mg Hb/kg的剂量重复注射HbV诱导ABC现象，这与抗HbV IgM的产生和增强的吞噬细胞活性密切相关。因此，我们得出结论，这可能是必要的，以考虑ABC现象的剂量方案的乙肝病毒治疗在临床设置。
The hemoglobin vesicle (HbV) is an artificial oxygen carrier in which a concentrated hemoglobin solution is encapsulated in a liposome. To apply liposome preparations in clinics, it is important to consider the accelerated blood clearance phenomenon (ABC phenomenon), which involves a loss in the long-circulation half-life after being administered repeatedly to the same animals. The objective of this study was to determine whether the ABC phenomenon is induced by repeated injection of HbV under conditions of hemorrhagic shock. We created a rat model of hemorrhagic shock and performed a pharmacokinetic study using 125I-HbV, in which the Hb inside of HbV was labeled with 125I. At 4 and 7 days after resuscitation from hemorrhagic shock by nonlabeled HbV (1400 mg Hb/kg), the second dose of 125I-HbV (1400 mg Hb/kg) was rapidly cleared from the circulation compared with normal rats. Of interest, IgM against HbV was produced at 4 days after the first injection of HbV, but decreased at 7 days. In addition, phagocyte activity was increased at both 4 and 7 days after the first injection of HbV. These results suggest that repeated injections of HbV at a dose of 1400 mg Hb/kg induce the ABC phenomenon under conditions of hemorrhagic shock, which is strongly related to both the production of anti-HbV IgM and enhanced phagocyte activity. We thus conclude that it might be necessary to considerer the ABC phenomenon in the dose regimen of HbV treatment in clinical settings.