Repeated Injection of High Doses of Hemoglobin-Encapsulated Liposomes (Hemoglobin Vesicles) Induces Accelerated Blood Clearance in a Hemorrhagic Shock Rat Model

Abstract

ABSTRACT: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 125 I-HbV, in which the Hb inside of HbV was labeled with 125 I. At 4 and 7 days after resuscitation from hemorrhagic shock by nonlabeled HbV (1400 mg Hb/kg), the second dose of 125 I-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.

Liposome-encapsulated hemoglobin (hemoglobin-vesicle) is not transferred from mother to fetus at the late stage of pregnancy in the rat model

“…This is also consistent with the results of Berlin Blue staining portions, which reflect the presence of excessive amounts of hemosiderin, most likely to be from HbV, in the maternal spleen, liver, kidney and placenta but not in the fetal liver. In pregnant rat mothers, a relatively large amount of the 125 I-HbV dose was distributed in the plasma, spleen and liver, which is consistent with a previous report (Taguchi et al, 2009a, b;Taguchi et al, 2011). Since HbV possesses a liposome structure, they are expected to be captured by the MPS (mononuclear phagocyte system) in the spleen and liver (Kiwada et al, 1998).…”

Carbon Monoxide-Bound Red Blood Cell Resuscitation Ameliorates Hepatic Injury Induced by Massive Hemorrhage and Red Blood Cell Resuscitation via Hepatic Cytochrome P450 Protection in Hemorrhagic Shock Rats

“…Forty‐five male SD rats (180–210 g, Kyudou Company, Kumamoto, Japan) were anesthetized and polyethylene catheters (PE 50 tubing, outer diameter equal to 0.965 mm, and an inner diameter equal to 0.58 mm; Becton Dickinson and Company, Tokyo, Japan) containing saline and heparin were then introduced into the left femoral artery. Hemorrhagic shock was induced in 30 rats by removing 40% of the total blood volume according to a previous report . The systemic blood volume was estimated to be 56 mL/kg .…”

“…Hemorrhagic shock was induced in 30 rats by removing 40% of the total blood volume according to a previous report. 12,13 The systemic blood volume was estimated to be 56 mL/kg. 14 Under these experimental conditions, the mean arterial pressure remained at less than 40 mm Hg for 30 min.…”

Carbon Monoxide–Bound Red Blood Cells Protect Red Blood Cell Transfusion-Induced Hepatic Cytochrome P450 Impairment in Hemorrhagic-Shock Rats

“…Eighty-eight male Sprague-Dawley rats (180-210 g; Kyudou Co., Kumamoto, Japan) were anesthetized, and polyethylene catheters (PE 50 tubing, outer diameter equal to 0.965 mm and inner diameter equal to 0.58 mm; Becton Dickinson and Co., Tokyo, Japan) containing saline and heparin were then introduced into the left femoral artery. Hemorrhagic shock was induced by removing 40% of the total blood volume according to a previous report (Taguchi et al, 2009(Taguchi et al, , 2011a. Systemic blood volume was estimated to be 56 ml/kg (Sakai et al, 2004).…”