ORCID Profile
0000-0002-0681-3032
Current Organisation
Nara Medical University
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Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 12-2011
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 consider the ABC phenomenon in the dose regimen of HbV treatment in clinical settings.
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.TAAP.2010.08.006
Abstract: The hemoglobin vesicle (HbV) is an artificial oxygen carrier in which a concentrated Hb solution is encapsulated in lipid vesicles. Our previous studies demonstrated that HbV is metabolized by the mononuclear phagocyte system, and the lipid components are excreted from the liver. It is well-known that many hepatically-metabolized and -excreted drugs show altered pharmaceutics under conditions of liver impairment, which results in adverse effects. The aim of this study was to determine whether the administration of HbV causes toxicity in rats with carbon tetrachloride induced liver cirrhosis. Changes in plasma biochemical parameters, histological staining and the pharmacokinetic distribution of HbV were evaluated after an HbV injection of the above model rats at a putative clinical dose (1400 mgHb/kg). Plasma biochemical parameters were not significantly affected, except for a transient elevation of lipase, lipid components and bilirubin, which recovered within 14 days after an HbV infusion. Negligible morphological changes were observed in the kidney, liver, spleen, lung and heart. Hemosiderin, a marker of iron accumulation in organs, was observed in the liver and spleen up to 14 days after HbV treatment, but no evidence of oxidative stress in the plasma and liver were observed. HbV is mainly distributed in the liver and spleen, and the lipid components are excreted into feces within 7 days. In conclusion, even under conditions of hepatic cirrhosis, HbV and its components exhibit the favorable metabolic and excretion profile at the putative clinical dose. These findings provide further support for the safety and effectiveness of HbV in clinical settings.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.JCONREL.2016.05.016
Abstract: Low concentrations of exogenous carbon monoxide (CO) have been reported to be useful for the treatment of various disorders related to inflammation and oxidative stress. However, a number of obstacles make it difficult to use CO in vivo. Among these are, at high concentrations, it is toxic and the fact that it is difficult to control its delivery in the body. Hemoglobin-encapsulated liposomes, Hemoglobin-vesicles (HbV), have the potential for use as a new type of nano-sized CO donor, referred to as CO-bound HbV (CO-HbV). In this study, we investigated the potential of CO-HbV as a CO donor in terms of toxicity and therapeutic efficacy using an experimental colitis model. Toxicological assessments of CO-HbV showed no severe adverse effects including death, and clinical laboratory tests and histopathological changes remained normal for 28days after the administration of doses up to 1400mgHb/kg. We then evaluated the therapeutic efficacies of CO-HbV on dextran sulfate sodium (DSS)-induced colitis model mice. A single administration of CO-HbV at 3days from beginning of the DSS treatment dramatically improved colitis symptoms, colonic histopathological changes and the duration of survival compared to both saline and HbV administration. In addition, the therapeutic effects of CO-HbV on colitis can be attributed to a decreased level of neutrophil infiltration, the production of pro-inflammatory cytokines and oxidative injuries. Interestingly, it appears that an increase in anti-inflammatory cytokine production contributes, in part, to therapeutic effects of CO-HbV in the treatment of colitis. These safety and efficacy profiles of CO-HbV suggest that it has the potential for use as a drug for treating, not only colitis but also a variety of other disorders associated with inflammation and oxidative stress.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 12-01-2011
Abstract: Hemoglobin vesicles (HbVs) could serve as a substitute for red blood cells (RBCs) in resuscitation from massive hemorrhage. A massive transfusion of RBCs can increase the risk of infection, which is not caused by contaminating micro-organisms in the transfused RBCs but by a breakdown of the host defense system. We previously found that complement activity was increased after resuscitation with HbVs at a putative dose in a rat model of hemorrhagic shock. It is known that complement system plays a key role in host defense in the embryonic stage. Therefore, the objective of this study was to address whether the suppression of bacterial infections in hemorrhagic shock rats was a result of increased complement activity after massive HbV transfusion. For this purpose, Escherichia coli were incubated with plasma s les obtained from a rat model of hemorrhagic shock resuscitated by HbVs or RBCs, and bacterial growth was determined under ex vivo conditions. As a result, E. coli growth was found to be suppressed by increased complement activity, mediated by the production of IgM from spleen. However, this antibacterial activity disappeared when the E. coli were treated with complement-inactivated plasma obtained from splenoctomized rats. In addition, the resuscitation of HbVs from hemorrhagic shock increased the survival rate and viable bacterial counts in blood in cecum ligation and puncture rats, a sepsis model. In conclusion, the resuscitation of HbVs in the rat model of hemorrhagic shock suppresses bacterial growth via complement activation induced by IgM.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 13-08-2009
Abstract: The hemoglobin vesicle (HbV) is an artificial oxygen carrier encapsulating a concentrated hemoglobin solution in a liposome of which the surface is covered with polyethylene glycol (PEG). It was recently reported that repeated injections of PEGylated liposomes induce the accelerated blood clearance (ABC) phenomenon, in which serum anti-PEG IgM plays an essential role. To examine this issue, we investigated whether HbV induces the ABC phenomenon in mice at a dose of 0.1 mg Hb/kg, a dose that is generally known to induce the ABC phenomenon, or at 1400 mg Hb/kg, which is proposed for clinical use. At 7 days after the first injection of nonlabeled HbV (0.1 mg Hb/kg), the mice received HbV in which the Hb had been labeled with (125)I. After a second injection, HbV was rapidly cleared from the circulation, and uptake clearances in liver and spleen were significantly increased. In contrast, at a dose of 1400 mg Hb/kg, the pharmacokinetics of HbV was negligibly affected by repeated injection. It is interesting to note that IgM against HbV was produced 7 days postinjection at both of the above doses, and their recognition site was determined to be 1,2-distearoyl-sn-glycero-3-phosphatidylethanolamine-N-PEG in HbV. These results suggest that a clinical dose of HbV does not induce the ABC phenomenon, and that suppression of ABC phenomenon is caused by the saturation of phagocytic processing by the mononuclear phagocyte system. Thus, we conclude that induction of the ABC phenomenon would not be an issue in the dose regimen used in clinical settings.
Publisher: Wiley
Date: 30-12-2021
DOI: 10.1111/AOR.14155
Abstract: Artificial placenta therapy (APT) is an experimental care strategy for extremely preterm infants born at 21–24 weeks’ gestation. In our previous studies, blood taken from the maternal ewe was used as the basis of priming solutions for the artificial placenta circuit. However, the use of maternal blood as a priming solution is accompanied by several challenges. We explored the use of synthetic red cells (hemoglobin vesicles HbV) as the basis of a priming solution for APT used to manage extremely early preterm ovine fetuses. Six ewes with singleton pregnancies at 95 d gestation (term = 150 d) were adapted to APT and maintained with constant monitoring of key vital parameters. The target maintenance period was 72 h in duration. A synthetic red cell solution consisting of HbV, sheep albumin and electrolytes was used as priming solutions for the APT circuit. Fetuses were evaluated on gross appearance, physiological parameters and bleeding after euthanasia. Two out of six APT fetuses were successfully maintained for the targeted 72 h experimental period with controllable anemia ( g/dl) and methemoglobinemia ( %) using an infusion of blood transfusion and nitroglycerin delivered h after APT commencement, a sufficient period of time to cross‐match blood products and screen for viral agents of concern. Extremely preterm sheep fetuses were maintained for a period of up to 72 h using APT in combination with circuit priming using a synthetic red cell (HbV) preparation. Although significant further refinements are required, these findings demonstrated the potential clinical utility of synthetic blood products in the eventual clinical translation of artificial placenta technology to support extremely preterm infants.
Location: United States of America
Location: Singapore
Location: Japan
No related grants have been discovered for Hiromi Sakai.