Setbacks in Blood Substitutes Research and Development: A Biochemical Perspective

Division of Hematology, Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration/PHS, 8800 Rockville Pike, Bethesda, MD 20892, USA.
Clinics in laboratory medicine (Impact Factor: 1.37). 06/2010; 30(2):381-9. DOI: 10.1016/j.cll.2010.02.009
Source: PubMed


Recent setbacks in using Hb-based technology to develop oxygen carriers or blood substitutes may spur new and fundamentally different approaches for the development of a new generation of hemoglobin-based oxygen carriers (HBOCs). This article briefly details some underlying mechanisms that may have been responsible for the adverse-event profile associated with HBOCs, with a focus on the contribution of the author's laboratory toward identifying some of these biochemical pathways and some ways and means to control them. It is hoped that this will aid in the development of a safe and effective second generation of HBOCs.

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    • "They had advantages when used as oxygen carrier for the treatment of organ ischemic. Reperfusion in a mouse model confirmeda decreased production of oxygen free Redikar, but studies on animals or even humans do not (9,20,39,40). "
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    ABSTRACT: Blood is a liquid tissue in which dissolved with abundant chemical factors and millions of different cells The reduction of unwanted side effects, especially diseases that emerge through blood such as HIV and hepatitis, has a significant role for modern medicine of transfusion and transplantation. The issues and costs of human blood collection and storage, direct this procedure towards the use of alternatives blood. Two important research fields of this area were oxygen carriers based on hemoglobin and perfluoro chemicals. While they do not have the same quality as the blood cell products, the oxygen carrier solutions have potential clinical and non-clinical applications. The result showed that these products can reach to the body tissues easier than normal red blood cells, and can control the oxygen directly. The final aim of transfusion is to establish a transfusion system with no side effects, and the fact that oxygen carrier artificial blood has this property. The article attempts to step towards solving some problems of blood transfusion through describing the properties of artificial blood alternatives
    04/2014; 4(2):72-7.
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    • "The presence of cell-free Hb in circulation as result of hemolytic anemias or when Hb is used as oxygen-carrying blood substitutes can present numerous serious complications including an immediate raise in systemic and pulmonary blood pressure due to removal of NO and subsequent tissue-damaging oxidative toxicity [8]. The use of NO donating compounds or nitrite have been advocated as possible countermeasures that can be infused with Hb to control hemodynamic imbalances in anemic patients or in patients exposed to hemoglobin-based oxygen carriers (HBOCs) [9]. NO-induced oxidation of free Hb and possible heme loss motivated the search for safer HBOCs. "
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    ABSTRACT: We examined carbon monoxide (CO) delivery by carbon monoxide-releasing molecule 2 (CORM-2) or hemoglobin (Hb) on cellular oxygen sensing and mitochondrial respiration in bovine aortic endothelial cells (BAECs). CORM-2 reduced hypoxia-inducible factor-1α (HIF-1α) and endothelin-1 (ET-1) expression in normoxic and hypoxic cells, but while Hb alone significantly reduced HIF-1α stabilization in hypoxic cells, CO delivered by Hb (Hb-CO) had no effect on HIF-1α stabilization. CO dose-dependently increased basal oxygen consumption and reduced overall mitochondrial respiratory capacity. Hb-CO increased basal oxygen consumption but did not alter respiratory capacity. Together, CO reduced ET-1, and, at low doses, had no effect on endothelial mitochondria oxygen consumption. CO ligation to Hb may be developed further as non-vasoactive oxygen therapeutic without compromising mitochondrial function.
    FEBS Open Bio 05/2012; 2:113-8. DOI:10.1016/j.fob.2012.05.003 · 1.52 Impact Factor
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    • "An evolutionary advantage was gained by encapsulating the RH in erythrocytes or myocytes which contain a collection of enzymes responsible for reducing any ferric heme formed back to its ferrous state [20], [21]. After multiple trials, the tendency of cell-free hemoglobin to undergo undesired oxidations has so far impeded efforts to use stabilized hemoglobin solutions as blood substitutes [22]. It is important to note that peroxides can also function as reducing agents [23]. "
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    ABSTRACT: The physiological role of the respiratory hemoproteins (RH), hemoglobin and myoglobin, is to deliver O(2) via its binding to their ferrous (Fe(II)) heme-iron. Under variety of pathological conditions RH proteins leak to blood plasma and oxidized to ferric (Fe(III), met) forms becoming the source of oxidative vascular damage. However, recent studies have indicated that both metRH and peroxides induce Heme Oxygenase (HO) enzyme producing carbon monoxide (CO). The gas has an extremely high affinity for the ferrous heme-iron and is known to reduce ferric hemoproteins in the presence of suitable electron donors. We hypothesized that under in vivo plasma conditions, peroxides at low concentration can assist the reduction of metRH in presence of CO. The effect of CO on interaction of metRH with hydrophilic or hydrophobic peroxides was analyzed by following Soret and visible light absorption changes in reaction mixtures. It was found that under anaerobic conditions and low concentrations of RH and peroxides mimicking plasma conditions, peroxides served as electron donors and RH were reduced to their ferrous carboxy forms. The reaction rates were dependent on CO as well as peroxide concentrations. These results demonstrate that oxidative activity of acellular ferric RH and peroxides may be amended by CO turning on the reducing potential of peroxides and facilitating the formation of redox-inactive carboxyRH. Our data suggest the possible role of HO/CO in protection of vascular system from oxidative damage.
    PLoS ONE 03/2012; 7(3):e33039. DOI:10.1371/journal.pone.0033039 · 3.23 Impact Factor
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