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Abdu I. Alayash - One of the best experts on this subject based on the ideXlab platform.
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Ascorbate removes key precursors to oxidative damage by cell-free haemoglobin in vitro and in vivo
The Biochemical journal, 2006Co-Authors: Jacqueline Dunne, Abdu I. Alayash, Michael T. Wilson, Alexis Caron, Patrick Menu, Paul W. Buehler, Radu Silaghi-dumitrescu, Beatrice Faivre, Chris CooperAbstract:Haemoglobin initiates free radical chemistry. In particular, the interactions of peroxides with the ferric (met) species of haemoglobin generate two strong oxidants: ferryl iron and a protein-bound free radical. We have studied the endogenous defences to this reactive chemistry in a rabbit model following 20% exchange transfusion with cell-free haemoglobin stabilized in tetrameric form [via cross-linking with bis-(3,5-dibromosalicyl)fumarate]. The transfusate contained 95% oxyhaemoglobin, 5% methaemoglobin and 25 μM free iron. EPR spectroscopy revealed that the free iron in the transfusate was rendered redox inactive by rapid binding to transferrin. Methaemoglobin was reduced to oxyhaemoglobin by a slower process (t1/2=1 h). No globin-bound free radicals were detected in the plasma. These redox defences could be fully attributed to a novel multifunctional role of plasma ascorbate in removing key precursors of oxidative damage. Ascorbate is able to effectively reduce plasma methaemoglobin, ferryl haemoglobin and globin radicals. The ascorbyl free radicals formed are efficiently re-reduced by the erythrocyte membrane-bound reductase (which itself uses intra-erythrocyte ascorbate as an electron donor). As well as relating to the toxicity of Haemoglobin-Based Oxygen Carriers, these findings have implications for situations where haem proteins exist outside the protective cell environment, e.g. haemolytic anaemias, subarachnoid haemorrhage, rhabdomyolysis.
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Oxygen therapeutics: can we tame haemoglobin?
Nature Reviews Drug Discovery, 2004Co-Authors: Abdu I. AlayashAbstract:The need for blood transfusions in wartime and the emerging threat of infection from blood and blood products have motivated several commercial companies to develop compounds that aim to substitute for the Oxygen-transport function of blood. At present, there are two classes of such 'blood substitutes' under active development: Haemoglobin-Based Oxygen Carriers (HBOCs) and fluorocarbon-based Oxygen Carriers (FBOCs). As the most widely explored approach for the development of blood substitutes has been the adaptation of haemoglobin (Hb), this review focuses on HBOCs. Hb in adult red-blood cells (RBCs) is a tetramer of two α and two β polypeptide chains. An iron-containing haem prosthetic group is buried in a hydrophobic pocket in each chain and is capable of carrying one Oxygen molecule per haem. A variety of HBOCs with chemical or genetic modifications that are intended to stabilize Hb outside its natural environment — red blood cells (RBCs) — in a functional tetrameric and/or polymeric form have been developed. However, because of the initial success in manufacturing, and preclinical and clinical testing in normal healthy volunteers, little attention was paid to the inner working of the Hb molecule, or to the effects of chemical and/or genetic modifications on the integrity and stability of the protein. There have now been several well-publicized setbacks in clinical trials of HBOCs. Hb outside its natural protective environment (that is, RBCs) is toxic owing to the fact that Hb is a redox-active molecule. Central to this activity is the haem group — it undergoes redox transition to higher oxidation states with increasing redox reactivity towards biological molecules, leading to tissue toxicity. Chemical and/or genetic modifications of Hb can suppress or enhance these reactions. So, one can design against these reactions by restricting the haem reactivity with biological molecules. Exploring endogenous protective mechanisms and/or inclusion of antioxidants in Hb solutions might also provide some protection against Hb oxidative toxicities. Chemically modified or genetically engineered haemoglobins (Hbs) developed as Oxygen therapeutics (often termed 'blood substitutes') are designed to correct Oxygen deficit due to ischaemia in a variety of clinical settings. These modifications are intended to stabilize Hb outside its natural environment — red blood cells — in a functional tetrameric and/or polymeric form. Uncontrolled haem-mediated oxidative reactions of cell-free Hb and its reactions with various oxidant/antioxidant and cell signalling systems have emerged as an important pathway of toxicity. Current protective strategies designed to produce safe Hb-based products are focused on controlling or suppressing the 'radical' nature of Hb while retaining its Oxygen-carrying function.
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Measurement of blood volume after haemodilution with Haemoglobin-Based Oxygen Carriers by a radiolabelled-albumin method.
Transfusion medicine (Oxford England), 2001Co-Authors: Alexis Caron, Abdu I. Alayash, J.-c. Mayer, P. Menu, P.-y. Marie, Céline VigneronAbstract:Recent studies have shown that the use of Haemoglobin-Based Oxygen-carrying solutions (HBOCs) for perioperative haemodilution could significantly reduce the need for packed red blood cells in clinical practice. Though the effects of HBOCs on plasma volume have been characterized in experimental models of volume resuscitation from hypovolaemic shock, little is known about their action in normovolaemic haemodilution conditions. We therefore applied a radiolabelled serumalbumin method to determine blood volume after haemodilution with crosslinked or conjugated haemoglobin, in comparison with a reference solution of hydroxyethyl starch (HES). Three groups of New Zealand white rabbits were studied (n = 7 each group) subjected to moderate exchange transfusion with low molecular weight HES, bis(3,5-dibromosalicyl)fumarate crosslinked haemoglobin (alphaalpha-Hb), or dextran-conjugated haemoglobin (Hb-Dex-BTC). HES induced no changes in heart rate and blood pressure. The amplitude and duration of blood pressure increase and bradycardia were similar in both haemoglobin groups. A significant contraction of blood volume (12%) was observed 60 min after haemodilution with alphaalpha-Hb, compared to HES and Hb-Dex-BTC. At the same time point, a decrease in absolute haemoglobin (plasma haemoglobin x plasma volume) was also noted. This study suggests that in haemodilution conditions, the specific oncotic properties and circulating persistence of crosslinked and conjugated haemoglobin solutions affect the pattern of blood volume distribution differently.
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Reactions of cross-linked methaemoglobins with hydrogen peroxide.
Advances in experimental medicine and biology, 1999Co-Authors: Jackie Dunne, Dimitri A. Svistunenko, Abdu I. Alayash, Michael T. Wilson, Chris CooperAbstract:The development of haemoglobin based Oxygen Carriers is intended to avoid the problems which can arise from the use of blood. Blood can only be stored for a short period of time and blood groups must be matched prior to use. In addition, the risk of the transfer of infectious agents such as viruses has become a major factor in the development of cell free haemoglobin solutions.
Kim D Vandegriff - One of the best experts on this subject based on the ideXlab platform.
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Haemoglobin-Based Oxygen Carriers.
Expert opinion on investigational drugs, 2000Co-Authors: Kim D VandegriffAbstract:Haemoglobin-Based Oxygen Carriers are being developed for use in blood replacement therapies, either for perioperative haemodilution or for resuscitation from haemorrhagic blood loss. There is a high demand for these products because of risks associated with blood transfusions and pending worldwide blood shortages. Development of these products has required new technologies in protein engineering; since the haemoglobin is cell-free in solution, the molecule must be modified to be retained within blood circulation. Three classes of haemoglobin are under development: intramolecular cross-linked, intermolecular polymerised and surface conjugated with polyethylene glycol. Two products based on cross-linking chemistry have been discontinued because of serious adverse events and/or increased mortality rate in Phase III clinical trials. Three products based on polymerisation chemistry are in ongoing Phase III clinical trials. A new product based on surface conjugation is in preclinical evaluation. Although cross-linked and polymerised products have shown to be safe in preclinical and early Phase I/II clinical trials, they have had difficulty in proving efficacy. The primary adverse effect for the majority of cross-linked or polymerised products is a haemodynamic response, leading to increased vascular resistance to blood flow. The physiological mechanisms are still incompletely understood, so that safety and efficacy cannot be completely dissociated. New understandings on the mode of action of these products will help to define their utility and application. New products are under development, designed specifically to maximise blood flow and tissue perfusion and therefore, Oxygenation.
Bruno Faivre - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological and physicochemical factors in the pressor effects of conjugated Haemoglobin-Based Oxygen Carriers in vivo.
Journal of Hypertension, 2007Co-Authors: Younes Smani, Alexandre Fifre, Pierre Labrude, Céline Vigneron, Bruno FaivreAbstract:Background The hypertension induced by Haemoglobin-Based Oxygen Carriers could be a result of different pharmacological and physicochemical factors. Objective To investigate whether production of superoxide anion (O 2 ·- ) and release of endothelin could be the factors responsible. Methods We studied the variation in mean arterial pressure (MAP) in guinea pigs by carrying out a 50% isovolaemic exchange transfusion with conjugated oxyhaemoglobin (non-oxidized form) or conjugated methaemoglobin (fully oxidized form) in the presence or absence of BQ-788 (5 nmol/l), an endothelin receptor type B (ETR-B) antagonist. At key timepoints of variation in MAP, the plasma concentrations of O 2 ·- were measured. The presence of conjugated oxyhaemoglobin and increases in ETR-B concentrations inside the vascular wall were investigated in different vessels, using western blotting. Results We found that the administration of conjugated oxyhaemoglobin induced a significant increase in MAP, whereas conjugated methaemoglobin had no significant haemodynamic effect. Pretreatment with BQ-788 attenuated the increase in MAP induced by conjugated oxyhaemoglobin. This haemoglobin induced the production of high concentrations of O 2 ·- that declined towards control values after 120 min and decreased in the presence of BQ-788. Western blot analysis showed that the presence of conjugated oxyhaemoglobin inside the vascular wall was time-dependent and correlated with increased ETR-B. Conclusion These results show that the release of O 2 ·- during auto-oxidation of conjugated oxyhaemoglobin is associated with the observed increase in MAP, which may be a result of the vasoconstriction caused by an increase in activation of ETR-B. This activation may be caused by the massive release of endothelin induced by the production of O 2 ·-.
Jerrold H. Levy - One of the best experts on this subject based on the ideXlab platform.
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The use of haemoglobin glutamer-250 (HBOC-201) as an Oxygen bridge in patients with acute anaemia associated with surgical blood loss.
Expert opinion on biological therapy, 2003Co-Authors: Jerrold H. LevyAbstract:For the treatment of substantial blood loss in surgery, allogeneic blood is transfused to maintain stability and organ perfusion and function. Continued concerns about the availability, safety, efficacy and storage-related problems of allogeneic blood products have led to an intense effort to find alternatives that can serve the same physiologic functions. Haemoglobin-Based Oxygen Carriers (HBOCs) are compounds that can match the Oxygen-carrying capacity of red blood cells (RBCs), and several HBOCs have reached advanced stages of development and clinical testing. Multi-centre, randomised, Phase III, controlled trials have demonstrated the safety and efficacy of haemoglobin glutamer-250 (bovine) (Hemopure), Biopure Corporation, Cambridge, MA, USA), also known as HBOC-201. HBOC-201 is bovine-derived, modified haemoglobin that has been ultrapurified to remove any plasma proteins, RBC stroma and potential pathogenic material. During the manufacturing process, crosslinking and polymerisation stabilise the haemoglobin molecule, which increases its vascular persistence as well as the efficiency of Oxygen transport to tissue. Results from clinical trials indicate that HBOC-201 can be used as an Oxygen 'bridge' for patients experiencing anaemia due to surgical blood loss, until their own red blood cells are replenished or have regenerated (haematinic effect). HBOC-201 is generally well-tolerated and is approved for use in South Africa, where it is indicated for use in adult surgical patients who are acutely anaemic, and is used to eliminate, delay or reduce the need for allogeneic RBCs. A Biologics License Application for HBOC-201 is currently under review by the US FDA.
John Freedman - One of the best experts on this subject based on the ideXlab platform.
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Hemolink, an o-raffinose cross-linked Haemoglobin-Based Oxygen carrier, does not affect activation and function of human platelets in whole blood in vitro.
British journal of haematology, 2003Co-Authors: Valery Leytin, David Mazer, Meera Mody, Bernadette Garvey, John FreedmanAbstract:Summary. Haemoglobin-Based Oxygen Carriers (HBOCs) are anticipated to be safe and efficient alternatives to RBC transfusions. Haemoglobin (Hb) raffimer (Hemolink™; Hemosol, Toronto, ON, Canada) is polymerized human Hb, cross-linked with o-raffinose. As administration of cell-free Hb may affect blood cells and tissues, this study was focused on evaluating effects of Hb raffimer on human platelets in whole blood in vitro. Citrated blood from healthy donors was incubated with Hb raffimer to achieve raffimer concentrations of 2–50 vol percentage (2–50 g/l). Platelet activation, phosphatidylserine exposure and microparticle generation were measured by flow cytometry. Aperture closure time on collagen/ADP- and collagen/epinephrine-coated membranes was determined by a platelet function analyser (PFA-100®). We found that addition of Hb raffimer to blood samples up to 50 vol % did not affect human platelets as measured by various markers of platelet activation (CD42b, CD41, PAC-1, CD62, CD63), procoagulant activity (annexin V) and microparticle formation; differences between Hb raffimer- and lactated Ringer's-diluted blood were not significant. Similarly, no adverse effect of Hb raffimer on closure time was observed at concentrations up to 50 vol %, in comparison with Ringer's solution. These data indicate that exposure of human blood to high concentrations of Hb raffimer in vitro did not cause platelet activation nor affect platelet function.