A phase I study of oxidized raffinose cross-linked human hemoglobin

Carmichael, F. J.; Ali, Arlene; Campbell, Janet A.; Langlois, Susan; Biro, George P.; Willan, Andrew R.; Pierce, Charles H.; Greenburg, A. Gerson

doi:10.1097/00003246-200007000-00017

Cited by 101 publications

(67 citation statements)

References 18 publications

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“…This would include situations of severe vascular hemolysis, such as sickle cell disease, paroxysmal nocturnal hemoglobinuria, severe thalassemias, and hereditary spherocytosis, whereby elevated levels of cell-free Hb overwhelm the normal clearance processes, leading to Hb oxidation, vascular injury, and thrombosis, hallmark features of severe hemolytic syndromes (7)(8)(9)(10). Second, the infusion of hemoglobin blood substitutes, whereby chemically modified or genetically engineered Hb molecules are infused at levels that greatly exceed the body's capacity to neutralize free Hb, results in oxidative injury, vascular dysfunction, and thrombotic events in ischemic patients (11)(12)(13). Third, clinical situations associated with the accumulation of RBCs outside the vessel lumen, including intracerebral hemorrhage, RBC extravasation at sites of venous insufficiency, and RBC accumulation in atherosclerotic plaques, lead to increased oxidative stress and tissue injury (14,40).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly administration of purified recombinant hemoglobin to humans promotes vascular injury and arterial thrombosis, precipitating acute myocardial infarction (11)(12)(13). Some of these vascular effects are related to nitric oxide scavenging by excess plasma hemoglobin, whereas others are linked to cytotoxic, proinflammatory, and pro-oxidant effects of iron-containing hemoglobin and heme (14 -19).…”

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confidence: 99%

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Erythrocyte Hemolysis and Hemoglobin Oxidation Promote Ferric Chloride-induced Vascular Injury

Woollard

Sturgeon

Chin-Dusting

et al. 2009

Journal of Biological Chemistry

106

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The release of redox-active iron and heme into the bloodstream is toxic to the vasculature, contributing to the development of vascular diseases. How iron induces endothelial injury remains ill defined. To investigate this, we developed a novel ex vivo perfusion chamber that enables direct analysis of the effects of FeCl 3 on the vasculature. We demonstrate that FeCl 3 treatment of isolated mouse aorta, perfused with whole blood, was associated with endothelial denudation, collagen exposure, and occlusive thrombus formation. Strikingly exposing vessels to FeCl 3 alone, in the absence of perfused blood, was associated with only minor vascular injury. Whole blood fractionation studies revealed that FeCl 3 -induced vascular injury was red blood cell (erythrocyte)-dependent, requiring erythrocyte hemolysis and hemoglobin oxidation for endothelial denudation. Overall these studies define a unique mechanism of Fe 3؉ -induced vascular injury that has implications for the understanding of FeCl 3 -dependent models of thrombosis and vascular dysfunction associated with severe intravascular hemolysis.Iron and heme-containing moieties are indispensable for the normal transport of oxygen in the blood; however, once released into the bloodstream these molecules are highly toxic to the vasculature because of their pro-oxidative effects on the endothelium (1-3). Humans have therefore evolved sophisticated iron transport and sequestration systems as well as hememetabolizing enzymes to rapidly clear iron and heme from the circulation (4, 5). There is growing evidence that defects in these natural protective mechanisms lead to endothelial dysfunction and vascular disease, and as a consequence, methods that reduce the pro-oxidative effects of iron and heme may have therapeutic benefit (2).Clinical syndromes associated with marked intravascular hemolysis and circulating free hemoglobin, such as sickle cell disease, paroxysmal nocturnal hemoglobinuria, thalassemias, and hereditary spherocytosis, lead to endothelial dysfunction, thrombosis, and vascular disease (5-10). Similarly administration of purified recombinant hemoglobin to humans promotes vascular injury and arterial thrombosis, precipitating acute myocardial infarction (11-13). Some of these vascular effects are related to nitric oxide scavenging by excess plasma hemoglobin, whereas others are linked to cytotoxic, proinflammatory, and pro-oxidant effects of iron-containing hemoglobin and heme (14 -19). Interestingly elevated levels of body iron stores are associated with an increased risk of myocardial infarction, and carriers of the hemochromatosis gene have an increased risk of myocardial infarction and cardiovascular death (20,21). Whether the pro-oxidative effects of iron per se are proatherogenic remains controversial; however, in the context of erythrocyte-dependent release of hemoglobin and heme, redox-active iron is likely to play an important role in promoting vascular dysfunction.The well defined pro-oxidative properties of redox-active iron have been exploited expe...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Erythrocyte Hemolysis and Hemoglobin Oxidation Promote Ferric Chloride-induced Vascular Injury

Woollard

Sturgeon

Chin-Dusting

et al. 2009

Journal of Biological Chemistry

106

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“…The first HBOC consisted of polymeric o-raffinose cross-linked hemoglobin raffimer (Poly OR-Hb) with a heterogeneous MW composition (~ 55% ≤ 128 kDa) and a High P 50 (low oxygen affinity), (High P 50 Poly OR-Hb, P 50 = 70 mmHg). 22 The other two HBOCs consisted of Poly OR-Hb prepared essentially entirely with a MW of > 128 kDa (5-10% ≤ 128 kDa). Two different HBOCs were utilized, one which had a low oxygen affinity (High P 50 > 128 Poly OR-Hb, MW > 128 kDa, P 50 = 70 mmHg) and one which had a high oxygen affinity (Low P 50 > 128 Poly OR-Hb, MW >128 kDa, P 50 = 11 mmHg).…”

Section: Hemoglobin Based Oxygen Carriersmentioning

confidence: 99%

Effect of oxygen affinity and molecular weight of HBOCs on cerebral oxygenation and blood pressure in rats

Hare

Harrington

Liu

et al. 2006

Can J Anesth/J Can Anesth

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Purpose: This study assessed the effect of oxygen affinity and molecular weight (MW) of o-raffinose cross-linked hemoglobin based oxygen carriers (HBOCs) on cerebral oxygen delivery and mean arterial blood pressure (MAP) following hemorrhage and resuscitation in rats.Methods: Isoflurane anesthetized rats (n = 6-7 per group) underwent 30% hemorrhage and resuscitation with an equivalent volume of one of three different HBOCs: 1) High P 50 Poly o-raffinose hemoglobin (Poly OR-Hb, P 50 = 70 mmHg); 2) High P 50 > 128 Poly OR-Hb (MW > 128 kDa, P 50 = 70 mmHg) and 3) Low P 50 > 128 Poly OR-Hb (MW >128 kDa, P 50 = 11 mmHg). Hippocampal cerebral tissue oxygen tension, regional cerebral blood flow (rCBF), MAP, total hemoglobin concentration and arterial blood gases were measured. Data analysis by two-way ANOVA and post hoc Tukey tests determined significance (P < 0.05, mean ± SD). Results:Hippocampal tissue oxygen tension increased in all HBOC groups following resuscitation. The rCBF remained unchanged after HBOC resuscitation in all groups. Following resuscitation, the peak MAP was higher in the High P 50 Poly OR-Hb group (152 ± 13 mmHg) when compared to either the Low or High P 50 large MW, (> 128 kDa) HBOC group (119 ± 15 mmHg or 127 ± 18 respectively, P < 0.05 for both).Conclusions: O-raffinose polymerized HBOC, with or without lower MW components, maintained cerebral tissue oxygen delivery following hemorrhage and resuscitation in rats. The higher MW HBOCs showed a decrease in peak MAP, which did not alter oxygen delivery. No significant effect of oxygen affinity on cerebral tissue oxygen tension or blood flow was observed. Objectif : Évaluer l'effet de l'affinité pour l'oxygène et du poids moléculaire (PM) des transporteurs d'oxygène à base d'hémoglobine (TOBH) avec o-raffinose sur l'apport d'oxygène cérébral et la tension artérielle moyenne (TAM) après une hémorragie et une réani-mation chez des rats. Méthode : Des rats anesthésiés à l'isoflurane (n = 6-7 par groupe) ont subi une hémorragie à 30% et une réanimation avec un volume équivalent de l'un des trois différents TOBH suivants : 1) de l'hémoglobine Poly o-raffinose à P 50 élevé (Poly OR-

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“…HBOCs have generally demonstrated promising safety and efficacy in animals, and, in many cases, favorable phase I clinical safety (Przybelski et al, 1996;Carmichael et al, 2000). However, recent well publicized late-phase clinical trial failures with certain HBOCs suggest that preclinical animal testing may not have been sufficiently predictive of safety in humans (Sloan et al, 1999;Kim and Greenburg, 2004).…”

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Effects of Endogenous Ascorbate on Oxidation, Oxygenation, and Toxicokinetics of Cell-Free Modified Hemoglobin after Exchange Transfusion in Rat and Guinea Pig

Buehler¹,

D’Agnillo²,

Hoffman³

et al. 2007

J Pharmacol Exp Ther

116

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Chemically modified hemoglobin (Hb) solutions are promising oxygen therapeutics; however, these agents are prone to intravascular oxidation. Using a 50% exchange transfusion (ET) model with bovine polymerized hemoglobin (PolyHbBv), we examined heme oxidation, oxygenation markers, and toxicokinetics in rats, an ascorbic acid (AA)-producing species, and in guinea pigs, a non-AA-producing species. Plasma AA decreased by 50% in guinea pigs after ET, but it was unchanged in rats for the first 20 h post-ET. Both species cleared PolyHbBv from the circulation at similar rates. However, exposure to ferric PolyHbBv over time was 5-fold greater in the guinea pig. Mass spectrometry analysis of plasma revealed oxidative modifications within the tetrameric fraction of PolyHbBv in guinea pig. Oxygen equilibrium curves of PolyHbBv measured in plasma after ET were more left-shifted in guinea pigs compared with rats, consistent with increased ferric PolyHbBv formation. Renal hypoxia-inducible factor (HIF)-1␣, whose activity strictly depends on the partial pressure of oxygen increased over time, and it correlated inversely with circulating ferrous PolyHbBv in both species. Interestingly, HIF-1␣ activity was greater in guinea pigs compared with rats at 72 h post-ET. Mean arterial pressure increases were also greater in guinea pigs; however, minimal differences in cardiac and renal pathology were observed in either species. The present findings suggest the importance of plasma AA in maintaining the stability of acellular Hb susceptible to oxidation, and they may be relevant to humans, which display a similar plasma/tissue antioxidant status to guinea pig.Hemoglobin (Hb)-based oxygen carriers (HBOCs) represent a class of complex biological entities being developed as oxygen-bridging agents with volume-expanding properties. Despite their therapeutic promise, HBOCs demonstrate a significant potential for toxicity based on administration of large quantities of Hb into the plasma compartment. Normally Hb remains protected in the red blood cell, where processes exist to reduce oxidized Hb and to modulate nitric oxide (NO) binding. It has become increasingly evident that Hb oxidative toxicity can limit the safety and efficacy of current generation HBOCs (Alayash, 2004). This prompted the design of new strategies aimed at reducing or controlling Hb-oxidative side reactions. In vivo oxidation of cell-free Hb is driven spontaneously and/or chemically by variety of oxidants, including hydrogen peroxide (H 2 O 2 ) and NO. NOinduced oxidation of heme iron has the added complication of producing an immediate elevation in blood pressure as a result of removal of NO (a vasodilator) by Hb. Thus, two primary safety concerns with HBOCs in the extracellular space include hypertension and oxidative stress (Riess, 2001;Alayash, 2004). The latter effect depends on plasma and tissue reductive capacity to maintain the HBOC in a reduced and functional state.HBOCs have generally demonstrated promising safety and efficacy in animals, and, in many cases...

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A phase I study of oxidized raffinose cross-linked human hemoglobin

Abstract: Oxidized-raffinose cross-linked hemoglobin, Hemolink, at doses < or =0.6 g/kg were well tolerated in healthy volunteers with no evidence of organ dysfunction. Further investigation of its potential use in surgical and trauma settings appears warranted.

Cited by 101 publications

References 18 publications

Erythrocyte Hemolysis and Hemoglobin Oxidation Promote Ferric Chloride-induced Vascular Injury

Erythrocyte Hemolysis and Hemoglobin Oxidation Promote Ferric Chloride-induced Vascular Injury

Effect of oxygen affinity and molecular weight of HBOCs on cerebral oxygenation and blood pressure in rats

Effects of Endogenous Ascorbate on Oxidation, Oxygenation, and Toxicokinetics of Cell-Free Modified Hemoglobin after Exchange Transfusion in Rat and Guinea Pig

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