Phase I study of the safety and pharmacologic effects of diaspirin cross-linked hemoglobin solution

Przybelski, Robert J.; Daily, Elaine K.; Kisicki, James C.; Mattia-Goldberg, Cynthia; Bounds, Marilyn J.; Colburn, Wayne A.

doi:10.1097/00003246-199612000-00011

Cited by 134 publications

(68 citation statements)

References 12 publications

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“…The administration of the blood substitute solutions in preclinical and clinical trials led to pulmonary and systemic hypertension, increased systemic vascular resistance, decreased organ perfusion, gastrointestinal spasm and dysmotility, and death (7,(36)(37)(38)(39)(40)(41)(42)(43). While studies of new generation Hb-based blood substitutes with heme pocket mutations designed to decrease the heme reactivity with NO have shown reduced vasopressor…”

Section: Figurementioning

confidence: 99%

Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin

Minneci¹

2005

Journal of Clinical Investigation

287

240

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During intravascular hemolysis in human disease, vasomotor tone and organ perfusion may be impaired by the increased reactivity of cell-free plasma hemoglobin (Hb) with NO. We experimentally produced acute intravascular hemolysis in a canine model in order to test the hypothesis that low levels of decompartmentalized or cell-free plasma Hb will severely reduce NO bioavailability and produce vasomotor instability. Importantly, in this model the total intravascular Hb level is unchanged; only the compartmentalization of Hb within the erythrocyte membrane is disrupted. Using a full-factorial design, we demonstrate that free waterinduced intravascular hemolysis produces dose-dependent systemic vasoconstriction and impairs renal function. We find that these physiologic changes are secondary to the stoichiometric oxidation of endogenous NO by cell-free plasma oxyhemoglobin. In this model, 80 ppm of inhaled NO gas oxidized 85-90% of plasma oxyhemoglobin to methemoglobin, thereby inhibiting endogenous NO scavenging by cell-free Hb. As a result, the vasoconstriction caused by acute hemolysis was attenuated and the responsiveness to systemically infused NO donors was restored. These observations confirm that the acute toxicity of intravascular hemolysis occurs secondarily to the accelerated dioxygenation reaction of plasma oxyhemoglobin with endothelium-derived NO to form bioinactive nitrate. These biochemical and physiological studies demonstrate a major role for the intact erythrocyte in NO homeostasis and provide mechanistic support for the existence of a human syndrome of hemolysis-associated NO dysregulation, which may contribute to the vasculopathy of hereditary, acquired, and iatrogenic hemolytic states. Introduction NO is continuously synthesized from endothelium and regulates homeostatic vascular functions such as vasodilation, inhibition of platelet activation and thrombosis, inhibition of endothelial adhesion molecule and endothelin-1 expression, and modulation of intimal and smooth muscle proliferation (1-5). A paradox and controversy in vascular biology surrounds the near diffusion-limited dioxygenation reaction of NO with oxyhemoglobin that oxidizes NO to nitrate, an inactive metabolite (Reaction 1).

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Section: Figurementioning

confidence: 99%

Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin

Minneci¹

2005

Journal of Clinical Investigation

287

240

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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).…”

mentioning

confidence: 99%

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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“…The oxygen-carrying property of hemoglobin has prompted its use as an alternative to red blood cells in transfusion medicine (9,31,38,40,46). The structure of hemoglobin is modified through various methods of chemical cross-linking to prevent dissociation of the tetramer into dimers for renal disposal, thereby prolonging the circulation time (31,38,46).…”

mentioning

confidence: 99%

“…The structure of hemoglobin is modified through various methods of chemical cross-linking to prevent dissociation of the tetramer into dimers for renal disposal, thereby prolonging the circulation time (31,38,46). These species are termed hemoglobin-based oxygen carriers.…”

mentioning

confidence: 99%

Binding of acellular, native and cross-linked human hemoglobins to haptoglobin: enhanced distribution and clearance in the rat

Ship

Toprak

Lai

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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Phase I study of the safety and pharmacologic effects of diaspirin cross-linked hemoglobin solution

Cited by 134 publications

References 12 publications

Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin

Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin

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

Binding of acellular, native and cross-linked human hemoglobins to haptoglobin: enhanced distribution and clearance in the rat

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