A Multicenter Clinical Study of the Safety and Activity of Maleimide-Polyethylene Glycol–modified Hemoglobin (Hemospan®) in Patients Undergoing Major Orthopedic Surgery

Olofsson, Christina; Ahl, Torbjörn; Johansson, Torsten; Larsson, Sune; Nellgård, Per; Ponzer, Sari; Fagrell, B; Przybelski, Robert J.; Keipert, Peter; Winslow, Nancy; Winslow, Robert M.

doi:10.1097/00000542-200612000-00015

Cited by 89 publications

(65 citation statements)

References 22 publications

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“…The half-life of the PEG-Hb moiety is approximately 20 hours in rats and humans. 27 Comparison of MP4CO and MP4OX in both the NY1DD and the HbAS mice allows clear distinction of CO gas from the solution properties of PEG-Hb, which includes effects on plasma volume and peripheral perfusion demonstrated previously with MP4OX. 28 The bioavailability of CO from MP4CO is demonstrated in the current study by the elevated concentration of CO in expired air from sickle mice treated with MP4CO, but not with MP4OX.…”

Section: Discussionmentioning

confidence: 92%

MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice

Belcher

Young²,

Chen

et al. 2013

Blood

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• Carbon monoxide treatment of murine sickle mice can ameliorate inflammation and vaso-occlusion.• MP4CO induces heme oxygenase-1 and Nrf2 to mediate these salutatory effects.Transgenic sickle mice expressing b S hemoglobin have activated vascular endothelium in multiple organs that exhibits enhanced expression of NF-ĸB and adhesion molecules and promotes microvascular stasis in sickle, but not normal, mice in response to hypoxia/reoxygenation (H/R), or heme. Induction of heme oxygenase-1 (HO-1) or administration of its products, carbon monoxide (CO) or biliverdin, inhibits microvascular stasis in sickle mice. Infusion of human hemoglobin conjugated with polyethylene glycol and saturated with CO (MP4CO) markedly induced hepatic HO-1 activity and inhibited NF-ĸB activation and H/R-induced microvascular stasis in sickle mice. These effects were mediated by CO; saline or MP4 saturated with O 2 (MP4OX) had little to no effect on H/R-induced stasis, though unmodified oxyhemoglobin exacerbated stasis. The HO-1 inhibitor, tin protoporphyrin, blocked MP4CO protection, consistent with HO-1 involvement in the protection afforded by MP4CO. MP4CO also induced nuclear factorerythroid 2 p45-related factor 2 (Nrf2), an important transcriptional regulator of HO-1 and other antioxidant genes. In a heterozygous (hemoglobin-AS) sickle mouse model, intravenous hemin induced cardiovascular collapse and mortality within 120 minutes, which was significantly reduced by MP4CO, but not MP4OX. These data demonstrate that MP4CO induces cytoprotective Nrf2 and HO-1 and decreases NF-ĸB activation, microvascular stasis, and mortality in transgenic sickle mouse models. (Blood. 2013; 122(15):2757-2764 IntroductionHeme oxygenase-1 (HO-1) is a cytoprotective enzyme that degrades free heme to carbon monoxide (CO), biliverdin, and iron. Induction of HO-1 activity elicits protective effects in a variety of models of inflammatory, ischemic, and oxidant injury, 1,2 and conversely, humans or mice lacking HO-1 are sensitized to oxidant injury. 3,4 In transgenic sickle mice, HO-1 plays a vital role in the inhibition of endothelial activation, rolling and adhesion of leukocytes to the vessel wall and vaso-occlusion. 5 The cytoprotective properties of HO-1 are mimicked by the products of the heme/HO-1 reaction, CO and biliverdin. 5 CO is a potent mediator of cell protection and has a number of properties that make it an attractive therapeutic option for treating sickle cell disease (SCD) including vasodilator, anti-inflammatory, left-shift of the hemoglobin (Hb)-oxygen dissociation curve, upregulation of HO-1, and activation of cytoprotective cell signaling pathways. 6,7 Beneficial effects of exogenous CO administration have been observed in SCD 5,6 because CO may prevent HbS polymerization, 8 Hb oxidation, and heme release 9 and provide antiinflammatory/antiadhesive actions. 5 Additionally, CO induces HO-1 expression indirectly by its action on the stress-induced, antioxidant response element transcription factor nuclear factor-erythroid 2 p45-re...

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Section: Discussionmentioning

confidence: 92%

MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice

Belcher

Young²,

Chen

et al. 2013

Blood

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“…A recent phase II multicenter randomized prospective safety study on 90 elderly patients undergoing elective hip arthroplasty has confirmed these observations. MP4 had no serious adverse effects; the mild elevation of amylase, lipase and liver enzyme was not statistically significant but there were a trend to more bradycardia events in the MP4 group [119]. However, there is no information about preoperative medical treatment, particularly β-blockers.…”

Section: Hemospan)mentioning

confidence: 93%

Haemoglobin, oxygen carriers and perioperative organ perfusion

Kocián¹,

Spahn²

2008

Best Practice & Research Clinical Anaesthesiology

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“…1) formed by linking one Hb molecule to soluble polymers. A maleimidepolyethylene glycol conjugated Hb was developed for clinical trial (Olofsson et al 2006;Winslow 2006).…”

Section: First-generation Oxygen Carriersmentioning

confidence: 99%

Nanobiotechnology-based Blood Substitutes and the Cardiovascular Systems in Transfusion Medicine

Hunter¹,

Preedy²

2011

Nanomedicine and the Cardiovascular System

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Red blood cell membrane contains blood group antigens, and typing and matching are needed before donor blood can be transfused into patients. This results in delays in emergency situations. Donor blood requires storage at 4ºC using standard methods and is good for less than 42 d. Red blood cells cannot be sterilized to remove hepatitis viruses, HIV and other potential emerging infective agents. There is also a shortage of donor blood especially in emergencies, war or disasters. Nanobiotechnology has allowed the development of different types of red blood cell substitutes. The fi rst-generation type is a simple modifi ed hemoglobin oxygen carrier that has immediate potential for clinical uses. In particular, such substitutes do not have blood group antigens and can be

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A Multicenter Clinical Study of the Safety and Activity of Maleimide-Polyethylene Glycol–modified Hemoglobin (Hemospan®) in Patients Undergoing Major Orthopedic Surgery

Abstract: In comparison with Ringer's acetate, Hemospan mildly elevates hepatic enzymes and lipase and is associated with less hypotension and more bradycardic events. The absence of a high frequency of serious adverse events suggests that further clinical trials should be undertaken.

Cited by 89 publications

References 22 publications

MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice

MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice

Haemoglobin, oxygen carriers and perioperative organ perfusion

Nanobiotechnology-based Blood Substitutes and the Cardiovascular Systems in Transfusion Medicine

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