Hemoglobinuria in Rats: A sensitive Test of Renal Filtering and Absorption of Peg-Hemoglobin, a Red Blood Cell Substitute

Gilbert, Carl W.; Nho, Kwang; Johnson, Marie; Linberg, Rita; Shorr, Robert G. L.

doi:10.3109/10731199409117881

Cited by 8 publications

(3 citation statements)

References 4 publications

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“…PEG-Hb with a molecular weight in excess of 100,000 daltons produces essentially no hemoglobinuria. This was not an isolated or model dependent effect because similar results have been observed in other models (11,44). Lack of detectable Hb in the urine may also be attributable to the reproducible PEGylation process and rigorous fractionation scheme that restricts unmodified Hb from entering the final formulation.…”

Section: Discussionsupporting

confidence: 72%

Physiological Effect of Polyethylene Glycol Conjugation on Stroma‐Free Bovine Hemoglobin in the Conscious Dog After Partial Exchange Transfusion

et al. 1997

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This study was designed to determine the effect of polyethylene glycol (PEG) conjugation on stroma-free bovine hemoglobin. This was accomplished by examining the effects of unmodified stroma-free bovine hemoglobin (bovine Hb), PEG modified bovine hemoglobin (PEGHb) and dextran 70 on heart rate (HR), mean arterial pressure (MAP), gross renal morphology, blood chemistry, and hemoglobinuria development in conscious beagle dogs following a 30% exchange transfusion. Dogs were implanted with telemetric blood pressure probes and after 2 weeks underwent an isovolumic 30% blood volume exchange transfusion. Dogs treated with bovine Hb displayed a significant increase in MAP for 2 h following the exchange transfusion with no effect on HR. These animals exhibited significant levels of hemoglobinuria (>20% of infused dose) within 24 h. Histopathologically, all bovine Hb infused dogs displayed renal tubular vacuolization, with 2 dogs showing regions of tubular casts and tubular cell regeneration. PEG-Hb was shown to have a circulatory half-life of 58.3 * 2.4 h and caused no significant changes in MAP or HR throughout the study period. Dogs excreted less than 0.1% of infused PEG-Hb within 24 h and displayed only renal tubular epithelial cell vacuolization. Dextran 70 caused a slight but insignificant decrease in MAP, elevated the HR, and exhibited only slight renal vacuole formation. Blood chemistry remained essentially stable following exchange transfusion with all the test articles. The conjugation of PEG to hemoglobin greatly increased the parent protein's vascular retention while attenuating some of its less favorable attributes.

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Section: Discussionsupporting

confidence: 72%

Physiological Effect of Polyethylene Glycol Conjugation on Stroma‐Free Bovine Hemoglobin in the Conscious Dog After Partial Exchange Transfusion

et al. 1997

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“…Still, mild hemoglobinuria has been observed after the administration of modifi ed HBOCs to both animals and humans (Keipert and Chang 1983, Lenz et al 1991, Keipert 1992, Keipert et al 1992, Anderson et al 1993, Gilbert et al 1994, Keipert et al 1994, Lee et al 1995, Conover et al 1997, Schubert et al 2002, Wicks et al 2003, Bonegio et al 2006, Olofsson et al 2006, Baek et al 2012. While this hemoglobinuria has been widely attributed to the presence of residual unmodifi ed Hb, intact tetramers were detected in urine as well (Keipert et al 1989b, Urbaitis et al 1991, Keipert et al 1992, Keipert et al 1994.…”

Section: Kidney Excretionmentioning

confidence: 91%

Pharmacokinetics and mechanisms of plasma removal of hemoglobin-based oxygen carriers

Estep¹

2015

Artificial Cells, Nanomedicine, and Biotechnology

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The circulatory persistence, distribution, and metabolism of hemoglobin-based oxygen carriers (HBOCs) is a major determinant of their safety and efficacy. In this communication, published data on the pharmacokinetics and routes of plasma elimination of HBOCs are summarized and evaluated. The circulating half-life of HBOCs is dose-dependent in both animals and humans. Half-life also increases with molecular weight in animals, at least up to the MDa range. The functional half-life of HBOCs is diminished by as much as 40% due to oxidation of the heme group relative to the overall rate of removal of hemoglobin (Hb) from plasma. Kidney excretion of HBOCs is greatly diminished compared to that of unmodified Hb, but the liver remains a primary site of catabolism. Both hepatocytes and Kupffer cells have been implicated in receptor-mediated HBOC uptake. Removal also occurs in the spleen and/or bone marrow and probably at dispersed sites in the endothelium as well. HBOCs extravasate into the lymph at a rate inversely proportional to their molecular weight and are taken up by monocyte/macrophage CD163 receptors, both as free Hb and in complexes with haptoglobin (Hp). The interactions with both Hp and the CD163 receptor are altered by Hb modification. However, monocyte/macrophage uptake may not be a quantitatively important route for the removal of clinically relevant doses of HBOCs. The relative contributions of different removal pathways have yet to be comprehensively determined, particularly in humans.

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“…The P 50 (ability to carry oxygen) was determined using a Hemox-Analyzer (TCS Medical Product Co., Huntington Valley, PA). Finally, the in vivo circulating life of the PEG-Hb was determined in female Sprague-Dawley rats as previously described (16). Plasma bHb/PEG-Hb levels were determined using Sigma Chemical Co. (St. Louis, MO) procedure 527 and reagents.…”

Section: Synthesis Of Compoundmentioning

confidence: 99%

PEG Thiazolidine-2-thione, a Novel Reagent for Facile Protein Modification: Conjugation of Bovine Hemoglobin

et al. 1996

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A novel PEG linker that employs a thiazolidine-2-thione group has been synthesized. Kinetic studies done on this compound demonstrate a relatively long half-life compared to those of traditional succinimidyl linkers. This new PEG derivative reacts with proteins under mild conditions and was utilized to conjugate bovine hemoglobin (bHb) to provide a PEG amide-linked protein. The physical characteristics of this conjugate were compared with those of the known PEG carbamate-linked bHb.

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Hemoglobinuria in Rats: A sensitive Test of Renal Filtering and Absorption of Peg-Hemoglobin, a Red Blood Cell Substitute

Cited by 8 publications

References 4 publications

Physiological Effect of Polyethylene Glycol Conjugation on Stroma‐Free Bovine Hemoglobin in the Conscious Dog After Partial Exchange Transfusion

Physiological Effect of Polyethylene Glycol Conjugation on Stroma‐Free Bovine Hemoglobin in the Conscious Dog After Partial Exchange Transfusion

Pharmacokinetics and mechanisms of plasma removal of hemoglobin-based oxygen carriers

PEG Thiazolidine-2-thione, a Novel Reagent for Facile Protein Modification: Conjugation of Bovine Hemoglobin

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