Effect of Polyethylene Glycol Conjugated Bovine Hemoglobin in Both Top‐Load and Exchange Transfusion Rat Models

Conover, Charles D.; Linberg, Rita; Gilbert, Carl W.; Shum, Kwok; Shorr, Robert G. L.

doi:10.1111/j.1525-1594.1997.tb00444.x

Cited by 33 publications

(13 citation statements)

References 34 publications

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“…So, it's reasonable that transfusion of PEG-bHb (about 100 kD) led to upregulate lysosome numbers in cytoplasm of liver and kidney as observed. The vacuolar changes were reversible, as proved by Conover et al [16], and confirmed by another research work on dogs in our lab.…”

Section: Discussionsupporting

confidence: 81%

Polyethylene Glycol Conjugated Bovine Hemoglobin Containing 15% MetHb Plays Approving Effect in Exchange Transfusion Rabbit Model

He¹,

Guan²,

Zhang³

et al. 2007

Artificial Cells, Blood Substitutes, and Biotechnology

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PEG-bHb was developed by Kaizheng Biotech (Beijing, China), and pre-clinical research was completed. The objective of this study was to investigate the safe concentration of MetHb in PEG-bHb. The study was accomplished by examining the effects of PEG-bHb containing 5%, 8%, 15%, and 25% methemoglobin (MetHb), respectively, on cardiovascular system, blood chemistry, pathology of liver and kidney in rabbits following a 50% exchange transfusion. The results showed that PEG-bHb containing 5%, 8%, 15%, and 25% MetHb could keep four groups of experimental rabbits (5/5) alive until the 8th day after 50% exchange infusion as autologous whole blood did, and were superior to dextran 40 (2/5). MetHb concentration in PEG-bHb, no more than 25%, did not affect the PEG-bHb function on resuscitation of hemorrhaged rabbits by physiological measurements and blood chemistry assays. Histology study using optic and electron microscopy showed that there were slight pathological changes in hepatocytes and renal tubule epithelia in rabbits, which were infused by PEG-bHb containing 5%, 8%, and 15% MetHb. Partial organelles collapse was observed in rabbits resuscitated by PEG-bHb containing 25% MetHb. In conclusion, PEG-bHb is safe and effective when the MetHb concentration is at or below 15%.

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Section: Discussionsupporting

confidence: 81%

Polyethylene Glycol Conjugated Bovine Hemoglobin Containing 15% MetHb Plays Approving Effect in Exchange Transfusion Rabbit Model

He¹,

Guan²,

Zhang³

et al. 2007

Artificial Cells, Blood Substitutes, and Biotechnology

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“…PEG-Hb™ has been previously reported to be safe and effective in a number of animal species models [59,60,61,62]. Changes in the plasma concentration of PEG-Hb™ after a top-load infusion (25 mL/kg) was examined in rats and rabbits, and the findings showed that the mean half-life was approximately 17 h and 43 h in rats and rabbits, respectively [61,63]. In addition, PEG-Hb™ was shown to have a half-life of 15 h and 58 h in rat and dog models of 30% blood volume exchange transfusion [62,64].…”

Section: Acellular Type Hbocsmentioning

confidence: 99%

“…Furthermore, PEG-Hb™ showed a longer half-life than native Hb in a canine hemorrhagic shock model [65] These long half-lives, as summarized in Table 3, indicate that PEG modification can prevent excretion via glomerular filtration due to the increase in overall molecular weight. In fact, less hemoglobinuria were observed in animals that had been injected with PEG-Hb™ than those injected with native Hb [61,63]. Although PEG-Hb™ had earlier proceeded to Phase Ib, its development for clinical use was stopped more than 20 years ago [3].…”

Section: Acellular Type Hbocsmentioning

confidence: 99%

Comparison of the Pharmacokinetic Properties of Hemoglobin-Based Oxygen Carriers

Taguchi

Yamasaki

Maruyama

et al. 2017

JFB

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Hemoglobin (Hb) is an ideal material for use in the development of an oxygen carrier in view of its innate biological properties. However, the vascular retention of free Hb is too short to permit a full therapeutic effect because Hb is rapidly cleared from the kidney via glomerular filtration or from the liver via the haptogloblin-CD 163 pathway when free Hb is administered in the blood circulation. Attempts have been made to develop alternate acellular and cellular types of Hb based oxygen carriers (HBOCs), in which Hb is processed via various routes in order to regulate its pharmacokinetic properties. These HBOCs have been demonstrated to have superior pharmacokinetic properties including a longer half-life than the Hb molecule in preclinical and clinical trials. The present review summarizes and compares the pharmacokinetic properties of acellular and cellular type HBOCs that have been developed through different approaches, such as polymerization, PEGylation, cross-linking, and encapsulation.

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“…In addition, the various studies investigating this issue have reported some contradictory findings. In the case of bHb, while tests in a rat model showed that PEG-bHb but not unmodified bHb induced formation of vacuoles in the renal proximal convoluted tubules and splenic macrophages [10], another study conducted in a rabbit model showed the opposite result in the hepatocyte cytoplasm [9]. The same agents when tested in dogs all displayed renal tubular vacuole formation [7].…”

Section: Introductionmentioning

confidence: 99%

“…Vacuolation caused by high dosages of PEG-TNFbp was only partially reversible. Interestingly, when PEG was tested alone in two of these studies, it did not show any sign of vacuolation [8,10]. Thus, the currently available information is not sufficient to conclude whether there is indeed a cause-and-effect relationship between PEGylation and vacuolation.…”

Section: Introductionmentioning

confidence: 99%

Protein–polymer conjugation — moving beyond PEGylation

Chilkoti

2015

Current Opinion in Chemical Biology

156

120

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In this review, we summarize —from a materials science perspective— the current state of the field of polymer conjugates of peptide and protein drugs, with a focus on polymers that have been developed as alternatives to the current gold standard, poly(ethylene glycol) (PEG). PEGylation, or the covalent conjugation of PEG to biological therapeutics to improve their therapeutic efficacy by increasing their circulation half-lives and stability, has been the gold standard in the pharmaceutical industry for several decades. After years of research and development, the limitations of PEG, specifically its non-degradability and immunogenicity have become increasingly apparent. While PEG is still currently the best polymer available with the longest clinical track record, extensive research is underway to develop alternative materials in an effort to address these limitations of PEG. Many of these alternative materials have shown promise, though most of them are still in an early stage of development and their in vivo distribution, mechanism of degradation, route of elimination and immunogenicity have not been investigated to a similar extent as for PEG. Thus, further in-depth in vivo testing is essential to validate whether any of the alternative materials discussed in this review qualify as a replacement for PEG.

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Effect of Polyethylene Glycol Conjugated Bovine Hemoglobin in Both Top‐Load and Exchange Transfusion Rat Models

Cited by 33 publications

References 34 publications

Polyethylene Glycol Conjugated Bovine Hemoglobin Containing 15% MetHb Plays Approving Effect in Exchange Transfusion Rabbit Model

Polyethylene Glycol Conjugated Bovine Hemoglobin Containing 15% MetHb Plays Approving Effect in Exchange Transfusion Rabbit Model

Comparison of the Pharmacokinetic Properties of Hemoglobin-Based Oxygen Carriers

Protein–polymer conjugation — moving beyond PEGylation

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