Physiological effect of polyethylene glycol conjugation on stroma-free bovine hemoglobin in the conscious dog after partial exchange transfusion.
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 (PEG-Hb) 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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Formulations-Toxicology Department, Enzon Inc., Piscataway, New Jersey 08854-3998, USA.
Lejeune
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Shum
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Gilbert
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Shorr
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D000704:Analysis of Variance; D000818:Animals; D001774:Blood Chemical Analysis; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D003911:Dextrans / Q000378:metabolism; D004285:Dogs; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D006456:Hemoglobinuria / Q000652:urine; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D014677:Pharmaceutical Vehicles / Q000378:metabolism* / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000378:metabolism* / Q000493:pharmacokinetics
D003911:Dextrans; D006454:Hemoglobins; C109960:PEG-hemoglobin; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols