Effect of polyethylene glycol conjugated bovine hemoglobin in both top-load and exchange transfusion rat models.
The purpose of this study was to determine the effect of the hemoglobin based oxygen carrier, polyethylene glycol conjugated bovine hemoglobin (PEG-Hb) on the physiology of the rat. This study was divided into the following 3 parts: pharmacokinetics, cardiovascular, and histopathology. Pharmacokinetic studies evaluated the PEG-Hb circulatory life and the resultant effect on urine composition. Telemetric intravascular blood pressure probes monitored the heart rate and mean arterial pressure. Renal arterial blood flow was determined by intraoperative perivascular ultrasound. Tissue histology was evaluated for both time and model dependent responses. The mean circulatory half-life of PEG-Hb was 17.7+/-0.3 h. Proteinuria and hemoglobinuria were greatly reduced with PEG conjugation. PEG-Hb treated rats produced 8.5 times and 49 times less proteinuria and hemoglobinuria, respectively, than unmodified bovine Hb treated animals. The mean arterial pressure (MAP) in PEG-Hb treated rats was insignificantly different from sham controls undergoing a 30% exchange transfusion while dextran caused an initial reduction and bovine Hb produced a prolonged elevation in the MAP. In these same anesthetized rats, PEG-Hb slightly decreased the heart rate while dextran caused an increase and bovine Hb had no effect. In addition, PEG-Hb was able to maintain the renal arterial blood flow while both Ringer's lactate and bovine Hb caused a reduction in the blood flow. Finally, PEG-Hb treated rats showed a dose and time dependent formation of vacuoles within the renal proximal convoluted tubules and splenic macrophages in both top-load and exchange transfusion models, but no other morphological changes. In conclusion, PEG-Hb had a relatively long vascular persistence that did not cause any significant alterations in the urinalysis, cardiovascular function, or tissue histopathology in the rat.
Conover
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Research and Development, Formulations-Toxicology Department, Enzon, Inc., Piscataway, New Jersey 08854-3998, U.S.A.
Linberg
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Gilbert
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Shum
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Shorr
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D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001802:Blood Substitutes; D002417:Cattle; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006454:Hemoglobins / Q000737:chemistry* / Q000493:pharmacokinetics; D006456:Hemoglobinuria / Q000652:urine; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D014677:Pharmaceutical Vehicles / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D013152:Splanchnic Circulation / Q000187:drug effects; D016482:Urinalysis; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
D001802:Blood Substitutes; D006454:Hemoglobins; C109960:PEG-hemoglobin; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols