In vivo evaluation of a pyridoxylated-hemoglobin-polyoxyethylene conjugate.
A pyridoxylated-hemoglobin-polyoxyethylene conjugate (PHP) was developed from outdated human red cell hemoglobin through chemical modifications. The PHP has a mean molecular weight of approximately 90,000 daltons, with an acceptable P50 of 22 +/- 0.7 mmHg. This report describes exchange transfusion studies (ET) to a final hematocrit of 5 +/- 2% (n = 5) with PHP in mongrel dogs. Hespan (a plasma expander) was used as a control (n = 6). All the animals with PHP tolerated the procedure well and have survived more than 8 months to date. Five out of the six dogs receiving Hespan died within a week (p = 0.004). Reduction of hematological and coagulation parameters occurred following the ET and returned to the normal range by 4 weeks post ET. Serum electrolytes and renal function parameters (urea, creatinine) remained in the normal range. A transient slight increase in the hepatic enzyme SGOT was observed. At 2 weeks post ET open biopsies of major organs showed vacuolized cells in the liver and kidneys. Normal histology was noted at 3 months. The oxygen transporting properties examined showed effective oxygen delivery to the tissues for 6 hours post ET. PHP continued to transport oxygen for up to 48 hours studied post ET. Half-life of PHP in the circulation was 36.3 +/- 3.5 hours. Urinary loss of hemoglobin measured up to 48 hours after ET was 9.4 +/- 1.6% of the injected net hemoglobin. The PHP effectively supported life at lethal levels of anemia and is a physiologically acceptable solution. It has a relatively long intravascular residence time and transports oxygen to the tissue effectively for at least 6 hours.
Matsushita
M
M
Department of Artificial Organs, Cleveland Clinic Foundation, Ohio 44106.
Yabuki
A
A
Malchesky
P S
PS
Harasaki
H
H
Nosé
Y
Y
D000818:Animals; D001692:Biological Transport; D001777:Blood Coagulation / Q000187:drug effects; D001802:Blood Substitutes / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D004573:Electrolytes / Q000097:blood; D004906:Erythrocyte Count; D005078:Exchange Transfusion, Whole Blood; D006207:Half-Life; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008970:Molecular Weight; D010100:Oxygen / Q000097:blood; D011092:Polyethylene Glycols / Q000378:metabolism
D001802:Blood Substitutes; D004573:Electrolytes; D006454:Hemoglobins; C050907:pyridoxalated-hemoglobin-polyethylene glycol conjugate; D011092:Polyethylene Glycols; D010100:Oxygen