Synthesis and properties of polymerized, diaspirin cross-linked hemoglobins.
During the course of our studies it became clear that there were therapeutic applications for which a polymeric hemoglobin having an extended half-life in circulation would be appropriate. Therefore, a process for the glutaraldehyde-polymerization of diaspirin cross-linked hemoglobin (DCLHb) was developed and used to prepare glutaraldehyde-polymerized DCLHb (GP-DCLHb) in lactated Ringer's solution in sufficient quantities for biological testing. Both isovolemic exchange-transfusion and "top-load" studies (rats; primates and swine, respectively) were completed in which a broad spectrum of physiologic, histopathologic and analytical parameters were monitored and assessed. In general, GP-DCLHb in lactated Ringer's solution was well-tolerated physiologically. When compared to DCLHb, GP-DCLHb offers the advantages of reduced renal clearance of hemoglobin and an extended half-life in circulation. GP-DCLHb has the disadvantages that (1) glutaraldehyde is an ineffective virucidal agent under the conditions of the polymerization reaction and a separate virus inactivation step is required; (2) low-endotoxin (LAL-negative) GP-DCLHb solutions are pyrogenic (rabbits); and (3) unusual deposition of hemoglobin-containing material in the small arterioles of the liver and kidney (rats) was sometimes seen even after a period of time (2 weeks) during which treatment-related organ pathologies are usually resolved, a finding peculiar to GP-DCLHb among the various hemoglobin derivatives we have tested.
Nelson
D
D
Blood Substitutes Program, Baxter Healthcare Corp., Round Lake, IL 60073.
Hai
T
T
Srnak
A
A
Ebeling
A
A
Kunas
G
G
Catarello
J
J
Burhop
K
K
D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives; D001802:Blood Substitutes / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D002522:Chlorocebus aethiops; D003432:Cross-Linking Reagents; D004353:Drug Evaluation, Preclinical; D005260:Female; D005976:Glutaral; D006454:Hemoglobins / Q000138:chemical synthesis* / Q000627:therapeutic use / Q000633:toxicity; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012769:Shock / Q000628:therapy; D013552:Swine
D001802:Blood Substitutes; D003432:Cross-Linking Reagents; D006454:Hemoglobins; C037158:polyhemoglobin; C030830:succinyldisalicylic acid; D001241:Aspirin; D005976:Glutaral