Hemoglobin-based oxygen carriers: From mechanisms of toxicity and clearance to rational drug design.
Hemoglobin-based oxygen carriers (HBOCs) have been developed to support blood oxygen transport capacity during hemorrhagic shock, hemolysis and ischemic insult. Existing product candidates have demonstrated considerable efficacy in experimental animal models and in clinical trial subjects; however, severe adverse safety signals that appeared in recent phase II and phase III clinical trials involving certain HBOCs have in part hindered further development and licensing. Emerging insights into hemoglobin (Hb) toxicity as well as physiologic Hb scavengers such as haptoglobin and CD163 that are capable of detoxifying extracellular Hb in vivo suggest that alternative product candidates could be designed. Together with novel animal models and biomarkers tailored to monitor the effects of extracellular Hb, a new generation of HBOCs can be envisioned.
Buehler
Paul W
PW
Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), Bethesda, MD 20892, USA.
D'Agnillo
Felice
F
Schaer
Dominik J
DJ
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001802:Blood Substitutes / Q000009:adverse effects / Q000633:toxicity*; D015195:Drug Design; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism*
D015415:Biomarkers; D001802:Blood Substitutes; D006454:Hemoglobins; D010100:Oxygen