Toxicities of hemoglobin solutions: in search of in-vitro and in-vivo model systems.
Several hemoglobin-based oxygen carriers (HBOCs) have been developed with a rationale focused on exploiting one or more physicochemical properties (e.g., oxygen affinity, molecular weight, viscosity, and colloid osmotic pressure) resulting from the chemical or recombinant modification of hemoglobin (Hb). Several chemically modified Hbs have reached late stages of clinical evaluation in the United States and Canada. These Hbs, in general, demonstrated mixed preclinical safety and efficacy, and reasonable safety in Phase I trials. However, as clinical development shifted into later stages, an undesirable safety and efficacy profile became clear in patient populations studied, and as a result some products were withdrawn from further clinical pursuit. Several questions still remain unanswered regarding the safety of Hb products for their proposed clinical indication(s). For example, 1) were preclinical studies predictive of clinical outcome? And, 2) were the most appropriate preclinical studies performed to predict clinical outcome? The primary objectives of this analysis are to explore prelinical safety issues associated with HBOCs and provide an overview of the in-vitro and in-vivo models employed. The methods for obtaining data to serve as a basis for discussion are compiled from a literature-based survey of safety and efficacy derived from biochemical, cellular, and whole animal assessment of HBOCs. Results from this overview of a vast body of published data may provide a means for identifying critical preclinical safety issues, which may ultimately lead to identification of potential limitations in the effective clinical use of certain HBOCs.
Buehler
Paul W
PW
Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Bethesda, Maryland, USA.
Alayash
Abdu I
AI
D000818:Animals; D001802:Blood Substitutes / Q000627:therapeutic use / Q000633:toxicity*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006454:Hemoglobins / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D010100:Oxygen / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D012996:Solutions; D016896:Treatment Outcome; D014661:Vasoconstriction / Q000187:drug effects
D001802:Blood Substitutes; D006454:Hemoglobins; D012996:Solutions; D010100:Oxygen