Gould S A, Sehgal L R, Sehgal H L, Moss G S
Department of Surgery, Michael Reese Hospital and Medical Center, Chicago University of Illinois, College of Medicine 60201, USA.
Transfus Sci. 1995 Mar;16(1):5-17. doi: 10.1016/0955-3886(95)93436-a.
Although the efficacy of hemoglobin-based oxygen carriers was established more than 60 years ago, all prior clinical trials have demonstrated significant toxicity characterized by renal dysfunction, gastrointestinal distress, and systemic vasoconstriction. The mechanisms of these toxicities now appear to be understood. Tetrameric forms of the hemoglobin molecule extravasate from the circulation and interact with endothelial derived relaxing factor, leading to unopposed vasoconstriction. Although numerous efforts are underway to chemically modify the native tetramer, it is likely that all tetrameric forms of the hemoglobin molecule will continue to extravasate. We have focused on developing a polymerized form of hemoglobin that is virtually free of unreacted tetramer. The development and characterization of this polymerized pyridoxylated hemoglobin solution (Poly SFH-P) is described. Clinical trials have been completed successfully in volunteers, and are now underway to assess the safety and efficacy of Poly SFH-P as a clinically useful red cell substitute in the treatment of acute blood loss in the setting of trauma and surgery.
尽管基于血红蛋白的氧载体的功效在60多年前就已得到证实，但此前所有的临床试验都显示出以肾功能障碍、胃肠道不适和全身血管收缩为特征的显著毒性。现在似乎已经了解了这些毒性的机制。血红蛋白分子的四聚体形式从循环中渗出，并与内皮衍生的舒张因子相互作用，导致无对抗的血管收缩。尽管正在进行大量化学修饰天然四聚体的努力，但血红蛋白分子的所有四聚体形式可能会继续渗出。我们专注于开发一种几乎不含未反应四聚体的聚合血红蛋白形式。本文描述了这种聚合吡哆醛化血红蛋白溶液（Poly SFH-P）的开发和特性。在志愿者中已成功完成临床试验，目前正在进行试验以评估Poly SFH-P作为临床有用的红细胞替代品在治疗创伤和手术引起的急性失血中的安全性和有效性。
