Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Perftoran, which has been rebranded as Vidaphor for marketing in North America, is an emulsion of perfluorocarbons in a surfactant and electrolyte mixture. It was developed in Russia as an oxygen-carrying intravenous plasma additive for hemorrhagic anemia and ischemic conditions from various etiologies. It was approved for clinical use in Russia in 1996 and used by the Russian Armed Forces and in civilian medical care. ⋯ It has been safely administered to more patients than any oxygen carrier currently under development. A newly formed United States Corporation (FluorO2 Therapeutics, Inc.) intends to manufacture the product in the United States under GMP standards and make it available for clinical use in Mexico and Latin America and pursue research to support eventual approval in the United States for human and veterinary use. This article will briefly review key information about this product and provide references for the interested reader.
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Several adverse events have been associated with the infusion of hemoglobin-based oxygen carriers (HBOCs), including transient hypertension, gastrointestinal, pancreatic/liver enzyme elevation, and cardiac/renal injury in humans. Although several mechanisms have been suggested, the basis of HBOC toxicity is still poorly understood. Scavenging of vascular endothelial nitric oxide (NO) and heme-mediated oxidative side reactions are thought to be the major causes of toxicity. ⋯ HBOCs display a diversity of physicochemical properties, including molecular size/cross-linking characteristics leading to differences in oxygen affinity, allosteric, redox properties, and even oxidative inactivation by protein/heme clearing mechanisms. These diverse characteristics can therefore be manipulated independently, leaving open the possibility of engineering a safe and effective HBOC. To date, several antioxidative strategies have been proposed to counteract the redox side reactions of current generation HBOCs.
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The in vivo study of microvascular oxygen transport requires accurate and challenging measurements of several mass transfer parameters. Although recommended, blood flow and oxygenation are typically not measured in many studies where treatments for ischemia are tested. Therefore, the aim of this communication is to briefly review cardinal aspects of oxygen transport, and the effects of perfluorocarbon (PFC) treatment on blood flow and oxygenation based mostly on studies performed in our laboratory. ⋯ In several cases, enhancement of flow and oxygenation could be demonstrated. Similar results were found in vitro: PFC emulsion mixed with blood (from healthy donors and sickle cell disease patients) enhanced oxygen transport. In summary, PFCs may provide beneficial effects in these models by mechanisms at the microvascular level including facilitated diffusion and bubble reabsorption leading to improved blood flow and oxygenation.
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In blood, the primary role of red blood cells (RBCs) is to transport oxygen via highly regulated mechanisms involving hemoglobin (Hb). Hb is a tetrameric porphyrin protein comprising of two α- and two β-polypeptide chains, each containing an iron-containing heme group capable of binding one oxygen molecule. In military as well as civilian traumatic exsanguinating hemorrhage, rapid loss of RBCs can lead to suboptimal tissue oxygenation and subsequent morbidity and mortality. ⋯ Several of these HBOCs have undergone rigorous preclinical and clinical evaluation, but have not yet received clinical approval in the USA for human use. While these designs are being optimized for clinical translations, several new HBOC designs and molecules have been reported in recent years, with unique properties. The current article will provide a comprehensive review of such HBOC designs, including current state-of-the-art and novel molecules in development, along with a critical discussion of successes and challenges in this field.
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This article reviews the key biochemical mechanisms that govern O2 transport, NO scavenging, and oxidative degradation of acellular hemoglobin (Hb) and how these ideas have been used to try to develop strategies to engineer safer and more effective hemoglobin-based oxygen carriers (HBOCs). Significant toxicities due to acellular Hb have been observed after the administration of HBOCs or after the lysis of red cells, and include rapid clearance and kidney damage due to dissociation into dimers, haptoglobin binding, and macrophage activation; early O2 release leading to decreased tissue perfusion in capillary beds; interference with endothelial and smooth muscle signaling due to nitric oxide (NO) scavenging; autooxidization of heme iron followed by production of reactive oxygen species; and iron overload symptoms due to hemin loss, globin denaturation, iron accumulation, and further inflammation. Protein engineering can be used to mitigate some of these side effects, but requires an in-depth mechanistic understanding of the biochemical and biophysical features of Hb that regulate quaternary structure, O2 affinity, NO dioxygenation, and resistance to oxidation, hemin loss, and unfolding.