Blood substitutes emulsion

Medical appHcations of PFC emulsions for organ perfusion and intravenous uses have received much attention in recent years. The first commercial blood substitute (Fluosol DA 20%, trademark of the Green Cross Corp.) employed perfluorodecalin, and improved, second generation products based on this PFC, or perfluorooctylbromide, are now under development (20,21). The relatively high oxygen dissolving capabiHty of PFCs undedies these appHcations (see Blood, artificial). 

C.S. Lai, S. Stair, H. Miziorko, J.S. Hyde, Effect of oxygen and the spin label TEMPO-Laurate on F and proton relaxation rates of the perfluorochemical blood substitute FC-43 emulsion, J. Magn. Reson. 57 (1984) 447-452. 

Further issues concern the design of appropriate protocols for evaluation of efficacy of a blood substitute so different from blood, the definition of indications, and conditions of use that befit PFC emulsions and provide maximum benefit for the patient. The latter issues depend largely on our understanding of the in vivo behavior of PFCs and PFC emulsions. 

Perfluorocarbons. In 1966, it was demonstrated (27) that a laboratory mouse could survive total immersion in a perfluorochemical (PFC) solution. This material, similar to commercial Teflon, is almost completely inert and is insoluble in water. A water-soluble emulsion was prepared that could be mixed with blood (28), and in 1968 (29) the blood volume in rats was completely replaced with an emulsion of perfluorotributylamine [311-89-7], C12F27N. The animals survived in an atmosphere of 90—100% 02 and went on to long-term recovery. However, the 02 content of the perfluorochemicals has a linear dependence on the partial pressure of oxygen, P, as can be seen in Figure 1. The very high 02 tension required to transport physiologic amounts of 02 (12) and the propensity of the perfluorocarbon to be taken up by the reticuloendothelial cells were considered to be severe limitations to the development of clinically useful perfluorocarbon blood substitutes (30). 

Blood Substitutes. Researchers in lapan (Fukushima Medical Center) and in other institutions in Europe and North America have been investigating substances that, in major characteristics, may serve as a substitute for blood, particularly in emergency situations where rare blood types are not immediately available to severely ill patients who require transfusions. For example, in early 1979, a lapanese patient with a rare O-negative blood was given an infusion of one liter of a new, oxygenated perfluorocarbon emulsion. This compound carried oxygen through the patient s circulatory system until the rare blood could be obtained. 

Among esters of sucrose, some derivatives of fluorinated fatty acids have been prepared for evaluation as surfactants specifically designed for fluorocarbons containing emulsions used for biomedical applications, notably as blood substitutes.98,402 Some sucrose aspartate surfactants have been described.403... 

The rate of Ostwald ripening depends on the size, the polydispersity, and the solubility of the dispersed phase in the continuous phase. This means that a hydrophobic oil dispersed as small droplets with a low polydispersity already shows slow net mass exchange, but by adding an ultrahydrophobe , the stability can still be increased by additionally building up a counteracting osmotic pressure. This was shown for fluorocarbon emulsions, which were based on perfluo-rodecaline droplets stabilized by lecithin. By adding a still less soluble species, e.g., perfluorodimorphinopropane, the droplets stability was increased and could be introduced as stable blood substitutes [6,7]. 

Another promising application of S-FFF is the characterization of emulsions and S-FFF is used as the standard technique for emulsion characterization in some laboratories [390]. Manifold emulsions or organelles have been fractionated with S-FFF [75,383,391-396] including perfluorocarbon blood substitutes [391]. 

This entry will first survey the reasons for developing blood substitutes and outline the principles of oxygen delivery by PFC emulsions. It will then focus on the main challenges encountered in the development of such emulsions, namely the selection of an appropriate excretable PFC and the preparation of a stable, biocompatible emulsion. It will also allude to questions related to raw material procurement, product manufacture, and cost. Further sections will concern the pharmacokinetics, efficacy, and side effects of these oxygen carriers. Finally, the potential applications of these products will be outlined, including the status of their clinical trials, and some forward looking comments will be made. 

Riess, J.G. Le Blanc, M. Preparation of perfluorochemical emulsions for biomedical use principles, materials and methods. In Blood Substitutes Preparation, Physiology, and Medical Applications Lowe, K.C., Ed. Ellis Horwood Ltd. Chichester, 1988 94-129. 

Riess, J.G. Fluorocarbon emulsions—designing an efficient shuttle service for the respiratory gases—the so-called blood substitutes . In Fluorine at the Millenium Banks, R.E., Ed. Elsevier Amsterdam, 2000 385-431. 

Naito, R. Yokoyama, K. Perfluorochemical blood substitutes. In FC-43 Emulsion, Fluosol-DA, 20% and 35% Green Cross Corp. Osaka, Japan, 1978, 1981. 

Kaufman, R.J. Clinical development of perfluorocarbon-based emulsions as red cell substitutes. In Blood Substitutes Physiological Basis of Efficacy Winslow, R.M., Vande-griff, K.D., Intaglietta, M., Eds. Birkhauser Boston, 1995 53-75. 

Rosoff J.D. Soltow, L.O. Vocelka, C.R. Schmer, G. Chandler, W.L. Cochran, R.P. Kunzelman, K.S. Spiess, B.D. A second-generation blood substitute (perfluorodi-chlorooctane emulsion) does not activate complement during ex vivo circulation model of bypass. J. Cardiothorac. Vase. Anesth. 1998, 12, 397 01. 

The characteristics of an ideal emulsion for use as a blood substitute are absence of red cell incompatibility, absence of a risk of transmission of infectious diseases, a long duration of conservation, easy access, and rheological parameters similar to those of blood (2). 

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