Blood substitutes oxygen

Alayash, A.I. Hemoglobin-based blood substitutes oxygen carriers, pressor agents, or oxidants Nature Biotech. 1999,17, 545-549. 

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). 

Perfluorinated compounds are also potentially useful as inert reaction media, particularly when one of the reactants is gaseous. The high solubiHty of oxygen and carbon dioxide in perfluorinated Hquids has allowed their use as blood substitutes (41) and as oxygenation media for biotechnology (42). One product, Fluosol DA (43) (Green Cross Corp.), has been commercialized, and there is an abundant patent art in this area (see Blood, artificial). 

T. M. S. Chang, ed.. Blood Substitutes and Oxygen Carriers, Marcel Dekker, New York, 1992. 

In 1982 a study of the usefulness of DBBF in the production of a blood substitute was reported (99). A single modification achieved the dual goals of reduced oxygen affinity and restricted tetramer—dimer dissociation. This work was confirmed in 1987 (98). The product, called aa-hemoglobin, was formulated in Ringer s lactate. P q under physiologic conditions is 3.7 kPa (28.0 torr). Hill s parameter is 2.2, and the Bohr effect was reduced (100). Plasma retention was increased, and the product appeared to be less heterogeneous than some of the other derivatives under study. Its production was scaled up by Baxter Healthcare Corp., under contract to the U.S. Army. 

Riess JG. Oxygen carriers ( Blood substitutes )—Raison d Etre, chemistry, and some physiology. Chem Rev 2001 101 2797. 

Takeoka S, Sakai H, Kobayashi K, et al. Evaluation of oxygen transporting capability of hemoglobin vesicles. In Tsuchida E, ed. Blood Substitutes Present and Future Perspectives. Tokyo Elsevier Science S.A., 1998 171. 

Kobayashi K, Tsuchida E, Nishide H. Totally synthetic hemes their characteristics and oxygen carrying capacity in dogs. In Tsuchida E, ed. Artificial Red Cells Materials, Performances and Clinical Study as Blood Substitutes. Chichester, England John Wiley Sons Ltd., 1995 93. 

Kavdia M, Pittman RN, Popel AS. Theoretical analysis of effects of blood substitute affinity and cooperativity on organ oxygen transport. J Appl Physiol 2002 93 2122. 

Fig. 17.4 The comparison of the costs of several blood substitutes companies to develop an oxygen carrying molecule vs. the Alios Therapeutics Inc. allosteric effector RSR 13 to an IND and phase one clinical trial.

Alios Therapeutics Inc. was then able to proceed through a phase-one study on the basis of the basic and preclinical studies for only 2 million. This is perhaps a record for a new drug. The following graph prepared by the former Alios CEO, Stephen Hoffman, compared the cost of development of RSR 13 to the blood substitute companies that also sought to increase oxygen delivery in vivo (Figure 17.4). 

Some of the research activities in blood substitutes use cow s blood without cells, which can be obtained from slaughterhouses. Another idea is perfluorohydrocarbons, which have a good solubility for oxygen and carbon dioxide, are free from immune-response problems, have no granules and easily go around partially clogged arterioles, and are metabolized in the body after a period of time (Feder 2001). 

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. 

J.E. Fishman, P.M. Joseph, M.J. Carvlin, M. Saadi-Elmandjra, B. Mukherji, H.S. Sloviter, In vivo measurements of vascular oxygen tension in tumors using MRI of a fluorinated blood substitute. Invest. Radiol. 24 (1989) 65-71. 

J.G. Riess, M.P. Krafft, Fluorinated materials for in vivo oxygen transport (blood substitutes), diagnosis and drug delivery. Biomaterials 19 (1998) 1529-1539. 

J.G. Riess, Injectable oxygen carriers (blood substitutes)—Raison d etre, chemistry and some physiology, Chem. Rev. 101 (2001) 2797-2920. 

Conversely, the role of perfluorocarbons for oxygen transport and in vivo delivery is investigated. In addition to possible use as temporary blood substitute, these fluorocarbon molecules can be applied as respiratory gas carriers, for instance as lung surfactant replacement compositions for neonates and possibly for the treatment of acute respiratory distress syndrome for adults. Another... 

This very specific ability of perfluorinated compounds to dissolve gases has found an application in oxygen carrier liquids (short-time blood substitutes). A perfluorocarbon dissolves three times more oxygen than the corresponding hydrocarbon, and ten times more than water. This property can be explained by the presence of large cavities in the liquid and by the weak intermolecular interactions of the medium, and not by specific interactions. 

This background in combination with their chemical stability makes these liquids promising candidates as oxygen carriers for artifical blood substitution.14... 

Several perfluoroalkyl and cycloalkyl bromides were tested for potential as oxygen carriers, blood substitutes, radiopaque agents, for other medical applications or as intermediates. Their LD50 toxicity data are listed in Table 14 (for additional information, see also ref 2). 

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). 

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