Methods and compositions for optimization of oxygen transport by cell-free systems

a cell-free system and oxygen transport technology, applied in the field of blood products, can solve the problems of affecting the efficiency of oxygen transporting plasma expanders, and whose production is tedious and expensive, and achieves the effects of marginal efficacy, and reducing the number of oxygen transporters

Inactive Publication Date: 2005-10-27
WINSLOW ROBERT M
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014] The present invention is directed at compositions comprising mixtures of an oxygen-carrying component and a non-oxygen carrying component and methods for their use. The compositions overcome the limited oxygen delivery characteristics of previous blood substitutes, and therefore lower doses may be used. They are a safer and more effective alternative to currently available blood substitutes.
[0059] The term “non-oxygen-carrying component” refers broadly to substances like plasma expanders that can be administered, e.g., for temporary replacement of red blood cell loss. In preferred embodiments of the invention, the non-oxygen-carrying component is a colloid (i.e., a substance containing molecules in a finely divided state dispersed in a gaseous, liquid, or solid medium) which has oncotic pressure (colloid osmotic pressure prevents, e.g., the fluid of the plasma from leaking out of the capillaries into the interstitial fluid). Examples of colloids include hetastarch, pentastarch, dextran-70, dextran-90, and albumin.

Problems solved by technology

Plasma expanders are blood products that are administered into the vascular system but are typically not capable of carrying oxygen.
Attempts to produce blood substitutes (sometimes referred to as “oxygen-carrying plasma expanders”) have thus far produced products with marginal efficacy or whose manufacture is tedious and expensive, or both.
Frequently, the cost of manufacturing such products is so high that it effectively precludes the widespread use of the products, particularly in those markets where the greatest need exists (e.g., emerging third-world economies).
Though the perfluorocarbon emulsions are inexpensive to manufacture, they do not carry sufficient oxygen at clinically tolerated doses to be effective.
Conversely, while liposome-encapsulated hemoglobin has been shown to be effective, it is far too costly for widespread use (See e.g., Winslow, supra).
The high costs of manufacturing HBOC products have greatly limited their commercial viability.
In addition, the present inventors have found that known HBOCs have a tendency to release excessive amounts of oxygen to the tissues at the arteriole walls rather than the capillaries; this can result in insufficient oxygen available for delivery by the HBOC to the tissues surrounding the capillaries.

Method used

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  • Methods and compositions for optimization of oxygen transport by cell-free systems
  • Methods and compositions for optimization of oxygen transport by cell-free systems
  • Methods and compositions for optimization of oxygen transport by cell-free systems

Examples

Experimental program
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Effect test

example 1

Blood Flow and Hematocrit During Colloid and Saline Hemodilution

[0235] The experiments of this example were directed at determining the effect of decreasing hematocrit, as a result of hemodilution, on blood flow velocity. The experiments of this example were conducted on hamsters using dextran 70 and saline.

[0236] The general experimental procedures (e.g., General Experimental Protocol and Capillary Red Blood Cell Velocity) described above were performed. FIG. 2 depicts a plot of flow velocity in the microcirculation as a function of hematocrit reductions with dextran hemodilution and saline hemodilution. The following designations are used in FIG. 2: i) dextran hemodilution: small circle=mesentery; square=skin; plus sign=muscle; and ii) saline hemodilution: large circle=skin fold. The results indicate that blood flow, as evidenced by the velocity of blood in the vessel of the microcirculation, increases as blood is diluted. The increase is linearly related to the decrease of hema...

example 2

pO2 Distribution During Dextran 70 and Hemolink® Hemodilution

[0238] The experiments of this example were directed at determining the effect of hemodilution on pO2 in the microcirculation by the phosphorescence decay method described above.

Dextran 70 Hemodilution

[0239] Measurements of pO2 were made in 50 μm arterioles and the tissue surrounding those arterioles. The results were as follows: arteriole pO2 (pO2.A)=53 mm Hg; tissue pO2 (pO2.T)=21 mm Hg. The following equation may then be utilized to calculate KA*, the constant representing the difference in the decrease in the oxygen partial pressure between i) the arterioles and the tissues and ii) the central arteries and the tissues:

KA*=In[(pO2.A−pO2.T) / (pO2.a−pO2.T)]

where pO2.a is the oxygen tension in a central artery. If one assumes a pO2.a=100 mm Hg, then KA*=In [(53-21) / (100-21)]=−0.90.

[0240] Table 5 sets forth previously obtained (by the present inventors) pO2 values for various hematocrit (α) levels with dextran 70 hemod...

example 3

Tissue Oxygenation Resulting from Hemodilution with 50% Hemolink® / 50% Dextran 70

[0247] The experiments of this example are directed at determining the adequacy of tissue oxygenation following administration of a mixture of Hemolink® and dextran 70.

[0248] A mixture of 50% Hemolink® and 50% dextran 70 was prepared, and tissue oxygenation was determined at hematocrit levels of 60% and 40% of baseline levels. Hemoglobin concentration in the resulting mixture was measured directly by spectrophotometry. In addition, the number of RBCs and the amount of Hemolink® were measured directly in blood samples. Though testing was initiated using four animals, only two animals satisfied all criteria for inclusion in an experimental run; the results for the two animals are set forth in Table 7.

TABLE 7pO2.A Meas.Wall Grad.pO2.THtc / αγγ / αpO2.Amm Hgmm Hgmm Hg0.6 / 0.680.640.86550.4 / 0.540.761.4143512715

[0249] When the data in Table 7 is compared with that derived from use of Hemolink® alone (see Table ...

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Abstract

Compositions, and methods of use thereof, for use as blood substitute products comprise aqueous mixtures of oxygen-carrying and non-oxygen carrying plasma expanders and methods for the use thereof. The oxygen-carrying component may consist of any hemoglobin-based oxygen carrier, while the non-oxygen carrying plasma expander my consist of any suitable diluent.

Description

[0001] The present application is a Continuation-in-Part of U.S. patent application Ser. No. 08 / 810,694, filed Feb. 28, 1997.[0002] This invention was made with Government support under the National Institutes of Health (NIH) awarded by contract P01 HL48018. The Government has certain rights in this invention.FIELD OF THE INVENTION [0003] The present invention relates generally to blood products, and more particularly to compositions comprising mixtures of oxygen-carrying and non-oxygen carrying plasma expanders and methods for their use. BACKGROUND OF THE INVENTION A. The Circulatory System and the Nature of Hemoglobin [0004] The blood is the means for delivering nutrients to the tissues and removing waste products from the tissues for excretion. The blood is composed of plasma in which red blood cells (RBCs or erythrocytes), white blood cells (WBCs), and platelets are suspended. Red blood cells comprise approximately 99% of the cells in blood, and their principal function is the ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/715A61K45/00A61K35/14A61K38/16A61K38/42A61P7/08
CPCA61K38/42Y10S530/829Y10S514/832Y10S514/833Y10S530/815Y10S530/813A61K2300/00A61P7/08
Inventor WINSLOW, ROBERT M.
Owner WINSLOW ROBERT M
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