Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1988-02-03
1992-01-07
Schain, Howard E.
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
525 541, C07K 1522, A61K 3714
Patent
active
050793373
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new, macromolecular conjugates, a procedure for their preparation and their uses as transporters of oxygen, particularly in the context of transfusions.
It is known that the intravenous injection of an aqueous solution of hemoglobin free of stroma and made isotonic with blood is possible. However, one of the disadvantages experienced with hemoglobin is that it does not remain in the circulation but diffuses outside of the vascular system, in particular on account of its small size.
Several procedures have been used to counteract this disadvantage, i.e. to enhance the intravascular persistence of free hemoglobin in the framework of its use as blood "substitute" or as filling solute acting as a transporter of oxygen.
For example, hemoglobin has been coupled to water-soluble macromolecules which have been rendered non-toxic, non-antigenic and hemocompatible. In this way many examples of hemoglobins modified by being chemically linked to water-soluble polymers have shown that the time during which hemoglobin resides in the organism can be considerably increased.
Among the various polymers used, the most common are the polysaccharides and, in particular, dextran (French patent No. 2.328.478), hydroxyethyl-starch (French patent No. 2.238.478), inulin (European patent application No. 43.675), and polyalkylene glycols, more especially polyethylene glycols.
However, in all of these cases the hemoglobin thus modified by being directly linked to these polymers possesses oxygen-carrying properties which are poorly suited to their use in blood transfusion.
In fact, it will be recalled that a blood substitute can only play a role equivalent to that fulfilled by native hemoglobin in the interior of erythrocytes to the extent that the adduct that it forms with oxygen is reversible, i.e. that it is capable of binding oxygen (the hemoglobin is then in the oxygenated form) but also that it is capable of easily releasing the oxygen (the hemoglobin is then in the deoxygenated form).
This property with respect to oxygen is characterized by the curve (called the Barcroft curve) which represents the variation in the amount of oxygen bound per unit mass of the transporter as a function of the partial pressure of oxygen contained in the atmosphere to which the hemoglobin is exposed.
In the case of an aqueous solution of native hemoglobin (concentration 15 .mu.moles/liter) at pH 7.2 and 25.degree. C. this variation is represented by the reference plot shown in FIG. 1.
One of the parameters associated with this curve is the half-saturation pressure (P.sub.50) which is the partial pressure of oxygen to which the solution of hemoglobin must be subjected for it to absorb an amount of oxygen equivalent to 50% of the maximal amount with which it is capable of combining. Now in the case of modified hemoglobin (hemoglobin coupled to polymers) as indicated above, the curve in FIG. 1 (dashed line) showing the percentage of oxygen combined with the hemoglobin at given partial pressures of oxygen is shifted to the left with respect to the curve representing native hemoglobin (continuous line).
This means that the pressure P.sub.50 of the modified hemoglobin is lower than that of native hemoglobin; in other words, the modified hemoglobin shows too strong an affinity for oxygen with the disadvantage that the oxygen cannot be returned rapidly to the irrigated tissues.
This change in the oxygen-carrying properties of the modified hemoglobin can be explained in particular by the following reasons: 2,3-diphosphoglycerate (2,3-DPG) which is the naturally occurring intraerythrocytic effector which binds to the amine groups at the allosteric site of deoxyhemoglobin, leading to a lowering of the affinity of hemoglobin for oxygen.
Improvements to counteract this disadvantage have been suggested in which the coupling between the polymers and the hemoglobin is carried out in the presence of temporary effectors (or ligands) such as 2,3-diphosphoglycerate or inositol hexaphosphate and in the total absence of oxygen (French patent No.
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Dellacherie Edith
Labrude Pierre
Leonard Michele
Neel Jean M. L.
Vigneron Claude
Pasteur Merieux Serums et Vaccins S.A.
Perkins Susan M.
Schain Howard E.
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