Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-10-07
2001-01-30
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S385000
Reexamination Certificate
active
06180598
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
None
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH & DEVELOPMENT
No Federally sponsored research & development was used in making this invention.
BACKGROUND OF THE INVENTION
The restoration of oxygen delivery is a key survival factor for humans and other mammals following oxygen deprivation, such as that which results from blood loss (global ischemia) or restrictions to blood flow following myocardial infarction or stroke (focal ischemia). Transfusion of warmed (37° C.) blood or packed red cells restores the circulating fluid volume and oxygen delivery following hemorrhage, but is not useful as a means for restoring oxygen delivery to tissues where the circulation has been impeded. Conversely, since hemoglobin (Hb) is much smaller in size than the red cell and is recognized as the natural oxygen transporting protein in mammals, solutions of this protein have the potential both to restore the circulating volume and to perfuse areas where the circulation has been compromised by infarcts. Thus, Hb solutions have been studied extensively as potential resuscitative fluids for the restoration of oxygen delivery.
However, native mammalian Hbs have two significant shortcomings that negate their therapeutic utility for the restoration of oxygen delivery following oxygen deprivation. First, following their isolation from red cells and purification, the oxygen affinity of native mammalian Hbs is too high to allow for effective oxygen delivery to ischemic tissues in vivo. Second, native mammalian Hbs break down in the circulatory system into alpha chain- or beta chain-containing subunits having dose-related nephrotoxicity.
These two shortcomings have been addressed by covalent modification of Hb. As a result of modification, Hb compositions have been produced that cannot break down into subunits and also have therapeutically useful oxygen binding properties at pH 7.4 and 37° C. Four general types of Hb modification are recognized: (1) intra-molecular cross-linking; (2) modification of amino acid residues on the surface of the protein (“decoration”); (3) polymerization; and (4) combinations of intra-molecular cross-linking with decoration and/or polymerization.
Hypothermia is a corollary treatment that is used in surgeries of the heart and brain, two organs that are very sensitive to oxygen deprivation, and in organ, tissue or cell preservation. Under hypothermic conditions the patient's body temperature (or the temperature of the organ, tissue or cell) is lowered from about 37° C. to about 20° C. As the temperature is decreased, both blood and many mammalian Hbs, both native and covalently modified, show an increase in oxygen affinity that adversely affects their oxygen delivery capability. As a consequence of this increase in oxygen affinity of the Hb, neither blood or any of the known Hb compositions has the capability to maintain therapeutically effective oxygen delivery at these low temperatures. Oxygen deprivation (ischemia) results.
Accordingly, there exists a therapeutic need for new covalently modified hemoglobin compositions having an oxygen affinity that is less adversely affected by decreases in temperature, i.e., hemoglobin compositions having a low temperature-dependent oxygen binding function. The present invention satisfies this need.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a covalently modified hemoglobin composition having an oxygen binding function that exhibits low temperature-dependence.
Moreover, the present invention provides a covalently modified hemoglobin composition wherein the subunits of the hemoglobin have been joined covalently by reaction of amino groups on the subunits of the protein with a heteropolyfunctional, intra-molecular cross-linker having the formula:
X—(CH
2
)
n
CO—Y
wherein X is selected from the group consisting of halide, sulfonate, phosphate, phosphonate, azide, oxirane, thiirane, azirane, maleimide and formyl; n is an integer from 0 to 8; and Y is a substituted activating ester or substituted activating thioester, wherein the activating esters are substituted with at least one anionic group selected from the group consisting of carboxyl, sulfate, sulfite, phosphonate, and phosphate; and each of at least five of the thiyl or amino groups on the surface of Hb has been joined covalently to a hydrodynamic volume-enhancing, anionic ligand having the formula:
−
O
2
C—CH
2
—(OCH
2
CH
2
)
m
—O—CH
2
—Z
wherein m is an integer from 1 to 100; and Z is CH
2
—Hb, CH(OH)CH
2
—Hb, CH(SH)CH
2
—Hb,
Moreover, the invention provides a method for delivering oxygen to cells or tissues comprising exposing said cells or tissues to a covalently modified hemoglobin composition of the present invention.
REFERENCES:
patent: Re. 34271 (1993-06-01), Walder
patent: 4301144 (1981-11-01), Iwashita
patent: 4600531 (1986-07-01), Walder
patent: 5128452 (1992-07-01), Hai
patent: 5585484 (1996-12-01), Acharya et al.
patent: 5599907 (1997-02-01), Anderson et al.
patent: 5900402 (1999-05-01), Shorr
Hai et al. Polymerization of Diaspirin Crosslinked Hemoglobin . . . Tetrahedron. vol. 55, pp. 2147-2156, 1999.
Rogers et al. Effects of polymerization on the oxygen . . . Biochim. Biophys. Acta. vol. 1248, pp. 135-142, 1995.
Willford, David C. and Hill, Esther P. “Modest effect of temperature . . . ” Respiration Physiology 1986; 64:113-123.
Zijlstra, Willem G, Anton HJ Maas, Robert F. Moran. “Definition, significance and measurement of quantities of human blood.” Scand J Clin Lab Invest 1996; 56, Suppl 224: 24-45.
Nelson Deanna J.
Russel Jeffrey E.
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