Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-11-30
2003-07-29
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S832000, C514S833000, C530S385000, C530S402000
Reexamination Certificate
active
06599878
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to compositions that enhance the in vivo oxygenating properties of hemoglobin products. More particularly, the present invention relates to time-controlled superoxygenating compositions that comprise hemoglobin colloid and guanosine 3′:5′-cyclic monophosphate (cyclic GMP) generating compounds, and to methods for treatment of diseases or medical conditions which utilize the time-controlled superoxygenating compositions as biocolloids, i.e. hemodiluents, blood substitutes, plasma expanders, or resuscitative fluids.
BACKGROUND
There are many medical conditions, for example hemorrhagic hypotension and anaphylactic shock, in which significant blood loss and/or hypotension (abnormally low blood pressure) occur leading to reduced tissue oxygenation. For patients with such medical conditions, it is desirable and often critical for their survival to stabilize their blood pressure and to increase the amount of oxygen provided to body tissues by their circulatory systems.
Considerable effort has therefore been expended in developing colloidal substances which may be used as resuscitation fluids and/or blood plasma expanders for stabilizing blood pressure by hemodilution (i.e., increasing blood plasma volume) and which are capable of carrying and delivering oxygen to bodily tissues. The costs, risks (including contamination with disease-causing viruses) and histocompatibility requirements associated with the transfusion of whole blood or blood fractions have stimulated researchers to develop alternate oxygen-carrying substances.
Hemoglobin, the natural respiratory protein of erythrocyte which carries oxygen to body tissues from the lungs, is a potential alternate oxygen-carrying biocolloid. Erythrocytes contain approximately 34 grams of hemoglobin per 100 ml of red cells.
Hemodilution experiments with hemoglobin have revealed that unlike hemodilution with albumin, hemodilution with hemoglobin does not augment cardiac output (whole-body blood flow). During hemodilution with inert colloids such as albumin, whole-body blood flow increases inversely proportional to the level of hemodilution. In other words, an ≈50% hemodilution (i.e., an ≈50% decrease in blood red cell mass) increases blood flow ≈100%, and so on. The physical basis of the hematocrit-blood flow inverse relationship is analogous to viscosity-flow mechanics. In other words, decreases in hematocrit cause decreases in blood viscosity which results in increases in blood flow. Hemoglobin, on the other hand, is not inert. Hemodilution with hemoglobin causes vasoconstriction which results in smaller diameter blood vessels. Therefore, even though blood viscosity is decreased during hemodilution with hemoglobin, the smaller diameter blood vessels resist increases in blood flow. This is analogous to direct mechanical relationship between flow and tube diameter, i.e., decreased diameter results in decreased flow. Whole-body flow (cardiac output) is not increased during hemodilution with hemoglobin because flow of the less viscous blood is opposed by the hemoglobin-mediated decrease in blood vessel diameter.
Increased cardiac output is desirable to increase oxygen delivery to the tissues. Examples of publications describing the lack of increased cardiac output during hemodilution with natural (unmodified) hemoglobin are Sunder-Plassmann et al.,
Eur. J. Int. Care Med.
1, 37-42 (1975) and Moss et al.,
Surg. Gyn. Ob.,
142, 357-362 (1976).
Hemodilution with modified hemoglobin that has been polymerized also has failed to increase cardiac output. See Vlahakes et al.,
J. Thorac. Cardiovasc. Surg.,
100, 379-388 (1990) which describes the hemodilution of sheep with polymerized bovine hemoglobin prepared by Biopure Corporation; Rausch et al., supra (assigned to Biopure Corporation), which describes similar experiments; and Gould et al.,
Ann. Surg.,
211, 394-398 (1990) and Hobbhahn et al.,
Acta Anaesthesiol. Scand.,
29, 537-543 (1985) which describe hemodiluting baboons and dogs, respectively, with polymerized human hemoglobin solutions. Thus, hemodilution with both natural and modified hemoglobin has failed to increase cardiac output.
Because cardiac output does not increase upon dilution of the blood with hemoglobin, body tissues are required, as one compensatory mechanism, to extract more oxygen from the diluted blood to prevent tissue damage from hypoxia. However, such compensatory mechanisms have real limits in vivo. The heart, for instance, normally functions at about 95% maximal oxygen extraction levels and thus is only capable of increasing oxygen extraction about 5% (assuming 100% efficiency is possible). In the case of hemodilution with albumin, even though arterial oxygen content is decreased, oxygen delivery is essentially maintained at baseline levels because of low viscosity blood that causes flow (cardiac output) to increase proportionally. Therefore, hemodilution with hemoglobin offers no physiological or clinical advantage over hemodiluting with albumin. In fact, oxygen delivery is suboptimal during hemodilution with hemoglobin. This leads us to the central idea of the invention. If cardiac output or whole-body flow were allowed to increase as blood was diluted with hemoglobin then oxygen delivery would be clinically superior to hemodilution with albumin because of the added arterial oxygen content provided by the plasma hemoglobin colloid.
The mechanism of unchanged cardiac output during hemodilution with hemoglobin may be caused by an inactivation of endogenous nitric oxide (NO), also called endothelium-derived relaxing factor (EDRF), which is an important regulator of blood vessel diameter. For nearly 100 hundred years, it has been known that hemoglobin inactivates NO that has been diffused to the blood via the lungs. Only recently has it been discovered that NO also forms biochemically in vivo. There is, however, uncertainty as to whether oxyHb directly reacts with NO or whether an indirect oxyHb-mediated product such as superoxide is responsible. An overview of the possible molecular interactions of oxyHb with NO and relevant compounds is give below.
Initially, the reaction equations between NO and oxyHb/deoxyHb are simple yielding
oxyHb+NO→metHb+NO
3
−
deoxyHb+NO→NOHb
where metHb is ferric(Fe
3+
)hemoglobin, NO
3
−
is nitrate and NOHb is nitrosylhemoglobin. However, NO
3
−
can react with deoxyHb to yield:
2deoxyHb+NO
3
−
+H
2
O→2metHb+NO
2
−
+2OH
−
and nitrite (NO
2
−
) can react with oxyHb or deoxyHb to yield:
2oxyHb+NO
2
−
+H
2
O→2metHb+NO
3
−
+2OH
2
−
oxyHb+NO
2
−
+2H
+
→metHb+NO
2
+H
2
O
2
deoxyHb+NO
2
−
+H
2
O
½[metHb+NO]+½[NOHb]+2OH
−
where NO
2
is nitrogen dioxide and H
2
O
2
is hydrogen peroxide. The free energy of activation (&Dgr;G) of the last equation is rather low (−21.23 kJ/mole) and therefore metHb . . . NO can be reduced to deoxyHb. However, in vivo experiments have shown that nitrite exposure results in about an equal amount of NOHb and metHb formed in the blood. Furthermore, the &Dgr;G of equation 2 is low (−46.02 Kj/mole) and in the presence of O
2
will proceed according to the &Dgr;G of equation 1(≈−170 Kj/mole). Finally, metHb and H
2
O
2
can react:
metHb+H
2
O
2
→ferrylhemoglobin+H
2
O
to produce a spectrophotometrically detectable red compound known as ferryl(Fe
++++
)hemoglobin. In many of the above reactions, heme or chelatable iron can be substituted for Hb.
Under physiological conditions, i.e., in an oxygenated and heated aqueous with a pH of about 7.4, NO is rapidly converted to nitrogen dioxide:
2 NO+O
2
→2 NO
2
Nitrogen dioxide is quite reactive, and in aqueous solution disproportionates to nitrate and nitrite as:
2NO
2
→N
2
O
4
+H
2
O→NO
3
−
+NO
2
−
&plus
Harris Leslie
Low Christopher S. F.
Mohamed Abdel A.
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