NITRITE AND NITRITE-METHEME THERAPY TO DETOXIFY STROMA-FREE HEMOGLOBIN BASED BLOOD SUBSTITUTES

• US 20100247681A1
• Filed: 08/29/2008
• Published: 09/30/2010
• Est. Priority Date: 08/31/2007
• Status: Active Grant

• Current Assignee: UAB Research Foundation (University of Alabama System), Wake Forest University
• Original Assignee: UAB Research Foundation (University of Alabama System)
• Inventors: Kerby, Jeffrey, Gladwin, Mark T., Patel, Rakesh P., Kim-Shapiro, Daniel B.
• Granted Patent: US 8,551,536 B2
• Time in Patent Office: Days
• US Class Current: 424/718
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 33/00 Medicinal preparations containing inorganic active ingredients
• CPC Class Codes: A61K 33/26 Iron; Compounds thereof
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This disclosure relates to methods of using nitrite to detoxify stroma-free hemoglobin based blood substitutes. In particular, methods are described for using a blood substitute comprised of about equimolar amounts of nitrite and hemoglobin (e.g., nitrite-metHb) to treat, prevent, or ameliorate diseases of the blood in a subject, or as a blood replacement in a subject.

Claims

1. A pharmaceutical composition, comprising a ferric (Fe^III) heme-containing molecule and nitrite, wherein the molar ratio of nitrite to the heme-containing molecule in the composition is between about 1:

2 and about 2;

1.

2. The composition of claim 1, wherein the heme-containing molecule is hemoglobin.

3. The composition of claim 1, wherein the heme-containing molecule is methemoglobin.

4. The composition of claim 1, wherein the heme-containing molecule is cross-linked hemoglobin.

5. The composition of claim 1, wherein the heme-containing molecule is cross-linked methemoglobin.

6. The composition of claim 1, wherein the heme-containing molecule is a protein that binds oxygen.

7. The composition of claim 1, wherein the molar ratio of nitrite to heme-containing molecule is greater than about 1:

1.

8. The composition of claim 1, wherein the molar ratio of nitrite to heme-containing molecule is less than about 1:

1.

9. The composition of claim 1, wherein the molar ratio of nitrite to heme-containing molecule is about 1:

1.

10. The composition of claim 1, further comprising a pharmaceutically acceptable carrier, an adjuvant, or a combination thereof.

12. A method of treating a subject having or predisposed to hypoxia, hypoxaemia, ischemia or anoxia, comprising administering to the subject a therapeutically effective amount of the composition of claim 1, thereby treating the subject.

13. A method of replacing blood in a subject, comprising administering to the subject a therapeutically effective amount of the composition of claim 1, thereby replacing blood in the subject.

14. The method of claim 12, wherein the subject has or is predisposed to anemia, bleeding disorder, trauma, injury, burn, coagulopathy, ectopic pregnancy, favism, gastrointestinal bleeding, hemolytic uremic syndrome, hemophilia, microcytosis, ulcer, bleeding in surgery, bleeding in pregnancy, hemorrhage, rhabdomyolysis, hemorrhagic shock, sickle cell anemia, hemoglobinopathy spherocytosis, thalassemia, and/or yellow fever.

15. The method of claim 12, wherein the subject has lost blood during a surgical procedure.

16. The method of claim 12, wherein the subject is a human.

17. The method of claim 12, wherein the subject is a non-human animal.

18. The method of claim 13, wherein the subject has or is predisposed to anemia, bleeding disorder, trauma, injury, burn, coagulopathy, ectopic pregnancy, favism, gastrointestinal bleeding, hemolytic uremic syndrome, hemophilia, microcytosis, ulcer, bleeding in surgery, bleeding in pregnancy, hemorrhage, rhabdomyolysis, hemorrhagic shock, sickle cell anemia, hemoglobinopathy spherocytosis, thalassemia, and/or yellow fever.

19. The method of claim 13, wherein the subject has lost blood during a surgical procedure.

20. The method of claim 13, wherein the subject is a human.

11. A method of producing a cell-free blood substitute comprising:

contacting a heme-containing molecule with nitrite,

wherein the molar ratio of heme-containing molecule and nitrite in the composition is between about 1;

2 and about 2;

1; and

forming nitrite-bound heme-containing molecules, wherein the nitrite-containing molecules produce dinitrogen trioxide.