Nitrite and nitrite-metheme therapy to detoxify stroma-free hemoglobin based blood substitutes

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.

1 . A pharmaceutical composition, comprising a ferric (Fe III ) heme-containing molecule and nitrite, wherein the molar ratio of nitrite to the ferric heme-containing molecule in the composition is between about 1:2 and about 2:1, and wherein the pharmaceutical composition is formulated for infusion into a subject. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the heme-containing molecule is hemoglobin, methemoglobin, cross-linked hemoglobin or cross-linked methemoglobin. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the heme-containing molecule is a protein that binds oxygen. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the molar ratio of nitrite to the ferric heme-containing molecule is greater than about 1:1. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the molar ratio of nitrite to the ferric heme-containing molecule is less than about 1:1. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the molar ratio of nitrite to the ferric heme-containing molecule is about 1:1. 
     
     
         7 . The pharmaceutical composition of  claim 1 , further comprising a pharmaceutically acceptable carrier, an adjuvant, or a combination thereof. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical composition is contained in an i.v. bag. 
     
     
         9 . 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 pharmaceutical composition of  claim 1 , thereby treating the subject. 
     
     
         10 . The method of  claim 9 , 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. 
     
     
         11 . The method of  claim 9 , wherein the subject has lost blood during a surgical procedure. 
     
     
         12 . The method of  claim 9 , wherein the subject is a human. 
     
     
         13 . The method of  claim 9 , wherein the subject is a non-human animal. 
     
     
         14 . A method of replacing blood in a subject, comprising co-infusing into the subject a first pharmaceutical composition comprising a ferric (Fe III ) heme-containing molecule and nitrite at a ratio of less than 1:1; and a second pharmaceutical composition comprising oxyhemoglobin, wherein the first pharmaceutical composition and the second pharmaceutical composition are co-infused into the subject at a ratio of less than 1:1. 
     
     
         15 . The method of  claim 14 , wherein the first pharmaceutical composition consists essentially of a ferric (Fe III ) heme-containing molecule and nitrite at a ratio of less than 1:1. 
     
     
         13 . The method of  claim 14 , wherein the first pharmaceutical composition, or the second pharmaceutical composition, or both the first pharmaceutical composition and the second pharmaceutical composition are contained in an i.v. bag. 
     
     
         14 . The method of  claim 14 , 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 14 , wherein the ferric (Fe III ) heme-containing molecule is methemoglobin. 
     
     
         16 . The method of  claim 14 , wherein the subject has lost blood during a surgical procedure. 
     
     
         17 . The method of  claim 14 , wherein the subject is a human. 
     
     
         18 . The method of  claim 14 , wherein the subject is a non-human animal.