Abstract: The invention provides methods, compositions, and medical kits comprising a nitrite-reductase promoter, such as an allosteric modulator of hemoglobin, for use in treating medical disorders and preservation of blood products. In one aspect, the invention provides methods, compositions, and medical kits comprising an inorganic nitrite salt and a nitrite-reductase promoter, such as an allosteric modulator of hemoglobin, for use in treating medical disorders, such as cancer, cardiovascular disorders, ischemic conditions, hemolytic conditions, and bacterial infections. Exemplary inorganic nitrite salts include sodium nitrite and arginine nitrite. Exemplary allosteric modulators of hemoglobin described herein include alkyl-substituted and acyl-substituted di-nitroheterocycles.

Abstract: Methods for making hemoglobin based blood substitute preparations and hemoglobin based blood substitute preparations. The methods involve preparing a low purity erythrocyte protein fraction comprising hemoglobin protein and endogenous non-hemoglobin protein complement, and chemically modifying the proteins in the protein fraction to form a cross-linked hemoglobin containing blood substitute preparation. The low purity erythrocyte protein preparation can contain from at least about 0.2% (mole/mole) up to about 20% (mole/mole) endogenous non-hemoglobin protein complement. At least about 90% (mole/mole) of the hemoglobin proteins can be cross-linked, so that the average molecular mass of cross-linked proteins comprising hemoglobin protein molecules in the preparation is at least about 300 kDa. The preparations can be used to prepare finished blood substitute formulations for in-vivo and ex-vivo use.

Abstract: The present invention relates to a method for removing biopolymer aggregates and viruses from a fluid. In a first step, the biopolymer aggregates are selectively removed by filtration through a porous, polyamide-comprising shaped body having a native surface. In a second step, the biopolymer aggregate-free fluid is filtered through at least one suitable virus-retentive membrane.

Abstract: In vitro and in vivo methods of removing carbon monoxide from hemoglobin in blood or animal tissue are described. Methods of treating carboxyhemoglobinemia (carbon monoxide poisoning) in a subject are also described. The methods include administering natural or artificial oxygen carriers that are in their reduced form. Methods of producing a reduced oxygen carrier are further described. Methods of treating cyanide poisoning or hydrogen sulfide poisoning with oxygen carriers are also described.

Abstract: The present invention relates to a polymer solution for use as a rheological blood substitute. The rheological blood replacement solution comprises in its basic composition a water-soluble cellulose polymer with a molecular weight of 100 kDa or greater, polyethylene oxide and a solvent. The rheological blood replacement solution of the invention can be used in a variety of applications, e.g. as blood substitute, calibration agent or reference agent. The blood replacement solution is based on a polymer solution, which can also be used as pharmaceutical composition, e.g. for the prevention or treatment of haemorrhage or shock-related disorders.

Abstract: The invention provides compositions containing hemoglobin, particularly PEGylated hemoglobin. The PEGylated hemoglobin molecule is capable of transferring oxygen or carbon monoxide bound thereto to a tissue with which it is in proximity. Exemplary PEGylated hemoglobin formulations of the invention are virally inactivated. Various compositions of the invention include hemoglobin, which may be conjugated with one or more water-soluble polymer. PEGylated hemoglobin includes those species in which the iron atom of the hemoglobin molecule is not bound to oxygen or any other species, and hemoglobin molecules in which a species other than oxygen, e.g., carbon monoxide, is bound to the iron atom. The compositions of the invention are formulated as hypo-, iso- or hypertonic solutions of the PEGylated hemoglobin. The compositions are of use to treat and/or ameliorate disease, injury and insult by providing for the oxygenation of tissues and/organs.

Abstract: The present invention provides an enteric-coated hemoglobin multiparticulate comprising a core, a hemoglobin formulation coating, an inner or sub-coating, and an enteric coating. The present invention also provides a method of preparing said enteric-coated hemoglobin multiparticulate. The present invention further provides a method for treating various diseases caused by oxygen deficiency comprising administering to a subject said enteric-coated hemoglobin multiparticulate in order to orally deliver the encapsulated hemoglobin-based oxygen carriers to a specific target of said subject in a controlled release manner.

Abstract: The present application relates to methods and compositions for the generation of therapeutic cells having reduced incidence of karyotypic abnormalities. In several embodiments cardiac stem cells are cultured in an antioxidant-supplemented media that reduces levels of reactive oxygen species, but does not down regulate DNA repair mechanisms. In several embodiments, physiological oxygen concentrations are used during culture in order to increase the proliferation of stem cells, decrease the senescence of the cells, decrease genomic instability, and/or augment the functionality of such cells for cellular therapies.

Abstract: A process for making hemoglobin based oxygen carrier (HBOC) containing pharmaceutical composition suitable for oral delivery and the composition formed thereby are described. There are three exemplary composition configurations which include (1) hemoglobin-loaded nanoparticles solution, (2) enteric-coated hemoglobin capsules and (3) enteric-coated hemoglobin tablets. To facilitate the bioavailability and bio-compatibility of hemoglobin, intestinal absorption enhancers are added in each of the HBOC formulations. Protective layers ensure delivery of an intact hemoglobin structure in intestinal tract without degradation in the stomach. The HBOC formulations may be used for preventive or immediate treatment of high altitude syndrome (HAS) or for treatment of hypoxic conditions including blood loss, anemia, hypoxic cancerous tissue, and other oxygen-deprivation disorders.

Abstract: Solutions and suspensions comprising polymerized hemoglobin derived from human blood are disclosed. The solutions and suspensions may comprise cell culture medium, an enzyme (such as a protease), and/or a buffer. Processes of preparing the solutions and suspensions are also disclosed. The solutions and suspensions may be employed in methods of isolating mammalian cells, such as pancreatic islets, methods of preserving mammalian tissue and organs, methods of aiding the recovery of mammalian cells following their isolation, methods of maintaining mammalian cells, methods of propagating mammalian cells, and methods of treating a mammal with diabetes.

Abstract: The present invention provides a pharmaceutical composition containing hemoglobin-based therapeutic agent for treating cancer. The hemoglobin moiety can target cancer cells and the therapeutic moiety (i.e. active agent/therapeutic drug) can kill the cancer cells efficiently. The hemoglobin-based therapeutic agent used in the present invention can be used in the treatment of various cancers such as pancreatic cancer, leukemia, head and neck cancer, colorectal cancer, lung cancer, breast cancer, liver cancer, nasopharyngeal cancer, esophageal cancer, prostate cancer, stomach cancer and brain cancer. The composition can be used alone or in combination with other therapeutic agent(s) such as chemotherapeutic agent to give a synergistic effect on cancer treatment, inhibiting metastasis and/or reducing recurrence. The presently claimed hemoglobin-based 5FU-two-dye conjugate and/or hemoglobin-based 5FU-one-dye conjugate can also be used in live-cell imaging and diagnostic imaging.

Abstract: The present invention relates to succinimide-activated nitroxyl compounds and methods for the synthesis of such compounds. The present invention also relates to the use of succinimide-activated nitroxyl compounds to prepare nitroxylated proteins, for example nitroxylated heme proteins (e.g., nitroxylated hemoglobin and nitroxylated myoglobin). The nitroxylated proteins are optionally also conjugated to a polyalkylene oxide (PAO), for example to a polyethylene glycol (PEG). Polynitroxylated heme proteins are useful as oxygen therapeutic agents (OTAs). The invention further relates to pharmaceutical compositions of the nitroxylated proteins and methods for the use of nitroxylated proteins in the treatment of various conditions.

Abstract: PEGylated diaspirin-crosslinked hemoglobin conjugates having high oxygen affinity are described which have enhanced nitrite reductase activity to deliver oxygen, carbon monoxide, nitric oxide or mixtures thereof to tissues to treat various diseases and conditions.

Abstract: The invention provides compositions containing hemoglobin, particularly PEGylated hemoglobin. The PEGylated hemoglobin molecule is capable of transferring oxygen or carbon monoxide bound thereto to a tissue or red blood cells with which it is in proximity. Exemplary PEGylated hemoglobin formulations of the invention are virally inactivated. Various compositions of the invention include hemoglobin, which may be conjugated with one or more water-soluble polymer. PEGylated hemoglobin includes those species in which the iron atom of the hemoglobin molecule is not bound to oxygen or any other species, and hemoglobin molecules in which a species other than oxygen, e.g., carbon monoxide, is bound to the iron atom. The compositions of the invention are formulated as hypo-, iso- or hypertonic solutions of the PEGylated hemoglobin. The compositions are of use to treat and/or ameliorate disease, injury and insult by providing for the oxygenation of tissues and/organs.

Abstract: A pharmaceutical composition comprising an amphiphilic emulsifier, a polar liquid carrier and, optionally, a lipid component. The amphiphilic emulsifier form free-moving, optionally lipid-carrying, micelles (LMs) in the polar liquid carrier. The pharmaceutical composition is free of hemoglobin and fluorocarbon and can be used for treating conditions related to lack of blood supply and to raise the blood pressure and correct hypovolemia.

Abstract: Compositions of matter and methods for making, storing and administering artificial blood substitutes. Artificial blood substitutes may have oxygen carriers that encapsulate an oxygen-binding compound in a polymer vesicle. Oxygen-binding compounds may include hemoglobin, myoglobin, or other oxygen binding compounds having characteristics similar to hemoglobin. Oxygen carriers may include nanoparticles, polymers and/or polymersomes comprising of poly(ethylene oxide)-block-poly(?-caprolactone) (PEO-b-PCL) and related diblock copolymers of poly(ethylene oxide)-block-poly(?-methyl ?-caprolactone) (PEO-b-PMCL). The oxygen carriers may have tunable oxygen-binding capacities, uniform and appropriately small size distributions, and human bloodlike viscosities and oncotic properties.

Abstract: Compositions of matter and methods for making, storing and administering artificial blood substitutes. Artificial blood substitutes may have oxygen carriers that encapsulate an oxygen-binding compound in a polymer vesicle. Oxygen-binding compounds may include hemoglobin, myoglobin, or other oxygen binding compounds having characteristics similar to hemoglobin. Oxygen carriers may include nanoparticles, polymers and/or polymersomes comprising of poly(ethylene oxide)-block-poly(?-caprolactone) (PEO-b-PCL) and related diblock copolymers of poly(ethylene oxide)-block-poly(?-methyl ?-caprolactone) (PEO-b-PMCL). The oxygen carriers may have tunable oxygen-binding capacities, uniform and appropriately small size distributions, and human bloodlike viscosities and oncotic properties.

Abstract: The present invention provides PEGylated hemoglobins and PEGylated albumins comprising polyethylene glycol (PEG) conjugated to hemoglobin or to albumin, wherein the PEG is a maleimide PEG, an alkylamide PEG, an iodoacetamide PEG, a p-nitro thio-phenyl PEG, a vinyl sulfone PEG, or a mixed disulfide PEG; and PEGylated albumins and PEGylated hemoglobins comprising polyethylene glycol (PEG) attached to a thiolated amino group of albumin or hemoglobin, wherein the amino group is thiolated using dithio sulfo succinimidyl propionate (DTSSP) or dithiosuccinimidyl propionate (DTSP) or dithiobispropionimidate. The invention also provides methods of preparing PEGylated hemoglobins and PEGylated albumins comprising a) reacting hemoglobin or albumin with a thiolating agent and with a PEGylating agent, and b) capping unPEGylated reactive thiols of hemoglobin or albumin with N-ethyl maleimide.

Abstract: A high temperature-stable and highly purified ?-? cross-linked tetrameric hemoglobin suitable for use in mammals without causing renal injury and vasoconstriction is provided. The dimeric form of hemoglobin is degenerated and purification processes are performed on red blood cells obtained from whole blood. Controlled hypotonic lysis in an instant cytolysis apparatus prevents the lysis of white blood cells. Nucleic acids from white blood cells and the phospholipids impurities are not detected. The blocking of reactive sulfhydryl groups in hemoglobin by a sulfhydryl reagent is performed in an oxygenated environment. Flowthrough column chromatography is used to remove different plasma protein impurities. N-acetyl cysteine is added to the ?-? cross-linked tetrameric hemoglobin solution to maintain a low level of met-hemoglobin. The stabilized hemoglobin is preserved in an infusion bag with aluminum overwrap to prevent formation of inactive met-hemoglobin from oxygen intrusion.

Abstract: A pharmaceutical composition comprising a lipid component; an amphiphilic emulsifier; and a polar liquid carrier. The lipid component and the amphiphilic emulsifier form free-moving lipid-carrying micelles (LMs) in the polar liquid carrier. The pharmaceutical composition is free of hemoglobin and fluorocarbon and can be used for treating conditions related to lack of blood supply and to raise the blood pressure.

Abstract: An oxygen delivery system is disclosed. The basis of the oxygen deliver system is a carbide-derived carbon (CDC). The CDC can be tuned to carry O2 directly (CDC OC), or hemoglobin can be adsorbed to provide a hemoglobin-based oxygen carrier (CDC HBOC). The delivery system allows the use of a variety of hemoglobins which differ in their oxygen dissociation profiles, including variant and mutant hemoglobins from other species. The delivery system is biocompatible and stable, and is able to irreversibly bind and hold large amounts of functional hemoglobin variants. The CDC HBOC and CDC OC provide a safe and effective blood substitute for combat casualty care, as well as being useful for oxygen delivery in other contexts.

Abstract: A pharmaceutical composition comprising a lipid component; an amphiphilic emulsifier; and a polar liquid carrier. The lipid component and the amphiphilic emulsifier form free-moving lipid-carrying micelles (LMs) in the polar liquid carrier. The pharmaceutical composition is free of hemoglobin and fluorocarbon and can be used for treating conditions related to lack of blood supply and to raise the blood pressure.

Abstract: The present invention relates to a modified porphyrin-based oxygen-carrying protein, such as haemoglobin, which has been found, in its unmodified state to have a low affinity site of electron transfer and a high affinity electron transfer between a reductant and ferryl haem iron via one or more protein amino acids. The invention provides such proteins that comprise a modification to enhance this pathway.

Abstract: H-NOX proteins are mutated to exhibit improved or optimal kinetic and thermodynamic properties for blood gas O2 delivery. The engineered H-NOX proteins comprise mutations that impart altered O2 or NO ligand-binding relative to the corresponding wild-type H-NOX domain, and are operative as physiologically compatible mammalian blood O2 gas carriers. The invention also provides pharmaceutical compositions, kits, and methods that use wild-type or mutant H-NOX proteins for the treatment of any condition for which delivery of O2 is beneficial.

Abstract: A method for treating conditions related to lack of blood supply with a lipid based resuscitation fluid is disclosed. The resuscitation fluid contains a lipid component and an aqueous carrier. The lipid component forms an emulsion with the aqueous carrier. The resuscitation fluid can be used to increase the blood pressure and to carry oxygen to tissues. The resuscitation fluid can also be used for preserving the biological integrity of donor organs for transplantation.

Abstract: The present technology provides synthesized particles that mimic key structural and functional features of red blood cells. Such RBC-mimicking particles possess the ability to carry oxygen (and carbon dioxide) and flow through capillaries smaller than their own diameter. Further, such particles can also deliver drugs and imaging agents. These particles provide a new paradigm for the design of drug delivery and imaging carriers since they combine the functionality of natural RBCs with the broad applicability and versatility of synthetic drug delivery particles. Further, such particles can be used for detoxification and other biomedical applications.

Abstract: A method for treating conditions related to lack of blood supply with a lipid based resuscitation fluid is disclosed. The resuscitation fluid contains a lipid component and an aqueous carrier. The lipid component forms an emulsion with the aqueous carrier. The resuscitation fluid can be used to increase the blood pressure and to carry oxygen to tissues. The resuscitation fluid can also be used for preserving the biological integrity of donor organs for transplantation.

Abstract: Peptide compounds that are agonists of the erythropoietin receptor (EPO-R) are described, as well as therapeutic methods using such peptide compounds to treat disorders associated with insufficient or defective red blood cell production. Pharmaceutical compositions, which comprise the peptide compounds of the invention, are also provided.

Abstract: The present invention includes compositions containing carboxamidomethylated cross-linked hemoglobin where the cysteine moiety of the hemoglobin includes a thiol protecting group and where the hemoglobin has a reduced ability to bind with nitric oxide. Preferably, the hemoglobin is deoxygenated, endotoxin free, and stroma free. The present invention also includes method of preparation, process of preparation and the method of use including supplementing blood volume in mammals and treating disorders in mammals where oxygen delivery agents are of benefit.

Abstract: An artificial oxygen carrier (AOC) for use in the body. A first gas permeable first shell encloses an oxygen carrying agent. The first shell has a second oxygen carrying agent surrounding it, and there is a second gas permeable shell enclosing the second agent. The concentric shells are not subject to turbulent breakup, or chemical decomposition, do not release the agents.

Abstract: A method for treating conditions related to lack of blood supply with a lipid based resuscitation fluid is disclosed. The resuscitation fluid contains a lipid component and an aqueous carrier. The lipid component forms an emulsion with the aqueous carrier. The resuscitation fluid can be used to increase the blood pressure and to carry oxygen to tissues. The resuscitation fluid can also be used for preserving the biological integrity of donor organs for transplantation.

Abstract: Methods of using an ETB receptor agonist, such as IRL-1620, for the treatment of stroke or cerebrovascular accidents are disclosed. The ETB receptor agonist is used alone or in combination with a second agent useful in the treatment of stroke or other cerebrovascular accident.

Abstract: A method heat treatment of cross-linked hemoglobin solutions including polymeric hemoglobin is disclosed. The method involves contacting the hemoglobin solution with a high temperature short time heat treatment apparatus. The high temperature short time process thermally denatures unmodified tetrameric hemoglobin (hemoglobin dimer form), protein impurities (e.g. immunoglobin-G, serum albumin), bacteria, and viruses so that renal injury, vascular detrimental effects and other toxicity reactions can be avoided.

Abstract: Contrary to current opinion that nitrite in general oxidizes hemoglobin with elimination of active nitric oxide, deoxygenated hemoglobin reacts with low concentration inorganic nitrite to produce very stable iron nitrosyl hemoglobin which on delivery into the body is converted to a hemoglobin capable of nitric oxide delivery and provides vasodilator and antiplatelet activity. This provides basis for ameliorated risk blood product transfusions.

Abstract: A method for treating conditions related to lack of blood supply with a lipid based resuscitation fluid is disclosed. The resuscitation fluid contains a lipid component and an aqueous carrier. The lipid component forms an emulsion with the aqueous carrier. The resuscitation fluid can be used to increase the blood pressure and to carry oxygen to tissues. The resuscitation fluid can also be used for preserving the biological integrity of donor organs for transplantation.

Abstract: A highly purified and heat stable cross-linked nonpolymeric tetrameric hemoglobin suitable for use in mammals without causing renal injury and vasoconstriction is provided. A high temperature and short time (HTST) heat processing step is performed to remove undesired dimeric form of hemoglobin, uncross-linked tetrameric hemoglobin, and plasma protein impurities effectively. Addition of N-acetyl cysteine after heat treatment and optionally before heat treatment maintains a low level of met-hemoglobin. The heat stable cross-linked tetrameric hemoglobin can improve and prolong oxygenation in normal and hypoxic tissue. In another aspect, the product is used in the treatment of various types of cancer such as leukemia, colorectal cancer, lung cancer, breast cancer, liver cancer, nasopharyngeal carcinoma and esophageal cancer. The inventive hemoglobin can also be used to prevent tumor metastasis and recurrence following surgical tumor excision.

Abstract: Disclosed is a multi-compartment medical device useful in the storage, processing and extended shelf life of perishable products, especially pharmaceutical, food and biological products. Particular biological materials processed according to the present methods are human blood and blood products (RBCs). Also disclosed are processes for preserving food, pharmaceutical and biological products for long-term storage and extended shelf life employing a process that reduces the hydration level of the material to less than native hydration levels of the specific product. The invention further provides stabilized biological products, such as in the form of glassified beads, prepared using a two-phase system according to the described processes that may be rehydrated and prepared for clinical use, and having essentially no loss of biological and/or pharmacological activity.

Abstract: A high temperature-stable and highly purified cross-linked (optionally ?70% ?-? linked) tetrameric hemoglobin with high efficiency of oxygen delivery suitable for use in mammals without causing renal injury and vasoconstriction is provided. The dimeric form of hemoglobin is degenerated and purification processes are performed on red blood cells from whole blood. Controlled hypotonic lysis in an instant cytolysis apparatus prevents lysis of white blood cells. Nucleic acids from white blood cells and phospholipids impurities are not detected. Blocking of reactive sulfhydryl groups by a sulfhydryl reagent is performed in an oxygenated environment. Flowthrough column chromatography removes different plasma protein impurities. N-acetyl cysteine is added to the cross-linked tetrameric hemoglobin to maintain a low level of met-hemoglobin. The stabilized hemoglobin is preserved in an infusion bag with aluminum overwrap to prevent formation of inactive met-hemoglobin from oxygen intrusion.

Abstract: An oxygen delivery system is disclosed. The basis of the oxygen deliver system is a carbide-derived carbon (CDC). The CDC can be tuned to carry O2 directly (CDC OC), or hemoglobin can be adsorbed to provide a hemoglobin-based oxygen carrier (CDC HBOC). The delivery system allows the use of a variety of hemoglobins which differ in their oxygen dissociation profiles, including variant and mutant hemoglobins from other species. The delivery system is biocompatible and stable, and is able to irreversibly bind and hold large amounts of functional hemoglobin variants. The CDC HBOC and CDC OC provide a safe and effective blood substitute for combat casualty care, as well as being useful for oxygen delivery in other contexts.

Abstract: A highly purified and heat stable cross-linked nonpolymeric tetrameric hemoglobin suitable for use in mammals without causing renal injury and vasoconstriction is provided. A high temperature and short time (HTST) heat processing step is performed to remove undesired dimeric form of hemoglobin, uncross-linked tetrameric hemoglobin, and plasma protein impurities effectively. Addition of N-acetyl cysteine after heat treatment and optionally before heat treatment maintains a low level of met-hemoglobin. The heat stable cross-linked tetrameric hemoglobin can improve and prolong oxygenation in normal and hypoxic tissue. In another aspect, the product is used in the treatment of various types of cancer such as leukemia, colorectal cancer, lung cancer, breast cancer, liver cancer, nasopharyngeal carcinoma and esophageal cancer. Another application is heart preservation in situations where there is a lack of oxygen supply in vivo, such as in heart transplant or oxygen-deprived heart.

Abstract: Described herein is the finding that a mutant form of human neuroglobin (H64L) with a stable five-coordinate geometry reduces nitrite to nitric oxide approximately 2000-times faster than the wild type neuroglobin. Five-coordinate neuroglobin is also capable of binding and releasing oxygen. Based on these findings, the use of five-coordinate neuroglobin as a blood substitute is described herein. Particularly provided is a method of replacing blood and/or increasing oxygen delivery to tissues in a subject by administering to the subject a therapeutically effective amount of neuroglobin with a stable five-coordinate geometry. In some cases, five-coordinate neuroglobin is administered in combination with another therapeutic agent or composition, such as a second blood replacement product (for example, a hemoglobin-based oxygen carrier), a blood product (such as red blood cells, serum or plasma) or whole blood.

Abstract: The present invention provides compounds of Formula (I): or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein the variables A, B, R1, R2, U, X, Y, Z, Ua, Xa, Ya, and Za are defined are as defined herein, which are useful as inhibitors of matrix metalloproteinases (MMP), and/or TNF-? converting enzyme (TACE), or a combination thereof.