Abstract: An evaluation and preservation solution for human and animal organs, tissues and parts thereof is described, wherein it comprises serum albumin at a concentration of 55-105 g/L, a scavenger and coating compound, preferably dextran compounds and derivatives thereof having essentially the same structure at a concentration of 1-55 g/L weight, and a physiological serum concentration of salts and nutrients in a physiologically acceptable medium.

Abstract: The present invention is directed to a stable fluorocarbon emulsion having a continuous aqueous phase and discontinuous fluorocarbon phase comprising two fluorocarbons and surprisingly demonstrates that perfluorodecyl bromide is as effective in stabilizing perfluorooctyl bromide emulsions of certain concentrations than much more highly concentrated perfluorooctyl bromide/perfluorodecyl bromide emulsions without the significant problems experienced in higher concentrated emulsions such as longer organ retention times, formation of PFDB crystals, larger emulsion particles, manufacturing problems and inability of repeat dosing inherent with higher concentrations of perfluorodecyl bromide.

Abstract: Perfluorocarbon emulsions having a high stability and good oxygen release are disclosed and described. These perfluorocarbon emulsions are typically for use as artificial oxygen carriers. The perfluorocarbon emulsions include a disperse phase of a perfluorocarbon and an emulsion stabilizer, and continuous phase. The emulsion stabilizer can primarily include a poly(ethylene oxide) block copolymer. These stabilized perfluorocarbon emulsions can be used in liquid and/or hydrogel phases of perfusion bioreactors or various other culture systems to enhance cell viability in thick tissue constructs, or as blood substitutes, although other applications may also be considered.

Abstract: A plurality of artificial red blood cell particles includes each particle of the plurality being substantially monodisperse and each particle having a largest common linear dimension of about 5 ?m to about 10 ?m. The particles can also have a modulus configured such that a particle of the plurality of particles can pass through a tube having an inner diameter of less than about 3 ?m.

Abstract: This disclosure provides, in part, fluorocarbon imaging reagents and formulations for the ex vivo labeling of cells. Labeled cells may be detected in vivo or ex vivo by a nuclear magnetic resonance technique, such as magnetic resonance imaging (MRI) or magnetic resonance spectroscopy (MRS). The disclosure additionally provides methods for using the imaging reagents in a variety of clinical procedures.

Abstract: The disclosure provides, in part, fluorocarbon imaging reagents and formulations for the ex vivo labeling of cells. Labeled cells may be detected in vivo or ex vivo by a nuclear magnetic resonance technique, such as magnetic resonance imaging (MRI) or magnetic resonance spectroscopy (MRS). The disclosure additionally provides methods for using the imaging reagents in a variety of clinical procedures.

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 process is disclosed for the preparation of an essentially tetramer-free, substantially stroma-free, polymerized, pyridoxylated hemoglobin. Also disclosed is an essentially tetramer-free, substantially stroma-free, polymerized, pyridoxylated hemoglobin product capable of being infused into human patients in an amount of up to about 5 liters.

Abstract: The present invention provides a method of making a FC emulsion. The method comprises mixing an FC immiscible hydrophilic liquid and a solid emulsifying agent by agitation at a temperature elevated above the phase transition temperature of the emulsifying agent and below the boiling temperature of the FC immiscible hydrophilic liquid, and adding FC to the mixture of step (a) and agitating at the elevated temperature to disperse droplets of FC in the FC immiscible hydrophilic liquid to form the FC emulsion. The invention also provides another method of making an FC emulsion, which does not require a solid emulsifying agent.

Abstract: A substantially tetramer free hemoglobin solution and a method for producing a substantially tetramer free hemoglobin solution. The method includes polymerizing a solution of hemoglobin, treating the polymerized hemoglobin solution to partially degrade the polymer to tetramer and removing tetramer from the hemoglobin solution.

Abstract: A stable FC emulsion is described. The FC emulsion of the present invention comprises a continuous FC immiscible hydrophilic liquid phase and a dispersed phase comprising FC suspended as droplets within the continuous phase. The emulsion further comprises an emulsifying agent and a stabilizing agent. The stabilizing agent of the present invention reduces the ability of the FC droplets to move within the continuous phase. The present invention also provides a method of making a FC emulsion. The method comprises mixing an FC immiscible hydrophilic liquid and a solid emulsifying agent by agitation at a temperature elevated above the phase transition temperature of the emulsifying agent and below the boiling temperature of the FC immiscible hydrophilic liquid, and adding FC to the mixture of step (a) and agitating at the elevated temperature to disperse droplets of FC in the FC immiscible hydrophilic liquid to form the FC emulsion.

Abstract: Carbonyl compounds generated and accumulated in the peritoneal dialysate can be inactivated or eliminated by a carbonyl compound-trapping agent such as aminoguanidine. Carbonyl compounds generated during sterilization and storage of the peritoneal dialysate can be eliminated by pre-contacting with the trapping agent. Further, it is possible to eliminate carbonyl compounds transferred from the blood to the peritoneal cavity of the patient during peritoneal dialysis treatment, by adding the trapping agent to the peritoneal dialysate or by circulating the fluid through a carbonyl compound-trapping cartridge. Intraperitoneal protein modification by carbonyl compounds is inhibited by the present invention, thereby sufficiently reducing peritoneal disorders associated with peritoneal dialysis treatment.

Abstract: Methods for treating a mammal suffering from massive blood loss comprising administering to the mammal a polymerized hemoglobin solution.

Abstract: A substantially tetramer free hemoglobin solution and a method for producing a substantially tetramer free hemoglobin solution. The method includes polymerizing a solution of hemoglobin, treating the polymerized hemoglobin solution to partially degrade the polymer to tetramer and removing tetramer from the hemoglobin solution.

Abstract: The present invention provides an isolated archael and bacterial heme binding protein which reversibly binds oxygen with a low affinity. The heme binding protein may be utilized as a blood substitute. The invention also provides a method for controlled storage of oxygen by contacting a bacterial heme binding protein with oxygen allowing the protein to bind and store oxygen. The also provides methods to sense gaseous ligands using the heme binding protein. In other embodiments, the invention provides chimeric proteins having a heme-binding domain of an isolated heme binding archael bacterial protein and a heterologous signaling domain.

Abstract: Compositions, and methods of use thereof, for use as blood substitute products comprise aqueous mixtures of oxygen-carrying and non-oxygen carrying plasma expanders and methods for the use thereof. The oxygen-carrying component may consist of any hemoglobin-based oxygen carrier, while the non-oxygen carrying plasma expander my consist of any suitable diluent.

Abstract: Carbonyl compounds generated and accumulated in the peritoneal dialysate can be inactivated or eliminated by a carbonyl compound-trapping agent such as aminoguanidine. Carbonyl compounds generated during sterilization and storage of the peritoneal dialysate can be eliminated by pre-contacting with the trapping agent. Further, it is possible to eliminate carbonyl compounds transferred from the blood to the peritoneal cavity of the patient during peritoneal dialysis treatment, by adding the trapping agent to the peritoneal dialysate or by circulating the fluid through a carbonyl compound-trapping cartridge. Intraperitoneal protein modification by carbonyl compounds is inhibited by the present invention, thereby sufficiently reducing peritoneal disorders associated with peritoneal dialysis treatment.

Abstract: An acellular red blood cell substitute which comprises an essentially tetramer-free, substantially stroma-free, cross-linked, polymerized, pyridoxylated hemoglobin and a nontoxic, pharmaceutically acceptable carrier, its use and a process for preparing said acellular red blood cell substitute.

Abstract: S-nitrosohemoglobin (SNO-Hb) can be formed by reaction of Hb with S-nitrosothiol and by other methods described herein which do not result in oxidation of the heme Fe. Other methods can be used which are not specific only for thiol groups, but which nitrosate Hb more extensively, and may produce polynitrosated metHb as a product or intermediate product of the method. SNO-Hb in its various forms and combinations thereof (oxy, deoxy, met; specifically S-nitrosylated, or nitrosated or nitrated to various extents) can be administered to an animal or human where it is desired to oxygenate, to scavenge free radicals, or to release NO+ groups to tissues. Thiols and/or NO donating agents can also be administered to enhance the transfer of NO+ groups. Examples of conditions to be treated by SNO-Hbs or other nitrosated or nitrated forms of Hb include ischemic injury, hypertension, angina, reperfusion injury and inflammation, and disorders characterized by thrombosis.

Abstract: Diseases which can be ameliorated by delivery of NO to tissues affected by the disease can be treated by administration of nitrosyl-heme-containing donors of NO, including nitrosylhemoglobin. Nitrosylhemoglobin can be made by the reaction of NO with hemoglobin under certain conditions in which the NO:hemoglobin ratio is critical, and is converted to SNO-Hb under physiological conditions.

Abstract: Nitric oxide (NO) interacts with hemoglobin (Hb) at its metal centers, whereas S-nitrosothiols (RSNOs) can donate the NO group to ?93 cysteine residues, thereby shielding the NO functionality from heme inactivation. S-nitrosylation of Hb is under the allosteric control of oxygen and the oxidation state of heme. NO group release from S-nitrosohemoglobin (SNO-Hb) is further facilitated by intracellular low molecular weight thiols, forming RSNOs which can be exported from the erythrocyte to regulate blood pressure. Hence, a dynamic cycle is established in which S-nitrosylation of Hb is initiated in the lung following oxygenation of red blood cells and is completed by SNO-Hb metabolism during arterial-venous transit. SNO-Hb can be formed by reaction of Hb with S-nitrosothiol. This procedure avoids oxidation of the heme.

Abstract: The present invention provides for methods of treating cardiovascular diseases in a mammal. The methods include a step of administering an effective amount of a botulinum toxin directly to a blood vessel of a mammal thereby treating a cardiovascular disease.

Abstract: The present invention provides superoxygenating compositions that comprise hemoglobin and guanosine 3′:5′-cyclic monophosphate (cyclic GMP) generating compounds, and methods for treatment of diseases or medical conditions which utilize the superoxygenating compositions as biocolloids, i.e. hemodiluents, blood substitutes, plasma expanders, or resuscitative fluids. The cardiac output-increasing compositions comprise a simple mixture of hemoglobin and the cyclic GMP generating compounds or hemoglobin physically or chemically coupled to the cyclic GMP generating compounds. The invention also provides time-controlled superoxygenating compositions of hemoglobin and cyclic GMP generating compounds that would be used for treatment of specific diseases or medical conditions requiring time-dependent use of biocolloids, i.e. hemodiluents, blood substitutes, plasma expanders, or resuscitative fluids.

Abstract: Nitrosylation of proteins and amino acid groups enables selective regulation of protein function, and also endows the proteins and amino acids with additional smooth muscle relaxant and platelet inhibitory capabilities. Thus, the invention relates to novel compounds achieved by nitrosylation of protein thiols. Such compounds include: S-nitroso-t-PA, S-nitroso-cathepsin; S-nitroso-lipoprotein; and S-nitroso-immunoglobulin. The invention also relates to therapeutic use of S-nitroso-protein compounds for regulating protein function, cellular metabolism and effecting vasodilation, platelet inhibition, relaxation of non-vascular smooth muscle, and increasing blood oxygen transport by hemoglobin and myoglobin. The compounds are also used to deliver nitric oxide in its most bioactive form in order to achieve the effects described above, or for in vitro nitrosylation of molecules present in the body.

Abstract: An emulsion of perfluoroorganic compounds (PFOC) comprises a rapidly eliminable perfluorocarbon (PFC) and a slowly eliminable perfluorinated cyclic tertiary amine, perfluoro-N-4-(methylcyclohexyl)-piperidine and additionally comprises not less then three rapidly eliminable and three slowly eliminable PFOC admixtures with the critical temperature of dissolution in hexane (CTDH) close to that of main PFOC. The PFOC emulsion is stabilized with a polyoxyethylene-polyoxypropylene copolymer having low viscosity to provide high dynamic oxygen capacity and enhancing oxygen delivery to tissues. To prepare the emulsion the stabilizing agent is heated up to 75° C., all components are saturated with carbon dioxide gas to minimize the reactogenicity in intravessel injection as a means of compensation for mass blood loses, perfusion of organs cut of blood flow, treating air-and fat embolism, obliterating vascular injuries of extremities and preventing toxic injuries caused by various xenobiotics.

Abstract: An acellular red blood cell substitute which comprises an essentially tetramer-free, substantially stroma-free, cross-linked, polymerized, pyridoxylated hemoglobin and a nontoxic, pharmaceutically acceptable carrier, its use and a process for preparing said acellular red blood cell substitute.

Abstract: A process is disclosed for the preparation of an essentially tetramer-free, substantially stroma-free, polymerized, pyridoxylated hemoglobin. Also disclosed is an essentially tetramer-free, substantially stroma-free, polymerized, pyridoxylated hemoglobin product capable of being infused into human patients in an amount of up to about 5 liters.

Abstract: A unified solution system for organ and/or tissue preservation and/or hypothermic blood substitution can be used to prepare multiple solutions for use in various stages of organ procurement, preservation and transplantation and bloodless surgery procedures.

Abstract: Compositions, and methods of use thereof, for use as blood substitute products comprise aqueous mixtures of oxygen-carrying and non-oxygen carrying plasma expanders and methods for the use thereof. The oxygen-carrying component may consist of any hemoglobin-based oxygen carrier, while the non-oxygen carrying plasma expander my consist of any suitable diluent.

Abstract: A biocompatible emulsifier for forming stable emulsions is disclosed. The emulsifier is particularly useful for emulsions of biological fluids, such as artificial blood, and for emulsions as drug delivery vehicles.

Abstract: A process is disclosed for the preparation of an essentially tetramerfree, substantially stromafree, polymerized, pyridoxylated hemoglobin. Also disclosed is an essentially tetramerfree, substantially stromafree, polymerized, pyridoxylated hemoglobin product capable of being infused into human patients in an amount of up to about 5 liters.

Abstract: An acellular red blood cell substitute which comprises an essentially tetramer-free, substantially stroma-free, cross-linked, polymerized, pyridoxylated hemoglobin and a nontoxic, pharmaceutically acceptable carrier, its use and a process for preparing said acellular red blood cell substitute.

Abstract: A hemodialysis acid concentrate which includes, before mixing, sodium chloride powder and sometimes dextrose powder as a powder component, and a liquid component which contains some or all of the following: potassium chloride, magnesium chloride, sodium chloride, dextrose, calcium chloride, and an acid from the group lactic acid, acetic acid, and citric acid. The liquid and powder components are added to a specified volume of water to make a final acid concentrate. The individual components are easily inspected for quality control and the shipping weight is greatly reduced compared to conventional liquid acid concentrates.

Abstract: Storage stable fluorocarbon emulsions having a continuous aqueous phase and a discontinuous fluorocarbon phase, in which the fluorocarbon phase comprises a major amount of a first fluorocarbon or fluorocarbon mixture, and a minor amount of a second fluorocarbon or fluorocarbon mixture, in which the second fluorocarbon has a molecular weight greater than that of the first fluorocarbon and the second fluorocarbon includes a lipophilic moiety in its structure, whereby the second fluorocarbon serves to promote particle size stability in the emulsion while simultaneously providing favorably short organ retention times when administered to animals in vivo.

Abstract: S-nitrosothiols (RSNOs) can donate the NO group to the &bgr;93 cysteine residues of hemoglobin (Hb) without inactivating the heme. S-nitrosylation of Hb is under the allosteric control of oxygen and the oxidation state of heme. NO group release from S-nitrosohemoglobin (SNO-Hb) is further facilitated by intracellular low molecular weight thiols, forming RSNOs which can be exported from the erythrocyte to regulate blood pressure and platelet activation. SNO-Hb can be formed by reaction of Hb with S-nitrosothiol. This procedure avoids oxidation of the heme. Other methods can be used which are not specific only for thiol groups, but which nitrosate Hb more extensively, and may produce polynitrosated metHb as a product or intermediate product of the method.

Abstract: Methods for time-regulated prophylaxis or treatment of animals or humans for limited circulatory oxygen delivery induced by the inhibitory effects of a plasma-borne hemoglobin-based material on L-arginine→nitric oxide→cGMP pathways in the arteriovenous vasculature. The properties of the invention restore and increase circulatory oxygen delivery by increasing circulatory flow of the blood-hemoglobin-based material through selective activation of L-arginine→nitric oxide→cGMP pathways in the arterial rather than venous vasculature. A method of the invention utilizes oxygen-carrying biocolloid compositions that consist of a hemoglobin-based material and a guanosine 3′:5′-cyclic monophosphate (cGMP) generating entity, for treatment of animals and humans in need thereof for diseases or medical conditions which utilize the biocolloids as hemodiluents, blood substitutes, plasma expanders, or resuscitative fluids.

Abstract: A method of treating a mammal suffering from hypotension by administering intermolecularly- or intramolecularly-crosslinked stroma-free hemoglobin to the mammal.

Abstract: Fluorocarbon emulsions comprising a stabilizing, particle size controlling fluorophilic/hydrophilic compound which can have the formulaR.sub.F.sup.1 --W--R.sub.H.sup.1 (I)whereinR.sub.F.sup.1 is a linear, branched or cyclic C.sub.2-14 fluorocarbon group;R.sub.H.sup.1 is a linear, branched or cyclic C.sub.2-18 saturated or unsaturated hydrocarbon group; andW is absent or is a bivalent species chosen from the group consisting of --O--, --S--, or various fluorinated structures. Use of the fluorophilic/lipophilic compound in the dispersions of the invention provides stable particle size and efficient emulsification. The dispersions of the invention can comprise biologically useful additive and can be used for various purposes, as oxygen carriers, contrast agents, or diagnostic agents.

Abstract: Therapeutic treatment of septic shock comprises administering to an animal stroma-free hemoglobin, typically at a dose ranging from the least amount effective to increase perfusion, up to a dosage of about 2500 milligrams kilograms per of body weight.

Abstract: The present invention provides a chemically modified form of hemoglobin that is stabilized and can efficiently bind and release oxygen. In addition the chemically modified hemoglobin may be polymerized to increase its molecular weight and increase its stability so that it will have a longer half life in the circulatory system and may be used as a stable oxygen transport mediator which is useful as the basis of a blood substitute.

Abstract: Compositions, and methods of use thereof, for use as blood substitute products comprise aqueous mixtures of oxygen-carrying and non-oxygen carrying plasma expanders and methods for the use thereof. The oxygen-carrying component may consist of any hemoglobin-based oxygen carrier, while the non-oxygen carrying plasma expander my consist of any suitable diluent.

Abstract: A method for increasing perfusion in a mammal suffering from cardiogenic shock by administering a perfusion-increasing effective amount of intermolecularly- or intramolecularly-crosslinked stroma-free hemoglobin to the mammal.

Abstract: A method for increasing perfusion in a mammal suffering from stroke by admninistering a perfusion-increasing effective amount of intermolecularly- or intramolecularly-crosslinked stroma-free hemoglobin to the mammal.

Abstract: The present invention is directed to the use of an inhibitor of NO activity, such as a nitric oxide scavenger or an NO synthase inhibitor, as as an adjunct to treatment of inappropriate tissue vascularization disorders.

Abstract: A process for preparing solutions of hemoglobin hyperpolymers by fractionating hemoglobin hyperpolymers having a nonuniform molecular weight distribution according to molecular weight using a polyhydroxy compound to precipitate different fractions of hemoglobin hyperpolymers, wherein each fraction has a different but more uniform molecular weight distribution as compared to the starting hemoglobin hyperpolymers. Preferably, the polyhydroxy compound is a polyalcohol, especially polyethylene glycol.

Abstract: A method for analyzing the ADME/PK properties of a mixture of compounds is (1) perfusing an animal or organ with a perfluorocarbon emulsion blood substitute, (2) administering the mixture of test compounds, (3) withdrawing an aliquot of the perfusate, (4) disrupting the emulsion, and (5) analyzing the aqueous phase of the perfusate for the concentration of test compounds.

Abstract: Artificial oxygen carrier composed of native or modified hemoglobins for direct biological or medical use, in which the oxygen binding site of the hemoglobin is provided with a protective ligand, preferably carbon monoxide, which does not have to be removed prior to use.

Abstract: Platelet substitutes, comprising fibrinogen, or analogous products useful in therapy, which further comprise an insoluble carrier to which is bound an essentially non-degraded active protein including the sequence Arg-Gly-Asp. Such conjugates can be made by a conjugation process comprising 0.01 to 2.5% by weight active fibrinogen, and no more that 50% inactive fibrinogen.

Abstract: The present invention provides a chemically modified form of hemoglobin that is stabilized and can efficiently bind and release oxygen. In addition the chemically modified hemoglobin may be polymerized to increase its molecular weight and increase its stability so that it will have a longer half life in the circulatory system and may be used as a stable oxygen transport mediator which is useful as the basis of a blood substitute.

Abstract: An injectable physiologically acceptable aqueous phase fluorocarbon emulsion, which has substantially no free fluorocarbon, has an excellent stability is prepared by a process of the invention. Typically, more than about 99.8 wt. % of the fluorocarbon remains in the size range of about 0.2 to 0.4 microns even after being stored at room temperature for one year or more in sealed containers under a non-oxidizing atmosphere. The emulsion is useful in medical applications, for example, coronary angioplasty, cancer therapy, among others.