WO1996019918A1 - Dextranes et substituts sanguins - Google Patents

Dextranes et substituts sanguins Download PDF

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Publication number
WO1996019918A1
WO1996019918A1 PCT/US1995/016680 US9516680W WO9619918A1 WO 1996019918 A1 WO1996019918 A1 WO 1996019918A1 US 9516680 W US9516680 W US 9516680W WO 9619918 A1 WO9619918 A1 WO 9619918A1
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Prior art keywords
solution
blood
oncotic
oxygen
molecular weight
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PCT/US1995/016680
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English (en)
Inventor
Paul E. Segall
Harold D. Waitz
Hal Sternberg
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Biotime, Inc.
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Application filed by Biotime, Inc. filed Critical Biotime, Inc.
Priority to AU45269/96A priority Critical patent/AU4526996A/en
Publication of WO1996019918A1 publication Critical patent/WO1996019918A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/41—Porphyrin- or corrin-ring-containing peptides
    • A61K38/42—Haemoglobins; Myoglobins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates generally to aqueous solutions and methods for using aqueous solutions to perfuse a mammalian subject in need of perfusion and which act as effective substitutes for blood.
  • the invention features a solution to replace all or a portion of the blood of a mammalian subject, including a primate, comprising K + , Mg ++ , Na + , Ca ++ , Cl " ; one or more water soluble oncotic agents; an organic carboxylic acid or salt thereof; and physiological levels of a sugar, with the proviso that the solution does not contain a conventional biological buffer.
  • a primate comprising K + , Mg ++ , Na + , Ca ++ , Cl " ; one or more water soluble oncotic agents; an organic carboxylic acid or salt thereof; and physiological levels of a sugar, with the proviso that the solution does not contain a conventional biological buffer.
  • the solutions of the invention may be used to replace all or a portion of the blood of a mammalian subject, including a primate, at normal temperatures or at temperatures substantially below those normally maintained by a mammal, generally less than 37°-38°C and greater than -2°C.
  • the solution includes one or more water soluble oncotic agents selected from the group consisting of high molecular weight hydroxyethyl starch, low molecular weight hydroxyethyl starch, dextran 70, dextran 40, albumin, and mannitol.
  • water soluble oncotic agent a molecule whose size is sufficient to prevent its loss from the circulation by readily traversing the fenestrations of the capillary bed into the interstitial spaces of the tissues of the body.
  • water soluble oncotic agents include starches, proteins, and sugars.
  • one aspect of the invention encompasses blood substitute solutions containing a blood clotting factor.
  • Another aspect of the invention encompass a method of administering a blood substitute followed by or with the simultaneous administration of a blood clotting factor.
  • the blood clotting factor is selected from the group consisting of vitamin K, Factors I, II, V, VII, VIII, VIIIC, IX, X, XI, XII, XIII, protein C, von Willebrand factor, Fitzgerald factor (prekallikrein) , Fletcher factor (high molecular weight kininogen) , and a proteinase inhibitor, such as aprotinin.
  • aprotinin is Trasylol® (Miles, West Haven, CT) , a saline solution of aprotinin containing 10,000 Kallikrein-Inhibitor Units (KIU)/ml.
  • blood clotting factor is meant a factor which accelerates, promotes, or allows the formation of a blood clot.
  • the blood clotting factor is present in an amount that results in a blood concentration in the subject of between 100 - 100,000 KlU/ml.
  • Oxygen-carrying solutions have been developed based on hemoglobin from human or animal sources, or made by genetic engineering, and modified by techniques such as crosslinking or the addition of polyethylene glycol (Spahn et al. (1994) Anesth. Analg. 78:1000-1021). However, these solutions are toxic in high quantities. When a subject has lost blood, it would be advantageous to administer a blood substitute with a physiological or hyperphysiological oxygen-carrying capacity.
  • the solution of the invention includes an oxygen-carrying component.
  • an oxygen-carrying component such as cross-linked or high molecular weight hemoglobin
  • the oxygen-carrying component is selected from the group consisting of hemoglobin or other respiratory pigments extracted from natural sources, such as hemocyanin, chlorocruorin, and hemerythrin, respiratory pigments made by recombinant DNA techniques, a crosslinked form of hemoglobin, and fluorocarbons.
  • the oxygen-carrying component may be modified by methods known to the art, for example, a fluorocarbon component may be encapsulated by a liposome, and respiratory pigments altered by crosslinking or reaction with polyethylene glycol.
  • oxygen-carrying component is meant a component which forms an easily reversible interaction with oxygen, which allows more oxygen to be solubilized than would otherwise be possible, and that results in delivery of the excess oxygen to the tissue.
  • a prefered oxygen- carrying component is hemoglobin, present in the concentration range of about between 20-200 g/1.
  • the solutions of the invention are useful for harvesting and/or delivering red blood cells to patients in need thereof.
  • Red blood cells for delivery may be obtained from a number of sources, including human donors, transgenic animals, or derived in vi tro .
  • Plasma expanders and blood substitutes having two or more oncotic agents with differential clearance rates are particularly advantageous in providing extensive protection of oncotic pressure without inhibiting the subject's production of replacement plasma proteins.
  • the present invention includes solutions having two or more oncotic agents with differential clearance rates.
  • differential clearance rates is meant the rate at which a first oncotic agent is removed from the blood circulation is faster than the rate at which a second oncotic agent is removed.
  • the solutions of the present invention include physiological levels of a sugar.
  • the sugar is a simple hexose sugar such as glucose.
  • physiological levels of a sugar is meant a sugar concentration of between 2 mM to 50 mM.
  • the preferred concentration of glucose is 5 mM.
  • solutions of the present invention can be terminally heat sterilized, and can support life when replacing 50%-80% of a subject's blood at normal body temperature, or 100% of a subject's blood at hypothermic temperatures.
  • the present invention includes plasma expanders and blood substitutes suitable for use in mammals, including primates.
  • the invention presented herein is in part described in USSN 08/253,384 filed June 3, 1994, USSN 08/133,527 filed October 7, 1993, and USSN 08/071,533, filed June 4, 1993, which applications are incorporated herein by reference.
  • This invention is in part based on the discovery that because of the special species-specific physiology of primates, prior art plasma expanders and blood substitutes containing physiological or hyperphysiological potassium concentrations present disadvantages when used for near ice-cold blood- substitution in primates.
  • Red blood cells of primates contain high concentrations of potassium ion (K + ) .
  • K + potassium ion
  • Even low levels of lysis of the red blood cells generally result in high potassium ion concentrations. This is due to release of potassium ion from inside the lysed primate red blood cells into the plasma surrounding the cells. Accordingly, the blood will be hyperkalemic when infused.
  • the increased potassium level can be diffused if blood is infused into patients with sufficient circulating blood since the high potassium ion concentration is diluted.
  • the problem increases if primate blood is transfused into a primate which has been perfused with a maintenance solution of the type described in U.S.
  • Patents 4,924,442, and 5,130,230 which contain high concentrations of potassium resulting in loading of the primate's tissues with excess potassium.
  • the potassium ion concentration in the transfused blood will not be diluted to safe levels. As a result, cardiac insufficiency may and frequently does occur. Hyperkalemia is also associated with tissue damage resulting from burns, accidents, surgery, chemotherapy, and other physical traumas.
  • the prior art teaches that organ preservation at low temperatures requires the presence of high potassium ion concentrations for the maintenance of tissue integrity.
  • the solution according to the present invention contains physiological or subphysiological amounts of potassium. Thus, the solution allows for dilution of the potassium ion concentration in stored transfused blood.
  • physiological amount of potassium is meant between 3.5 - 5 mEq/1 K + (3.5 - 5 mM) , preferably 4-5 mEq/1 K + (4-5 mM) .
  • physiological amount of potassium is meant between 0-3.5 mEq/1 K + (0-3.5 mM) , preferably 2-3 mEq/1 K + (2-3 mM) .
  • the solution of the present invention comprises a mixture of materials which when placed in aqueous solution may be used to perfuse a subject in need thereof. While the materials may be provided as a dry mixture to which water is added prior to heat sterilization or as a dry sterile mixture to which sterile water is added, the solution is preferably provided in the form of a sterile aqueous solution.
  • the solution of the present invention may be used as a single solution for all phases of procedures in which a subject's blood is removed and replaced or a subject is cooled. Such phases include hemodilution or plasma extension at normal body temperatures, blood replacement and exchange at hypothermic body temperatures, blood substitution at substantially hypothermic body temperatures, and subject warming.
  • Hypothermic body temperatures are defined as 3-5°C below normal body temperatures of 37-38°C, e.g.. about 32-35°C.
  • Substantially hypothermic body temperatures also referred to as “near-ice cold” temperatures are defined as body temperatures just below the freezing point (-2°C) to about 10°C. Therefore, the term “hypothermic body temperature” or “hypothermia” as used herein encompasses body temperatures of about -2 to 3°C to about 32-35°C.
  • the solution of the present invention does not include a conventional biological buffer.
  • conventional buffer is meant a compound which in solution, in vitro , maintains pH at a particular range.
  • conventional biological buffer is meant a compound which in a cell-free system maintains pH in the biological range of 7-8.
  • Examples of conventional biological buffers include N-2-Hydroxyethylpiperazine-N'- 2-hydroxypropanesulfonic acid (HEPES) , 3-(N-Morpholino) propanesulfonic acid (MOPS), 2-([2-Hydroxy-l,l- bis(hydroxymethyl)ethyl]amino)ethanesulfonic acid (TES) , 3-[N-tris(Hydroxy-methyl) ethylamino]-2-hydroxyethyl]-l- piperazinepropanesulfonic acid (EPPS) ,
  • Conventional biological buffers function independently of normal biological processes, e.g., the conventional buffer is not metabolized in vivo , and are most potent in cell-free systems.
  • the solution of the present invention uses normal biological components to maintain in vivo biological pH, a concept termed a "dynamic buffering system".
  • the dynamic buffering system concept rests on the discovery by the inventors that compounds with no intrinsic buffering capacity in the biological range, such as lactate, acetate, or gluconate, capable of being metabolized in vivo, act with other solution components to maintain a biologically appropriate pH in an animal, even at hypothermic temperatures and at essentially bloodless conditions.
  • the dynamic buffering system of the present invention depends in part on oxygenation and removal of carbon dioxide (C0 2 ) ; and allows but does not require additional bicarbonate (NaHC0 3 ) .
  • the dynamic buffer of the invention has no or substantially no ability to act as a buffer outside of a biological system, i.e., a dynamic buffer maintains pH in the biological range in vivo but not in a cell free environment.
  • a component of the dynamic buffering system of the invention include a carboxylic acid, salt or ester thereof.
  • a carboxylic acid, salt or ester thereof is a compound having the general structural formula RCOOX, where R is an alkyl, alkenyl, or aryl, branched or straight chained, containing 1 to 30 carbons which carbons may be substituted, and preferably one of the carbon chains that compose the carbon chain of lactate, acetate, gluconate, citrate, pyruvate, or other biological metabolites; and X is hydrogen or sodium or other biologically compatible ion substituent which can attach at the oxygen position.
  • RCOOX where R is an alkyl, alkenyl, or aryl, branched or straight chained, containing 1 to 30 carbons which carbons may be substituted, and preferably one of the carbon chains that compose the carbon chain of lactate, acetate, gluconate, citrate, pyruvate, or other biological metabolites; and
  • terminally heat sterilized or "heat sterilized” as used herein references to the process involving heating a solution to 120°C for 15 minutes under pressure, i.e., maintaining heat and pressure conditions for a period of time sufficient to kill all or substantially all bacteria and inactivate all or substantially all viruses in the solution. This procedure is normally performed in an autoclave, and is also known as "autoclaving".
  • heat sterilization is to kill possible infectious agents present in the solution. Infectious agents are known to tolerate temperatures up to 100°C. It is generally considered by the art that heating a solution under pressure to 120°C for about 15 minutes is sufficient to insure sterility. Governmental regulations may require heating a solution at even higher temperatures and pressures.
  • Transplant or blood substitute solutions containing proteins or a variety of organic compounds of which the inventors are aware cannot tolerate terminal heat sterilization at high temperatures and pressures. It is known that heat sterilizing a solution having containing carbohydrates or proteins, with a pH above 7.0, results in substantial degradation of solution components.
  • the solution of the present invention is designed to be heat sterilizable with minimal degradation of other solution components, such as sugar.
  • the solutions of the present invention are heat sterilized prior to use.
  • components to the base solution e.g., addition of NaHC0 3 to HL solution to form HLB solution for use under hypothermic conditions
  • NaHC0 3 is added as a commercially- available sterile 1 M solution to sterile HL solution.
  • 5 ml of a 1 M NaHC0 3 solution is added per liter of HL solution to form 1 1 of HLB solution.
  • more NaHC0 3 may be added.
  • the blood clotting factor or oxygen- carrying component is added as a sterile solution to the autoclaved base solution.
  • the HLB solution of the present invention may also be used to sustain cultured tissues and cells in vitro.
  • the dynamic buffering system of the solution maintains cultured tissues and cells at the appropriate biological pH. We have shown that the addition of lactate and bicarbonate to cultured cells is sufficient to sustain normal cell growth and morphology.
  • the solution of the present invention includes an organic carboxylic acid or salt thereof.
  • organic carboxylic acid or salt thereof includes any carboxylic acid or carboxylic acid derivative capable of being metabolized by the mammal.
  • carboxylic acids and carboxylic acid salts suitable for use in the solution of the present invention include lactate and sodium lactate, citrate and sodium citrate, gluconate and sodium gluconate, pyruvate and sodium pyruvate, succinate and sodium succinate, and acetate and sodium acetate.
  • sodium lactate is used. When metabolized in vivo, lactate helps maintain bicarbonate levels, and thereby functions as a component of the dynamic buffering system of the solution to maintain an in vivo biological pH.
  • the mixture according to the invention will be discussed as an aqueous solution. From the following description of the invention, it is expected that one ordinarily skilled in the art would be enabled to provide the mixture as a dry mixture and make the adjustments to amounts of sodium chloride and organic salt of sodium as necessary to accommodate the amounts of sodium chloride found in normal saline solution, which may be used as a diluent for the dry mixture according to the invention.
  • the sodium ion concentration is preferably in a range from 70 mM to about 160 mM, and preferably in a range of about 130 to 150 mM.
  • the concentration of calcium ion is in a range of about 0.5 mM to 4.0 mM, and preferably in a range of about 2.0 mM to 2.5 mM.
  • the concentration of magnesium ion is in a range of 0 to 10 mM, and preferably in a range of about 0.3 mM to 0.45 mM. It is important not to include excessive amounts of magnesium ion in the solution according to the invention because high magnesium ion concentrations negatively affect the strength of cardiac contractile activity.
  • the concentration of chloride ion is in the range of 80 mM to 170 mM, preferably in the range of 110- 135 mM cr.
  • the solution also includes a physiological amount of simple hexose sugar such as glucose, fructose and galactose, of which glucose is preferred.
  • simple hexose sugars such as glucose, fructose and galactose, of which glucose is preferred.
  • nutritive hexose sugars are used and a mixture of sugars can be used.
  • physiological amount or “physiological levels” means the concentration of sugar is in a range between 2 mM and 50 mM with concentration of glucose of 5 mM being preferred. At times, it is desirable to increase the concentration of hexose sugar in order to lower fluid retention in the tissues of a subject. Thus the range of hexose sugar may be expanded up to about 50 mM if necessary to prevent or limit edema in the subject under treatment.
  • the oncotic agent is comprised of molecules whose size is sufficient to prevent their loss from the circulation by readily traversing the fenestrations of the capillary bed into the interstitial spaces of the tissues of the body.
  • oncotic agents are exemplified by blood plasma expanders.
  • Examples of oncotic agents suitable for use in the solution of the present invention include human serum albumin, polysaccharides such as glucan polymers, and cross-linked or high molecular weight hemoglobin.
  • the polysaccharide is non-antigenic.
  • Hetastarch (McGaw, Inc.) is an artificial colloid derived from a waxy starch composed almost entirely of amylopectin with hydroxyethyl ether groups introduced into the alpha (1 ⁇ 4) linked glucose units.
  • the colloid properties of a 6% solution (wt/wt) of Hetastarch approximates that of human serum albumin.
  • Other polysaccharide derivatives may be suitable as oncotic agents in the solutions according to the invention including hydroxymethyl alpha (l-»4) or (1 ⁇ 6) polymers. Cyclodextrins are suitable oncotic agents.
  • D-glucose polymers may be used.
  • dextran which is D-glucose linked predominantly in alpha (l->6) linkage, may be used as the oncotic agent in the solution of the invention.
  • Polysaccharides such as dextran in a molecular weight range of 30,000 to 85,000 daltons (D) are preferred.
  • the concentration of the polysaccharide is sufficient to achieve (when taken together with chloride salts of sodium, calcium and magnesium, organic ion from the organic salt of sodium and hexose sugar discussed above) colloid osmotic pressure approximating that of normal human serum, about 28 mm Hg.
  • the solution contains two or more oncotic agents with differential clearance rates.
  • Natural colloids such as plasma proteins and human serum albumin, are useful for restoration of blood oncotic agent in a hypovolemic patient.
  • natural colloids are expensive and in short supply. Also, they cannot be terminally sterilized at high temperatures and pressures.
  • Recombinant human albumin is under development, and may pose less of a threat in transmitting a pathogenic vector. However, this may also prove expensive to produce, and may present difficulties for sterilization and purity.
  • Use of artificial colloids overcome these deficiencies, with the important advantage of lessening the risk of transmitted disease.
  • the solutions of the present invention having two or more oncotic agents with differential clearance rates provide additional advantages in restoring blood oncotic pressure in a hypovolemic subject over an extended period of time, while encouraging the subject's own production of plasma proteins.
  • Artificial oncotic agents with relatively slow clearance rates include high molecular weight Hetastarch (molecular weight 300,000 - 1,000,000) and dextran 70, measured to have intravascular persistence rates of 6 hours (Messmer (1989) Bodensee Symposium on Microcirculation (Hammersen & Messmer, eds.), Karger, N.Y., pg. 59).
  • Artificial oncotic agents with relatively fast clearance rates include low molecular weight Hetastarch (average molecular weight 40,000-200,000) and dextran 40, having intravascular persistence rates of 2-3 hours (Messmer (1989) supra) .
  • the solution may be used as a circulating solution in conjunction with oxygen or hyperbaric oxygen at normal body temperatures, or with or without hyperbaric oxygen in subjects during procedures.
  • the solution may also be used as a circulating solution in subjects during procedures when the subject's body temperature is reduced significantly below the subject's normal temperature.
  • the solutions of the present invention may include a blood clotting factor able to accelerate or promote the formation of a blood clot.
  • the invention further encompasses a method of using the solutions of the present invention with administration of a blood clotting factor to a subject in need thereof.
  • Preferred blood clotting factors for use in the solution of the invention include vitamin K, Factors I, II, V, VII, VIII, VIIIC, IX, X, XI, XII, XIII, protein C, von Willebrand factor, Fitzgerald factor, Fletcher factor, and a proteinase inhibitor.
  • the concentration of the blood clotting factor is determined by one skilled in the art depending on the specific circumstances of treatment. For example, generally when vitamin K is administered, its concentration will be sufficient to deliver 5 - 10 mg to the patient.
  • Oxygen-carrying compounds have been studied as a means for increase the oxygen-carrying capacity of a subject.
  • oxygen-carrying compounds in an effective amount have been shown to be toxic to the recipient subject.
  • administration of hemoglobin may result in kidney toxicity, stimulation of febrile and immunogenic responses, and stimulation of bacterial growth.
  • Administration of an effective amount of a fluorocarbon may interfere with lung function.
  • the solutions of the present invention may include an oxygen- carrying component in a concentration sufficiently low so as not to be toxic to the subject.
  • Oxygen-carrying components include hemoglobin extracted from human and non-human sources, recombinant hemoglobin, hemocyanin, chlorocruorin and hemerythrin, and other naturally occurring respiratory pigments extracted from natural sources or made by recombinant DNA or in vitro methods. These compounds may be modified by a number of means known to the art, including by chemical crosslinking or pegylation.
  • the solutions of the present invention may include a sufficient amount of oxygen-carrying component to deliver enhanced oxygen to the tissues of a subject without resulting in toxicity to the subject.
  • a "sufficient amount" of an oxygen-carrying component is an amount allowing a resting subject with an unimpaired circulation and physiology to survive and recover from trauma, illness or injury. In normal humans at normal body temperature, this is at least 5-6 ml O 2 /100 ml of intravascular fluid.
  • the oxygen-carrying component is hemoglobin, it is preferably present in the concentration range of between about 20-200 g/1.
  • the solution may be used in a variety of surgical settings and procedures.
  • the solution may be used to maintain a subject (which has lost a significant amount of blood, e.g. 20% to 98% of its blood) at normal body temperatures in a pressurized environment at increased oxygen concentration above atmospheric oxygen tension up to 100% oxygen.
  • the subject is maintained in a high oxygen concentration until enough blood components can be synthesized by the subject to support life at atmospheric pressure and oxygen concentration.
  • the solution according to the invention may be used to maintain a subject at temperatures lower than normal body temperature and at a reduced rate of metabolism after traumatic life threatening injury until appropriate supportive or corrective surgical procedures can be performed.
  • the solution may be used to maintain a patient having a rare blood or tissue type until an appropriate matching donor can be found and replacement blood units or other organ can be obtained.
  • the procedure for replacing substantially all of a mammalian subject's circulating blood may be carried out with the mammalian subject's body temperature being maintained at its substantially normal temperature.
  • the procedure may be carried out with cooling of the subject and reduction of the mammalian subject's body temperature below that of its normal temperature. Cooling may be accomplished by chilling the subject in an ice bath, ice-salt slurry, or cooling blanket.
  • the subject may be further cooled by chilling the solution according to the invention prior to perfusing the subject with the solution.
  • the solution is also suitable for use for plasmapheresis.
  • Plasmapheresis is a process in which all or a portion of the blood plasma is replaced while one or more groups of formed elements such as red blood cells or lymphocytes are retained.
  • the blood plasma is removed by methods such as centrifugation or filtration. The procedure allows removal of autoantibodies and other toxic agents.
  • the solution of the invention may be used to replace the plasma fraction of the blood during the plas apheretic procedure. This presents several distinct advantages. Blood plasma cannot be terminally sterilized at high temperatures and pressures. Moreover, plasma is expensive and is sometimes unavailable. In some cases, it can provoke hypersensitivity reactions in patients. These problems are overcome by replacement of all or a portion of the removed plasma with the solutions of the present invention.
  • the solutions of the present invention are also suitable for use in lowering the body temperature of an organ or tissue donor, and as a blood replacement in organs and tissues harvested, stored, or transported for transplantation.
  • Example 1 Solution Compositions.
  • composition of L solution The composition of L solution is as follows: Na + 143 mM; Ca ++ 2.5 mM; Mg ++ 0.45 mM; K + mM 3.0; Cl" 124 mM; glucose 5 mM; and lactate 28 mM.
  • the solution is filtered to remove undissolved material and placed in autoclavable containers and heated in an autoclave to a temperature of 120°C for 15 minutes.
  • Composition of HL BioTime HextendTM-lactate. Solution. To each liter of L solution, 60 g of high molecular weight Hetastarch is added. HL solution is filtered and heat sterilized after the addition of Hetastarch.
  • HLB CBioTime HextendTM-lactate- bicarbonate Solution. To each heat sterilized liter of HL solution is added 5 ml of a sterile 1 M solution of NaHC0 3 , medical grade, forming HLB solution .
  • DL solution was prepared with a concentration of constituents identical to HL except 6% Dextran 40 is used in place of 6% Hetastarch.
  • DL-HL solution was prepared by mixing an equal amount of DL and HL solutions.
  • AL solution is prepared by adding 5% sterile albumin to sterilized L solution.
  • ALB solution is prepared by adding 5 ml of a sterile 1 M solution of NaHC0 3 to each liter of AL solution.
  • composition of HL-Heme Solution To sterile HL solution is added 20-200 g/1 hemoglobin.
  • a 240 g female rat was anesthetized with ketamine, xylazine an acepromazine mixture injected i.m.
  • the animal was placed on a stage and its right femoral artery and vein cannulated.
  • the animal was perfused isovolemically with 10 ml of HL-DL solution until its hematocrit reached 17.2%.
  • the cannulas were removed, vessels ligated, and the incision closed.
  • the animal tolerated perfusion well, and was active and eating within 3 days of the procedure. The animal remains alive and healthy.
  • a 26.8 kg male dog was anesthetized with nembutal and intubated. It was moved to the operating room, ventilated, and catheterized with venous, Foley, arterial, and Swan-Ganz catheters, and after i.v. heparin, its right femoral artery and vein were cannulated. An esophageal tube was inserted and antacid administered. Temperature sensors were placed in the esophagus and the rectum. Methyl prednisolone was injected i.v.
  • the animal was wrapped in a cooling blanket, and surface cooling initiated.
  • the animal's cannulas were connected to a bypass circuit, which consisted of a vortex blood pump, an oxygenator with a built-in heat exchanger, a secondary in-line heat exchanger, and a funnel for the rapid administration of blood and blood substitute.
  • Whole blood 225 ml was removed from the dog and saved for rewarming. Blood volume was quickly replaced with HLB solution.
  • the bypass circuit containing 1.05 liters of HLB solution was opened to the animal, and core cooling began.
  • the animal was warmed. When body temperature climbed past 10°C, venous effluent and whole blood previously collected, as well as donor blood, was returned to the circuit; hematocrit increased with increasing temperature. Lidocaine and bicarbonate were administered, the heart defibrillated, and ventilation begun. When blood pressure and body temperatures approached normal, the animal was weaned from bypass, and protamine and Lasix injected. Several hours after warm-up, the animal was conscious and responsive. The animal remained alive and healthy after the procedure.
  • Baboon A 24 kg male baboon of the species Papio annubis was anesthetized first with ketamine and acepromazine i.m., then with i.v. pentothal. It was then immobilized with pancuronium bromide. It was intubated, ventilated, and catheterized with venous, Foley, and arterial catheters. The animal was wrapped in a cooling blanket, and surface cooling initiated. After i.v. heparin was administered, the baboon's right femoral artery and bilateral femoral veins were cannulated. Temperature sensors were placed in the esophagus, rectum and brain.
  • the animal was instrumented for EKG, somatosensory evoked potentials (SSEPs) and EEG. Dexamethazone was injected i.v.
  • the animal's cannulas were connected to a bypass circuit, which consisted of a vortex blood pump, an oxygenator with a built-in heat exchanger, and a funnel for the rapid administration of blood and blood substitute.
  • Whole blood 300 ml was removed from the baboon and saved for rewarming. The volume was quickly replaced with 300 ml of physiological saline solution.
  • the bypass circuit containing 2 liters of Plasmalyte (commercially available electrolyte solution) , was opened to the animal and core cooling begun.
  • the animal's deep esophageal temperature had been below 15°C for 3 hours, and below 10°C for 2 hours 17 minutes, with a minimum recorded temperature of 2.8°C
  • Example 5 Blood Replacement with Two Solution System in a Patient Undergoing Cardiopulmonary Bypass Surgery.
  • a patient is anesthetized, cannulated and instrumented for cardiopulmonary bypass.
  • the patient is wrapped in a cooling blanket and surface cooled to 30°C.
  • the patient is then placed on bypass with the circuit primed with ALB solution.
  • the patient is core and surface cooled until his deep esophageal temperature reaches 20°C.
  • Blood is collected with 4 L of ALB solution, and immediately replaced with HLB solution.
  • the body is then cooled and maintained while surgical procedures and performed on the heart or brain.
  • the patient is then warmed, and the HLB solution replaced first with ALB solution, and then with the AL-blood solution originally removed. 5 - 10 mg of vitamin K is administered.
  • albumin functions as the naturally-occurring compound, maintaining blood oncotic agent without impeding the patient's own ability to synthesize albumin.
  • a patient suffering from severe blood loss is infused with HL solution containing 5 mg/1 of blood- clotting factor vitamin K and 30 g/1 of the oxygen- carrying component hemoglobin.
  • the patient's blood pressure is stabilized and normal oxygen delivery to the patient's tissues is resumed.
  • the patient's body gradually clears the Hetastarch component while synthesizing its own albumin such that blood oncotic pressure remains stabilized during the recovery period.
  • Use of HL solution containing blood-clotting factors and oxygen-carrying components allows the use of substitute blood to be reduced or completely avoided.
  • Example 7 Use of Blood Clotting Factor in He odiluted Mammals.
  • the average blood loss was 4.8 ⁇ 0.54 ml, and only 3 of the 8 animals survived. Compared to untreated controls, mortality (P ⁇ 0.02) and blood loss (P ⁇ 0.002) in the HL-treated animals without Trasylol® was significantly greater.

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Abstract

Cette invention concerne des solutions pouvant être utilisées comme dextranes et substituts sanguins chez les mammifères, y compris les primates, ainsi que les procédés d'utilisation de ces solutions.
PCT/US1995/016680 1994-12-28 1995-12-19 Dextranes et substituts sanguins WO1996019918A1 (fr)

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AU45269/96A AU4526996A (en) 1994-12-28 1995-12-19 Plasma expanders and blood substitutes

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Cited By (8)

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Publication number Priority date Publication date Assignee Title
WO1999002034A1 (fr) * 1997-07-09 1999-01-21 Wayne State University Solution de lavage et de conservation pour organes de donneurs
WO1999022746A1 (fr) * 1997-10-31 1999-05-14 Biotime, Inc. Solutions aqueuses physiologiquement acceptables et procedes d'utilisation desdites solutions
US6300322B1 (en) 1993-06-04 2001-10-09 Biotime, Inc. Plasma-like solution
EP0977480B1 (fr) * 1995-12-15 2002-10-02 Xenodevice Aktiebolag Solution pour la conservation d'organes ou de tissus ou des parties de ceux-ci d'humains ou d'animaux
US6680305B1 (en) 1993-06-04 2004-01-20 Biotime, Inc. Physiologically acceptable aqueous solutions and methods for their use
US6794124B2 (en) 1995-12-15 2004-09-21 Stiftelsen Facthor Preservation solution
EP1820516A3 (fr) * 1999-02-22 2009-10-07 University of Connecticut Nouvelles formulations de facteur VIII sans albumine
US10512674B2 (en) 2008-11-07 2019-12-24 Baxalta Incorporated Factor VIII formulations

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US5374624A (en) * 1991-08-08 1994-12-20 Segel; Leigh D. Fluorocarbon blood substitute
US5407428A (en) * 1993-06-04 1995-04-18 Biotime, Inc. Solutions for use as plasma expanders and substitutes

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US3937821A (en) * 1971-08-21 1976-02-10 Kyorin Seiyaku Kabushiki Kaisha Plasma substitute including artificial starch and method for the preparation thereof
US5374624A (en) * 1991-08-08 1994-12-20 Segel; Leigh D. Fluorocarbon blood substitute
US5407428A (en) * 1993-06-04 1995-04-18 Biotime, Inc. Solutions for use as plasma expanders and substitutes

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Title
A.L. LEHNINGER, "Principles of Biochemistry", Published 1982, by WORTH PUBLISHERS, INC., pages 705-713. *
CLINICAL PHARMACY, Volume 12, issued May 1993, WAGNER et al., "DRUG REVIEW: Pharmacologic and Clinical Considerations in Selecting Crystalloid, Colloidal and Oxygen-Carrying Resuscitation Fluids, Part 1", pages 335-346. *
HAMMERSEN and MESSMER, Eds., "Bodensee Symposium on Microcirculation", Published 1988, by KARGER (N.Y.), MESSMER K., "Characteristics, Effects and Side-Effects of Plasma Substitutes", pages 52-70. *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6680305B1 (en) 1993-06-04 2004-01-20 Biotime, Inc. Physiologically acceptable aqueous solutions and methods for their use
US7943292B2 (en) 1993-06-04 2011-05-17 Biotime, Inc. Physiologically acceptable aqueous solutions and methods for their use
US6300322B1 (en) 1993-06-04 2001-10-09 Biotime, Inc. Plasma-like solution
EP0977480B1 (fr) * 1995-12-15 2002-10-02 Xenodevice Aktiebolag Solution pour la conservation d'organes ou de tissus ou des parties de ceux-ci d'humains ou d'animaux
US6794124B2 (en) 1995-12-15 2004-09-21 Stiftelsen Facthor Preservation solution
WO1999002034A1 (fr) * 1997-07-09 1999-01-21 Wayne State University Solution de lavage et de conservation pour organes de donneurs
AU739632B2 (en) * 1997-07-09 2001-10-18 Wayne State University Flush-storage solution for donor organs
WO1999022746A1 (fr) * 1997-10-31 1999-05-14 Biotime, Inc. Solutions aqueuses physiologiquement acceptables et procedes d'utilisation desdites solutions
EP1820516A3 (fr) * 1999-02-22 2009-10-07 University of Connecticut Nouvelles formulations de facteur VIII sans albumine
US8058226B2 (en) 1999-02-22 2011-11-15 Baxter International Inc. Albumin-free factor VIII formulations
US8372800B2 (en) 1999-02-22 2013-02-12 Baxter International Inc. Albumin-free factor VIII formulations
US8765665B2 (en) 1999-02-22 2014-07-01 Baxter International Inc. Albumin-free factor VIII formulations
US9352027B2 (en) 1999-02-22 2016-05-31 Baxalta Incorporated Albumin-free factor VIII formulations
US9669076B2 (en) 1999-02-22 2017-06-06 Baxalta Incorporated Albumin-free factor VIII formulations
US10512674B2 (en) 2008-11-07 2019-12-24 Baxalta Incorporated Factor VIII formulations
US11020459B2 (en) 2008-11-07 2021-06-01 Baxalta Incorporated Factor VIII formulations

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AU4526996A (en) 1996-07-19

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