WO2000030442A1 - Solution de conservation d'organes contenant du pyruvate - Google Patents

Solution de conservation d'organes contenant du pyruvate Download PDF

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Publication number
WO2000030442A1
WO2000030442A1 PCT/US1999/027988 US9927988W WO0030442A1 WO 2000030442 A1 WO2000030442 A1 WO 2000030442A1 US 9927988 W US9927988 W US 9927988W WO 0030442 A1 WO0030442 A1 WO 0030442A1
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WO
WIPO (PCT)
Prior art keywords
solution
organ
organ preservation
preservation solution
accordance
Prior art date
Application number
PCT/US1999/027988
Other languages
English (en)
Inventor
Ronald L. Morgan
Richard A. Frable, Sr.
Lhanoo Gunawardhana
Carlos Chavez
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to AU19222/00A priority Critical patent/AU1922200A/en
Publication of WO2000030442A1 publication Critical patent/WO2000030442A1/fr

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Classifications

    • 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
    • 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
    • A01N1/0221—Freeze-process protecting agents, i.e. substances protecting cells from effects of the physical process, e.g. cryoprotectants, osmolarity regulators like oncotic agents
    • 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
    • A01N1/0226—Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients

Definitions

  • the field of the present invention is organ preservation. More particularly, this invention pertains to an organ preservation solution containing relatively high concentrations of pyruvate.
  • Transplantation of organs from a donor to a recipient is a mainstay of therapeutic medicine. Because the donor and recipient are often separated by substantial distances, compositions and methods for preserving the viability of the organs, after their explantation from the donor and before their implantation into the recipient, are necessary to successfully complete such transplantation procedures. A number of such compositions and methods have been described to date.
  • U.S. Patent No. 4,798,824 discloses a perfusate for the preservation of organs intended for implantation into a patient.
  • the perfusate contains energy sources (e.g., sugars), buffers, agents that reduce damage from the generation of oxygen-free-radicals, antibiotics, and hydroxyethyl starch having a weight average molecular weight of from about 200,000 to about 300,000 Daltons.
  • the osmolality of this solution is about 320 mOsm/kg. This solution does not contain any pyruvate.
  • U.S. Patent No. 4,879,283 discloses a hypothermic perfusate and storage solution that includes a hydroxyethyl starch having an average molecular weight of from about 150,000 to about 350,000 Daltons, electrolytes, a lactobionate salt, raffinose, and glutathione.
  • the solution disclosed in U.S. Patent No. 4,879,283 does not contain any pyruvate.
  • U.S. Patent No. 5,306,711 discloses a solution and a method for organ preservation.
  • the solution contains about 20-30 weight percent dextran having an average molecular weight of about 10,000 Daltons or less.
  • This solution can further contain glutathione, buffers, and non-dextran osmotic agents. These solutions do not contain any pyruvate.
  • Pyruvate is a known therapeutic agent.
  • the oral administration of pyruvate to animals is known to prevent the accumulation of fatty deposits in the liver, reduce total body fat deposition and reduce weight gain (See, e.g.. U.S. Patent Nos., 4,158,057; 4,351,835; 4,415,576; 4,548,937; 4,645,764; and 4,812,479).
  • the orally administered pyruvate can be given in combination with other agents such as dihydroxyacetone and riboflavin.
  • U.S. Patent No. 4,874,790 provides a method for treating animals having diabetic tendencies to improve glucose metabolism in that animal.
  • the method disclosed in the '790 patent involves the oral administration of a therapeutically effective amount of pyruvate and dihydroxyacetone.
  • U.S. Patent No. 5,134,162 provides a process for lowering the blood cholesterol of hyperlipidemic patients.
  • the process disclosed in the '162 patent involves the oral administration of pyruvate in a confection.
  • U.S. Patent No. 5,294,641 provides a process for treating patients prior to or during heart trauma.
  • the process disclosed in the '641 patent includes administering an effective therapeutic dose of pyruvate to a patient so as to increase cardiac output and stroke volume, decrease heart rate and reduce the oxygen demand of the heart.
  • Pyruvate can be administered either intravenously or orally.
  • U.S. Patent No. 5,480,909 provides for the use of pyruvate as an oxygen free-radical scavenger or as an inhibitor of oxygen free-radical generation.
  • U.S. Patent No. 5,508,308 provides a therapeutic method to reduce ischemia-reperfusion injury to the heart.
  • the process includes the step of perfusing pyruvylglycine into the circulatory system of a patient following a heart attack or coronary occlusion incident.
  • U.S. Patent No. 5,066,578 discloses compositions and methods for preserving organs for transplantation.
  • the compositions are solutions that contain inorganic salts to retain action potentials across cell membranes, proteins selected from the group consisting of albumin and fetal calf serum, and pyruvate.
  • the '578 patent discloses that the pyruvate concentration in the composition is approximately 6 - 12 mM, preferably about 10 mM.
  • U.S. Patent No. 5,075,210 discloses compositions and methods for the long-term preservation of hearts intended for transplantation.
  • the solutions contain electrolytes, a protein selected from the group consisting of albumin and fetal calf serum, and pyruvate in a concentration range of from about 6 mM to about 15 mM.
  • Preservation methods include perfusing the heart with the composition at body temperature (i.e., about 37° C) followed by a second perfusion with a solution containing pyruvate and ethanol at a temperature of from about 4 to about 37° C and storing the heart in a solution that contains pyruvate at a temperature of between about 2° C and 10° C.
  • the present invention provides an organ preservation solution containing pyruvate in a concentration of at least about 25 mM.
  • the present invention provides an organ preservation solution that includes the following components: a) about 0.9 mM to about 3 mM calcium chloride; b) about 12 mM to about 20 mM magnesium chloride; c) about 4 mM to about 80 mM potassium chloride; d) about 0 mM to about 165 mM sodium chloride; e) about 0.5 mM to about 12.0 mM hydroxyethyl starch having an average molecular weight of from about 580,000 Daltons to about 780,000 Daltons; f) about 15 mM to about 45 mM melezitose; g) about 0.1 mM to about 7 mM adenosine; h) about 0.5 mM to about 5 mM allopurinol; i) about 0.1 mM to about 10 mM sodium bicarbonate; and j) about 25 mM to about 200 mM sodium pyruvate.
  • the present invention provides a method for preserving an explanted organ.
  • the method includes the steps of providing an organ preservation solution having a pyruvate concentration of at least about 25 mM and placing the organ to be preserved in contact with the organ preservation solution.
  • the present invention provides a method for preserving an explanted organ.
  • the method includes the steps of providing an organ preservation solution having the characteristics of the second embodiment of the present invention and placing the organ to be preserved in contact with the organ preservation solution.
  • organ preservation solutions of the present invention have use in maintaining and preserving organs for transplantation into patients.
  • the solutions disclosed herein are used with organs after they have been isolated
  • the solutions of this invention can be used to extend the preservation or viability of a variety of organs intended for transplantation.
  • the solutions of the present invention contain pyruvate at concentrations not previously appreciated to be efficacious in organ preservation.
  • the solutions of the present invention have a pyruvate concentration of at least about 25 mM.
  • the solutions of the present invention can include one or more inorganic salts which serve to maintain physiological transmembrane chemical/electrical electrolyte gradients (e.g., preserve the ability of cells to initiate and or retain action potentials across cell membranes), and pyruvate.
  • inorganic salts which serve to maintain physiological transmembrane chemical/electrical electrolyte gradients (e.g., preserve the ability of cells to initiate and or retain action potentials across cell membranes), and pyruvate.
  • the solutions of the present invention also can include agents that supply energy to the organ (e.g., metabolizable compounds that allow for regeneration of high-energy phosphate compounds), osmotic agents, buffers to regulate pH, agents that prevent cell damage from oxygen free-radicals and antibiotics for fighting infection.
  • agents that supply energy to the organ e.g., metabolizable compounds that allow for regeneration of high-energy phosphate compounds
  • osmotic agents e.g., metabolizable compounds that allow for regeneration of high-energy phosphate compounds
  • buffers to regulate pH e.g., buffers to regulate pH
  • agents that prevent cell damage from oxygen free-radicals and antibiotics for fighting infection e.g., osmotic agents, buffers to regulate pH, agents that prevent cell damage from oxygen free-radicals and antibiotics for fighting infection.
  • mammalian cells are characterized by a high level of potassium (about 120 mM) and low levels of sodium (about 10 mM) and chloride (about 5 mM).
  • extracellular fluid contains low levels of potassium (about 3 mM) and high levels of both sodium (about 140 mM) and chloride (about 120 mM).
  • Action potentials across the cell membrane separating the intracellular and extracellular fluid is the result in part of these concentration differences.
  • retention of action potentials means the maintenance of these transmembrane gradients such that the movement of one or more of the ions across the membrane gives rise to the action potential.
  • the organ preservation solution is formulated to maintain intracellular electrolyte balance.
  • Organ intracellular electrolyte balance and retention of action potentials across cell membranes is accomplished by establishing the potassium level of the solution between about 100 mM and about 150 mM.
  • the potassium concentration of the organ preservation solution is between about 115 mM and 135 mM and, most preferably is about 125 mM.
  • the potassium acts to maintain organ intracellular potassium concentration at or about normal physiological levels (100 to 150 mM).
  • Preferred potassium sources for use in such a solution include potassium chloride and potassium hydroxide.
  • Pyruvate can be included in this alternative embodiment of the organ preservation solution of the present invention, the pyruvate serving as an energy source and as agent that minimizes reperfusion injury.
  • concentration of pyruvate in the solution preferably is at least about 25 mM. More preferably, the pyruvate concentration is between about 25 mM and 200 mM.
  • a preferred salt of pyruvate used in a present solution is sodium pyruvate.
  • Osmotic agents can be included in the organ preservation solution of the present invention to prevent cell swelling during storage of the preserved organ.
  • a preferred osmotic agent is hydroxyethyl starch.
  • the hydroxyethyl starch preferably has an average molecular weight of between about 580,000 and about
  • the hydroxyethyl starch may have a degree of substitution
  • the solution can optionally contain other agents such as carbohydrates.
  • Suitable carbohydrates include, but are not necessarily limited to, melezitose, raffinose, and trehalose.
  • the organ preservation solution of the present invention preferably has an osmolality of between about 200 mOsm/kg and about 400 mOsm/kg. More preferably, the solution osmolality is from about 250 mOsm/kg to about 350 mOsm/kg.
  • the pH of the organ preservation solution preferably is between about 6.9 and 7.8. A pH of approximately 7.8 is believed to be beneficial in organ transplantation procedures in order to neutralize the metabolic acidosis that occurs during transplantation of organs.
  • the pH of the solution can be maintained at a given level by the presence of known buffers in the solution. Preferred buffers are those naturally present in biological fluids such as phosphate and bicarbonate. Other known, non-toxic buffers can also be used without departing from the scope of the present invention.
  • the solution may further contain agents that serve to prevent or minimize damage due to the generation of oxygen free-radicals, e.g., allopurinol.
  • agents that serve to prevent or minimize damage due to the generation of oxygen free-radicals e.g., allopurinol.
  • a preferred concentration of allopurinol is from about 0.05 to about 0.2 g/liter of solution.
  • the organ preservation solution of the present invention may also contain compounds that serve to provide energy to the stored organ.
  • agents include both metabolic energy sources, such as sugars, and compounds used to regenerate high-energy phosphate compounds.
  • Any metabolizable sugar known in the art can be used as an energy source.
  • Exemplary sugars include monosaccharides such as glucose and polysaccharides such as melezitose.
  • the sugar is typically present in the solution in a concentration of from about 5 mM to about 50 mM. More preferably, the sugar concentration is from about 10 mM to about 40 mM.
  • An exemplary and preferred high-energy phosphate regenerating agent is adenosine.
  • adenosine can be present in the organ preservation solution of the present invention at a concentration of from about 0.1 mM to about 10 mM. More preferably, the concentration of adenosine in the solution is from about 1 mM to about 6 mM.
  • the solution is formulated to provide a reduced potassium concentration relative to the first alternative embodiment of the present invention.
  • the second alternative embodiment solution has relatively high concentrations of chloride together with multiple other electrolytes such as calcium, sodium and potassium.
  • the preferred chloride concentration is from about 15 mM to about 270 mM and, more preferably is about 150 mM.
  • the preferred calcium concentration is from about 0.8 to about 3 mM.
  • the preferred sodium concentration is from about 5 mM to about 270 mM and, more preferably is from about 125 mM to about 225 mM.
  • the preferred potassium concentration is from about 5 mM to about 110 mM and, more preferably is about 15 mM to about 50 mM.
  • concentrations represent total concentrations and can be the result of more than one compound in the organ preservation solution.
  • total potassium can be the sum of potassium chloride and potassium phosphate.
  • total sodium can be the sum of sodium chloride, sodium pyruvate and sodium bicarbonate.
  • the solution can further contain energy sources (e.g., saccharides) as set forth above.
  • the solution also can contain at least about 25 mM pyruvate (e.g., sodium pyruvate). More preferably, the pyruvate concentration is from about 25 mM to about 200 mM.
  • the osmolality and pH of the solution are set as set forth. The pH can be maintained through the use of buffers such as phosphate or bicarbonate, as above-discussed.
  • the present invention further provides processes for preserving and/or storing organs intended for transplantation.
  • the process comprises the steps of providing an organ preservation solution in accordance with one embodiment of the present invention and placing the organ or organs to be preserved in contact with the organ preservation solution.
  • the organ preservation can be used to flush the organ or to perfuse the organ using known techniques in order to provide the desired "contact" between the organ preservation solution and the organ.
  • Preservation can be conducted using warm storage techniques and cold storage techniques without departing from the scope of the present invention.
  • VIASPAN * solution is pentafraction-

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
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  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
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Abstract

Solution de conservation d'organes contenant du pyruvate en une concentration d'au moins environ 25 mM et méthode de conservation d'organes utilisant cette solution.
PCT/US1999/027988 1998-11-25 1999-11-24 Solution de conservation d'organes contenant du pyruvate WO2000030442A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU19222/00A AU1922200A (en) 1998-11-25 1999-11-24 Organ preservation solution containing pyruvate

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US19954198A 1998-11-25 1998-11-25
US09/199,541 1998-11-25

Publications (1)

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WO2000030442A1 true WO2000030442A1 (fr) 2000-06-02

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7510823B2 (en) 2000-11-22 2009-03-31 The Leeds Teaching Hospitals Nhs Trust Flush preservation solution
CN105532646A (zh) * 2016-01-27 2016-05-04 武汉仝干生物科技有限公司 肝细胞保存液及其制备方法和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004127A2 (fr) * 1996-07-25 1998-02-05 Stanko Ronald T Solutions au pyruvate pour greffons, et procedes de transplantation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004127A2 (fr) * 1996-07-25 1998-02-05 Stanko Ronald T Solutions au pyruvate pour greffons, et procedes de transplantation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7510823B2 (en) 2000-11-22 2009-03-31 The Leeds Teaching Hospitals Nhs Trust Flush preservation solution
US8236486B2 (en) 2000-11-22 2012-08-07 The Leeds Teaching Hospital NHS Trust Flush preservation solution
CN105532646A (zh) * 2016-01-27 2016-05-04 武汉仝干生物科技有限公司 肝细胞保存液及其制备方法和应用
CN105532646B (zh) * 2016-01-27 2017-10-13 武汉仝干医疗科技股份有限公司 肝细胞保存液及其制备方法和应用

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