EP0797384A1 - Solutions pour la transplantation d'organes et technique de transplantation d'organes - Google Patents

Solutions pour la transplantation d'organes et technique de transplantation d'organes

Info

Publication number
EP0797384A1
EP0797384A1 EP95943059A EP95943059A EP0797384A1 EP 0797384 A1 EP0797384 A1 EP 0797384A1 EP 95943059 A EP95943059 A EP 95943059A EP 95943059 A EP95943059 A EP 95943059A EP 0797384 A1 EP0797384 A1 EP 0797384A1
Authority
EP
European Patent Office
Prior art keywords
amiloride
solution
organ
containing compound
heart
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP95943059A
Other languages
German (de)
English (en)
Other versions
EP0797384A4 (fr
Inventor
Richard M. Raymond
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Charlotte Mecklenburg Hospital
Original Assignee
Charlotte Mecklenburg Hospital
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
Priority claimed from US08/354,503 external-priority patent/US5554497A/en
Application filed by Charlotte Mecklenburg Hospital filed Critical Charlotte Mecklenburg Hospital
Publication of EP0797384A1 publication Critical patent/EP0797384A1/fr
Publication of EP0797384A4 publication Critical patent/EP0797384A4/fr
Withdrawn legal-status Critical Current

Links

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
    • 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 present invention relates to cardioplegic solutions, to organ preservation solutions, and to methods for transplanting organs. More particularly, this invention relates to cardioplegic solutions for arresting an organ for transplantation, to preservation solutions for perfusing and storing an organ while awaiting implantation, and to methods for using the cardioplegic and preserving solutions during transplantation of an organ.
  • organ transplantation including heart transplantation
  • a significant factor limiting the clinical application of organ transplantation is the deviation of viability of the organ after removal from the donor.
  • the two most frequently used methods for heart transplantation are simple hypothermic storage and continuous pulsatile perfusion.
  • simple hypothermic storage the heart is arrested with a cardioplegic solution, then removed from the donor and cooled rapidly. This is usually achieved by a combination of cooling and a short period of perfusion to drop the heart temperature as quickly as possible to a temperature between 0°C. and 4°C. where it may be held up to about 6 hours.
  • cold storage enables organs to be transplanted, the time during which the organ is viable is short. Cold storage decreases the rate at which intracellular enzymes, essential cellular components necessary for organ viability, degrade but does not stop metabolism.
  • the second method of organ preservation which has undergone extensive investigation, continuous pulsatile perfusion, includes the following steps: (1) pulsatile flow, (2) hypothermia, (3) membrane oxygenation, and (4) a perfusate containing both albumin and lipids.
  • compositions of numerous cardioplegic and preservation solutions have been extensively studied.
  • the protective properties of three cardioplegic solutions were compared by Gali ⁇ anes et al .
  • a comparison of cold preservation solutions was set forth in G. Tian et al . (1991) The Journal of Heart and Lung
  • a storage solution for preserving organs which can be used at temperatures from 0°C. to 37°C. but was limited in storage time was disclosed in U.S. Patent No. 5,145,771 to Lemasters et al .
  • the solution requires the use of the colloid, hydroxyethyl starch, for oncotic support against interstitial edema.
  • edema is not a problem because no oxygen-derived free radicals are available to injure the organ.
  • Preserving organs at between 0°C. and 4°C. results in damage to the organ during storage and upon reperfusion with a warm reperfusion solution. Damage to the organ occurs through the loss of endothelial cells due to dissolved oxygen in the reperfusion solution.
  • reperfusion itself although necessary for the survival of the tissue, may initiate a series of events known as reperfusion induced injury, which, if occurring, limit the extent or rate of recovery.
  • reperfusion induced injury which, if occurring, limit the extent or rate of recovery.
  • modification of the nature of reperfusion is desirable to improve the recovery of the ischemic/reperfused myocardium.
  • the sodium pump which normally maintains the intracellular composition high in potassium, magnesium, and phosphate and low in sodium and chloride, ceases to function due to the lack of energy, resulting in an inflow of sodium and chloride into the cells, and an outflow of potassium and to a lesser extent magnesium from the cells.
  • the result of these rapid changes in Na * - H * distribution in the cell is a net gain, not merely an exchange, of intracellular ions followed by water and a profound loss of potassium and magnesium resulting in damage to the organ.
  • Yet another object of the present invention is to provide a method of transplanting organs in which storage of the organ may be carried out at room temperature for up to at least 24 hours without significant damage to the organ.
  • cardioplegic solutions and preserving solutions for use in the transplantation of organs, and to methods for transplanting organs using the solution in combination with cardioplegic solutions, which methods increase storage times and lessen injury to the organ.
  • the cardioplegic solution includes a balanced isotonic solution including sodium, potassium, calcium and magnesium ions and bicarbonate in a physiologically acceptable amount, at least 0.5 ⁇ M, preferably from about 1.0 ⁇ M to about 5.0 ⁇ M, and most prefereably 1.0 ⁇ M to 3.0 ⁇ M of an amiloride-containing compound, and water sufficient to make a liter of solution.
  • the cardioplegic solution also preferably contains glucose to enhance organ preservation, adenosine to prevent fibrillation of the organ prior to removal from the donor, and EDTA as a chelating agent.
  • the cardioplegic solution contains heparin and at least one antioxidant.
  • the preservation solution while similar to the cardioplegic solution in starting composition in that it is based on a balanced isotonic solution including sodium, potassium, calcium, magnesium ions and bicarbonate in a physiologically acceptable amount also includes from 1.0 ⁇ M to about 5.0 ⁇ M of an amiloride-containing compound.
  • the preservation solution preferably includes at least one antioxidant, such as, dimethyl thiourea (DMTU) , catalase as a hydrogen peroxide scavenger and apoferritin to decrease iron content within the preservation solution. Since the organ has been arrested by the cardioplegic solution, the preservation solution includes less adenosine and heparin is not normally needed. In addition, the preservation solutions optionally may include hormones, such as insulin and prostaglandin and antibiotics.
  • DMTU dimethyl thiourea
  • catalase as a hydrogen peroxide scavenger
  • apoferritin to decrease iron content within the preservation solution. Since the organ has been arrested by the cardioplegic solution, the preservation solution includes less adenosine and heparin is not normally needed.
  • the preservation solutions optionally may include hormones, such as insulin and prostaglandin and antibiotics.
  • amiloride-containing compound may be amiloride itself, or amiloride analogs, such as hexamethylene amiloride (HMA) , dimethyl amiloride (DMA) , ethyl isopropyl amiloride (EIPA) , or methyl PC17US95/16065
  • HMA hexamethylene amiloride
  • DMA dimethyl amiloride
  • EIPA ethyl isopropyl amiloride
  • PC17US95/16065 methyl PC17US95/16065
  • MIA isobutyl amiloride
  • the invention also provides a method for transplanting an organ which includes steps for arresting and removing the organ from the donor, and for preserving and storing the organ intended for implantation.
  • the method of the invention includes arresting the organ to be donated with a cardioplegic solution.
  • the organ is removed and connected to a perfusion apparatus where it is maintained at a temperature between about 0°C. to about 37°C, preferably from about 15°C. to about 25°C. while perfusing with the preservation solution.
  • the novel features of the present invention include storing the organ at warm temperatures, i.e., up to about room temperature, while perfusing the organ.
  • the present invention is directed to new cardioplegic solutions for arresting an organ intended for transplantation and to new preservation solutions for storing and perfusing organs intended for implantation in a patient requiring such implant.
  • Suitable organs on which the solutions of this invention may be used include, for example, heart, liver, kidney and pancreas.
  • the individual components of the present invention are all nontoxic and have been found to be stable during storage . While some of the components of the present invention are similar to those of other known cardioplegic and preservation solutions, it has surprisingly been found that the addition of amiloride or an amiloride-containing compound to a balanced isotonic solution including sodium, potassium, calcium, magnesium, and bicarbonate ions in a physiologically acceptable amount to form a cardioplegic solution and its use with the preservation solution of the present invention allows organs to be preserved at room temperature for at least 24 hours without significant damage to the organ.
  • Both the cardioplegic solutions and the preservation solutions of the present invention are based on a balanced isotonic solution including sodium, potassium, calcium and magnesium ions as well as glucose and sodium bicarbonate in a physiologically acceptable amount.
  • Certain of these types of solutions are well known, such as the one described below, known as Krebs-Henseleit-bicarbonate solution, which has the following composition:
  • the cardioplegic Solution is made by starting with the balanced isotonic solution described above.
  • the amount of potassium chloride in the cardioplegic solution is preferably from about 20 mM to about 30 mM.
  • an amiloride-containing compound in an amount of at least 0.5 ⁇ M, preferably from about 1.0 ⁇ M to about 5.0 ⁇ M, and most preferably from 1.0 ⁇ M to 3.0 ⁇ M.
  • amiloride-containing compound it is meant to include amiloride and amiloride analogs.
  • amiloride designated chemically as 3, 5-diamino-6- chlor-N- (diaminomethylene) pyrazinecarboxamide monohydrochloride has been found to inhibit the ⁇ a * - H * exchange.
  • amiloride-containing compounds or analogues which may be used in the cardioplegic solution include, for example, hexamethylene amiloride (HMA) designated chemically as 5- (N, N-hexamethylene) - amiloride, dimethyl amiloride (DMA) designated 5 - (N, N- dimethyl) -amiloride, ethyl isopropyl amiloride (EIPA) , designated 5- (N-ethyl -N-isopropyl) -amiloride, and methyl isobutyl amiloride (MIA) , designated 5- (N- methyl -N-isobutyl) -amiloride.
  • HMA hexamethylene amiloride
  • DMA dimethyl amiloride
  • EIPA
  • the cardioplegic solution needs to prevent fibrillation of the organ in a relatively short period of time, e.g., 2 minutes to 5 minutes or less.
  • adenosine is added to the solution in an amount from about 5 ⁇ M to about 15 ⁇ M per liter, preferably about 10 ⁇ M per liter.
  • Adenosine rapidly arrests the heart (within seconds) , improves the preservation properties and increases the glucose uptake.
  • the cardioplegic solution also preferably includes ethylene diaminetetraacetic acid (EDTA) in an amount from 0.5 mM to about 1.5 mM as a chelating agent.
  • EDTA ethylene diaminetetraacetic acid
  • the solution also may optionally contain other ingredients, such as at least one antioxidant, for example, catalase, in an amount effective to inhibit the generation of oxygen-derived free radicals via hydrogen peroxide.
  • Heparin is used in carrying out the method of this invention, and may be included either directly in the cardioplegic solution or it may be administered to the donor organ separately. The addition of heparin in an amount of from about 500 units to about 1500 units, preferably 1000 units is required to prevent blood clots from forming within the coronary arteries during cardioplegic arrest and excision prior to organ storage and implantation.
  • the preservation solution is designed to '• prevent various mechanisms which cause injury to the organ and thus must be a composition that (1) prevents or restricts intracellular acidosis, (2) prevents the expansion of intracellular space, (3) prevents injury from oxygen-derived free radicals, especially during reperfusion, (4) enables the regeneration of high- energy phosphate compounds during reperfusion, (5) sustains appropriate metabolic requirement, and (6) prevents the rapid changes in intracellular Na + -H + -Ca ++ following reperfusion.
  • the preservation solution begins with the isotonic solution, wherein the potassium concentration is maintained at preferably from 3.0 mM to about 8.0 mM.
  • Magnesium chloride may be used in place of potassium chloride.
  • amiloride-containing compound in an amount from about 1.0 ⁇ M to about 5.0 ⁇ M, preferably 1.5-3.0 ⁇ M.
  • amiloride-containing compound it is meant to include amiloride and amiloride analogs.
  • amiloride designated chemically as 3, 5-diamino-6- chlor-N- (diaminomethylene) pyrazinecarboxamide onohydrochloride has been found to inhibit the ⁇ a + - H + exchange.
  • amiloride-containing compounds or analogues which may be used in the cardioplegic solution include, for example, hexamethylene amiloride (HMA) designated chemically as 5- (N, N-hexamethylene) - amiloride, dimethyl amiloride (DMA) designated 5- (N, N- dimethyl) -amiloride, ethyl isopropyl amiloride (EIPA) , designated 5- (N-ethyl -N-isopropyl) -amiloride, and methyl isobutyl amiloride (MIA) , designated 5- (N- methyl -N-isobutyl) -amiloride . (Merck Sharpe & Dohme, West Point, Pa) .
  • HMA hexamethylene amiloride
  • DMA dimethyl amiloride
  • EIPA ethyl isopropyl amiloride
  • MIA methyl isobutyl amiloride
  • MIA isobutyl amiloride
  • the amount of adenosine is considerably less than the amount of adenosine present in the cardioplegic solution because the organ has been previously arrested.
  • the amount of adenosine in the preservation solution is normally from 0.7 ⁇ M to about 2.0 ⁇ M, preferably about 1.0 ⁇ M.
  • the preservation solution also preferably includes ethylene diaminetetraacetic acid (EDTA) in an amount from 0.5 ⁇ M to about 1.5 ⁇ M as a chelating agent.
  • EDTA ethylene diaminetetraacetic acid
  • Suitable antioxidants include, but are not limited to, allopurinol, glutathione, beta-carotene, catalase, superoxide dismutase, dimethyl thiourea (DMTU) , diphenyl phenylene diamine (DPPD) , mannitol or cyanidanol in an amount effective to inhibit the generation of oxygen-derived free radicals.
  • the antioxidants are present in an amount from 1 77M to 10 77M.
  • Antibiotics may be added for transplantable organs, but is not generally added during acute studies.
  • the transplantation method of the present invention is to arrest the organ using the cardioplegic solution, preserve and store the organ with the preservation solution and reperfuse with the preservation solution.
  • sufficient cardioplegic solution is injected to arrest, for example the heart and prevent fibrillation.
  • the surgeon then removes the organ and connects the heart to a perfusion apparatus comprising tubing and pumps .
  • the preservation solution is then perfused through the heart while gassed with oxygen and carbon dioxide while it is awaiting implantation into a patient .
  • a perfusion rate of 50 mL/hour at 1.0°C. has been found to be effective.
  • the method of perfusing the heart can be at either a constant flow or pressure.
  • the solution can be used at all temperatures ranging from 0°C. to normal body temperature, 37°C. At temperatures of from about 12°C. to about 37°C, the solution is more protective than other known preservation solutions. Unlike other storage solutions, it continues to be protective above 10°C. for at least 24 hours.
  • Example 1 is provided to further illustrate the present invention and are not to be construed as limiting the invention in any manner.
  • Example 1
  • a liter of cardioplegic solution having the following composition was prepared.
  • a liter of preservation solution having the following composition was prepared.
  • the preservation solution was prepared in much the same manner as the cardioplegic solution of Example I, that is, by adding a Krebs-Heneseleit solution to a 1000 mL volumetric flask with double distilled water to make one liter while stirring. The rest of the components were added one at a time and the pH of the solution was adjusted to about 7.3 with NaOH and gassed with 95% oxygen plus 5% carbon dioxide.
  • a female mongrel dog weighing about 20 kg. was anesthetized.
  • An IV hydrating solution of 5.0% dextrose in 0.45% saline at 75 cc/hr was given throughout the procedure .
  • the heart was exposed by a sternotomy.
  • the cardioplegic solution of Example 1 was administered to arrest the heart, the heart was then excised.
  • the heart was placed in ice and promptly transferred to the laboratory and placed in a perfusion apparatus at room temperature where the aorta was attached to a tube for continuous perfusion with the preserving solution of Example 2. After 2-3 minutes the heart started beating at a pulse rate of 50 beats per minute.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Physiology (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

Solutions cardioplégiques pour arrêter un organe à transplanter et solutions de conservation pour perfuser et conserver un organe en attente de transplantation. Les solutions cardioplégiques contiennent, par litre de solution, un soluté isotonique équilibré d'ions sodium, potassium, calcium et magnésium et des bicarbonates en quantité acceptable sur le plan physiologique, au moins 0,5 νM d'un composé à base d'amiloride et de l'eau en quantité suffisante pour constituer un litre de solution. Les solutions de conservation contiennent, par litre de solution, un soluté isotonique équilibré d'ions sodium, potassium, calcium et magnésium et des bicarbonates en quantité acceptable sur le plan physiologique, d'environ 1,0 à environ 5,0 νM d'un composé à base d'amiloride et de l'eau en quantité suffisante pour constituer un litre de solution. La solution de conservation peut en outre contenir en outre d'autres composants tels que de l'EDTA, une faible quantité d'adénosine et au moins un anti-oxydant. Le composé à base d'amiloride peut être de l'amiloride, de l'héxaméthylène amiloride, du diméthylamiloride, de l'éthylisopropylamiloride ou du méthylisobutylamiloride. Est également présentée une technique d'arrêt, de conservation et de transplantation d'un organe à température ambiante pour une durée allant jusqu'à au moins 24 heures.
EP95943059A 1994-12-12 1995-12-11 Solutions pour la transplantation d'organes et technique de transplantation d'organes Withdrawn EP0797384A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US08/354,503 US5554497A (en) 1994-12-12 1994-12-12 Cardioplegic solution for arresting an organ
US354503 1994-12-12
US08/563,222 US5693462A (en) 1994-12-12 1995-11-27 Organ transplant solutions and method for transplanting an organ
PCT/US1995/016065 WO1996018293A1 (fr) 1994-12-12 1995-12-11 Solutions pour la transplantation d'organes et technique de transplantation d'organes
US563222 2000-05-02

Publications (2)

Publication Number Publication Date
EP0797384A1 true EP0797384A1 (fr) 1997-10-01
EP0797384A4 EP0797384A4 (fr) 2000-07-19

Family

ID=26998430

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95943059A Withdrawn EP0797384A4 (fr) 1994-12-12 1995-12-11 Solutions pour la transplantation d'organes et technique de transplantation d'organes

Country Status (5)

Country Link
EP (1) EP0797384A4 (fr)
AU (1) AU4420396A (fr)
CA (1) CA2207324A1 (fr)
MX (1) MX9704374A (fr)
WO (1) WO1996018293A1 (fr)

Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8409846B2 (en) 1997-09-23 2013-04-02 The United States Of America As Represented By The Department Of Veteran Affairs Compositions, methods and devices for maintaining an organ
US5972903A (en) * 1997-10-07 1999-10-26 Regents Of The University Of California Corporation Method for promoting angiogenesis using heparin and adenosine
CA2305726A1 (fr) * 1997-10-07 1999-04-15 Regents Of The University Of California Traitement de la vasculopathie peripherique obliterante et de la coronarite au moyen de conbinaisons d'heparine et d'un agoniste a2 adenosine, ou au moyen d'adenosine
ITRM20010337A1 (it) 2001-06-14 2002-12-16 Sigma Tau Ind Farmaceuti Soluzione per la conservazione e perfuzione di organi in attesa che vengano trapiantati.
US9301519B2 (en) 2004-10-07 2016-04-05 Transmedics, Inc. Systems and methods for ex-vivo organ care
US8304181B2 (en) 2004-10-07 2012-11-06 Transmedics, Inc. Method for ex-vivo organ care and for using lactate as an indication of donor organ status
CA3178010A1 (fr) 2004-10-07 2006-04-20 Transmedics, Inc. Systemes et procedes de soins a des organes ex vivo
US9078428B2 (en) 2005-06-28 2015-07-14 Transmedics, Inc. Systems, methods, compositions and solutions for perfusing an organ
US9457179B2 (en) 2007-03-20 2016-10-04 Transmedics, Inc. Systems for monitoring and applying electrical currents in an organ perfusion system
US9462802B2 (en) 2008-01-31 2016-10-11 Transmedics, Inc. Systems and methods for ex vivo lung care
CA2809514C (fr) * 2010-09-01 2014-10-28 Organ Perfusion Pty Limited Composition de perfusion
WO2012078968A2 (fr) * 2010-12-10 2012-06-14 Lifeline Scientific, Inc. Perfusion assistée par machine, par des inhibiteurs du complément
NZ616699A (en) 2011-04-14 2016-03-31 Transmedics Inc Organ care solution for ex-vivo machine perfusion of donor lungs
PL227045B1 (pl) 2012-09-14 2017-10-31 Blirt Spółka Akcyjna Płyn do przechowywania narządów w czasie zabiegów chirurgicznych, zwłaszcza transplantacji.
IL303658B1 (en) 2014-06-02 2024-03-01 Transmedics Inc Extracorporeal system for organ treatment
AU2015361996B2 (en) 2014-12-12 2019-09-26 Transmedics, Inc. Apparatus and method for organ perfusion
IL310004A (en) 2015-09-09 2024-03-01 Transmedics Inc A tube and a catheter for a system to treat organs outside the body

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2089336C (fr) * 1990-09-12 2000-04-25 Stephen A. Livesey Methode de traitement et de conservation des tissus collageniques pour la transplantation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO9618293A1 *

Also Published As

Publication number Publication date
WO1996018293A1 (fr) 1996-06-20
AU4420396A (en) 1996-07-03
MX9704374A (es) 1998-02-28
CA2207324A1 (fr) 1996-06-20
EP0797384A4 (fr) 2000-07-19

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