WO1998004127A2 - Solutions au pyruvate pour greffons, et procedes de transplantation - Google Patents

Solutions au pyruvate pour greffons, et procedes de transplantation Download PDF

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Publication number
WO1998004127A2
WO1998004127A2 PCT/US1997/013160 US9713160W WO9804127A2 WO 1998004127 A2 WO1998004127 A2 WO 1998004127A2 US 9713160 W US9713160 W US 9713160W WO 9804127 A2 WO9804127 A2 WO 9804127A2
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WO
WIPO (PCT)
Prior art keywords
pyruvate
transplantation
transplant
organ
concentration
Prior art date
Application number
PCT/US1997/013160
Other languages
English (en)
Other versions
WO1998004127A3 (fr
Inventor
Ronald T. Stanko
Luca Cicalese
Original Assignee
Stanko Ronald T
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 Stanko Ronald T filed Critical Stanko Ronald T
Publication of WO1998004127A2 publication Critical patent/WO1998004127A2/fr
Publication of WO1998004127A3 publication Critical patent/WO1998004127A3/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
    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid

Definitions

  • the present invention is based upon the discovery that the use of pyruvate in transplant
  • tissue which is an aggregation of cells more or less of similar morphology and functionality.
  • body is composed of four (4) primary tissues, namely, epithelium, connective tissue (including
  • pyruvate means any salt or esters of pyruvic acid. Pyruvic acid has the formula:
  • the mineral salts of pyruvic acid such as sodium pyruvate or calcium pyruvate or mixtures thereof are useful in the present invention.
  • Pyruvate precursors in the form of pyruvamides or pyruvyl-amino acids are also useful in the present invention.
  • Pyruvyl-glycine is representative of the useful pyruvyl-amino acids.
  • the pyruvate may be disbursed or
  • a beverage product may be included in cookies, candies or other foods. Pyruvate may also be introduced as an aqueous solution parenterally.
  • transplantation of an organ and/or to the recipient subsequent to the transplantation of the organ will significantly increase the likelihood of a successful transplantation. Further, the use of pyruvate-containing transplant solutions or pyruvate irrigation solutions will greatly enhance the
  • Transplantation is the removal of part of an organism and its replacement in the body of a
  • transplantation of cells, tissues or organs is an important procedure for treating a number of diseases and for studying a wide variety of problems.
  • Transplantation of organs is a widely accepted medical therapy for diseases such as cardiac disease, liver disease and
  • An aspect of the present invention con ⁇ rises administering
  • transplant solutions (for preservation and irrigation) containing pyruvate of the present invention also lessens the injury to the transplanted organ during periods of preservation and during the reperf sion event. Restoration of the flow of blood to a particular region of an
  • reperfusion i.e., muscles or organs.
  • One additional aspect of the present invention resides in the discovery that accepted solutions used to transport the donated organ which contain pyruvate produce an unexpected benefit in the preservation of the organ.
  • transplant solution comprising water, a buffer system and pyruvate.
  • the concentration of the pyruvate can range from 1-100 mmol or mM (millimolar). More
  • the concentration of the pyruvate can range from 1-25 mM.
  • transplant solution of this invention may contain antibiotics, steroids, insulin, nucleotides, carbohydrates, peptides and other components that are currently
  • a method for the transplantation of an organ in a mammal comprises the administration of pyruvate enterally or parenterally to the recipient mammal
  • method comprises the perfusion of the organ with a transplant solution comprising water, a
  • transplant solution comprising water, at least one steroid at a
  • transplant solution has an Osmolality of 250-375 mmos.
  • pyruvate means the mineral salts of pyruvic acid, for example the sodium, potassium or calcium salts, and pyruvate precursors in the form of pyruvamide or a pyruvyl-amino acid. Examples of the pyruvyl-amino acids useful in this
  • inventions are pyruvyl-glycine, pyruvyl-alanine, pyruvyl-leucine, pyruvyl valine, pyruvyl-isoleucine,
  • buffer system means medically accepted salts
  • transplant solution means an aqueous
  • preservation solution that is used to store the organ to be transplanted, an irrigation solution which is used to flush a body part for removing a foreign object or medicating the body part, a
  • the method also relates to the recipient mammal subsequent to the transplantation of the organ.
  • the method also relates to the recipient mammal subsequent to the transplantation of the organ.
  • pancreatic islet cells to treat diabetes.
  • One aspect of the present invention resides in the discovery that long term culture of pancreatic islet cells in a
  • the cells were cultured at 37°C in 5% CO 2
  • mice model on days 30, 60 and greater than 60 days to reverse experimentally induced diabetes in a male nude mice model was utilized.
  • the animals were rendered diabetic by a single injection of streptozotocin (185 ml/kg). 72 hours subsequent to the streptozotocin injection, approximately 700 islet cells were implanted into the mice from the experimental and control cultures.
  • the response of the transplanted islets to stress was evaluated on post-operative day 20 by an intraperitoneal glucose tolerance test (IPGTT).
  • IPGTT intraperitoneal glucose tolerance test
  • the viability of the transplanted cells was also determined on post- operative day 37 by
  • transplant solutions present an alternative to existing in vitro culture and cryopreservation
  • transplantation limits their hypothermic preservation to about 20 hours. There is therefore, a need
  • Group A which consisted of 5 rats, had the livers preserved and flushed before revascularization with the control solution.
  • Group B consisted of 5 rats and had the livers preserved with the experimental solution but flushed with the control solution prior to
  • This experiment demonstrates that a pyruvate containing transplant solution protects the hver to be transplanted. This experiment also supports the use of pyruvate containing solutions for extended hypothermic preservation (ischemic period), perfusion of the organ (flushing) and
  • hypothermic preservation time 48 hours
  • the grafts were then harvested and stored for 2 hours in cold (4°C) Ringer's solution.
  • Mucosal parameters were compared between the untreated and pyruvate treated grafts two hours after reperfusion. Tissue injury was evaluated by histopathology. Mucosal injury, after reperfusion of the preserved grafts and during acute rejection was significantly inhibited by pyruvate.
  • This experiment is designed to evaluate the use of pyruvate containing preservation
  • Small bowel grafts are harvested from male Sprague Dawley rats and are stored in cold (4°C) Ringer's lactate solution for 2 hours prior to undergoing orthotopic transplantation into Sprague Dawley recipients.
  • One aspect of the present invention relates to the discovery that feeding of pyruvate to the donor prior to removal of the organ and feeding of pyruvate to the recipient prior to and subsequent to transplantation can provide a beneficial effect.
  • This experiment used rejection of an
  • intravascular platelet aggregation The experimental group also evidenced preservation of Goblet cells and increased mitotic events as compared to controls. These observations support the feeding of pyruvate prior to and/or subsequent to transplantation of organs.
  • the medical community is constantly searching for improvements to the transplantation of organs.
  • the present invention provides a transplant solution of improved performance and a
  • transplant solutions of this invention are isotonic aqueous solutions that contain
  • organ recipient pyruvate prior to and/or subsequent to the transplant operation.

Abstract

La présente invention repose sur la découverte qu'on accroît dans de grandes proportions les capacités de survie du récepteur et la viabilité de l'organe greffé en utilisant du pyruvate dans les solutions pour greffons, et en apportant du pyruvate et/ou des dérivés de pyruvate aux receveurs d'organes, avant et après la transplantation. En l'occurrence, l'administration de pyruvate, avant la transplantation d'un organe et/ou à la suite de la transplantation de l'organe, accroît normalement de façon importante les chances de réussite de la transplantation. En outre, l'utilisation de solutions au pyruvate pour la conservation, l'irrigation et la perfusion du greffon permet une meilleure conservation des organes avant la transplantation. Les solutions pour greffon et les solutions d'irrigation de la présente invention contiennent des composants connus selon l'état de la technique, et du pyruvate dont la concentration se situe entre 1 et 100 mM.
PCT/US1997/013160 1996-07-25 1997-07-25 Solutions au pyruvate pour greffons, et procedes de transplantation WO1998004127A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US68631396A 1996-07-25 1996-07-25
US08/686,313 1996-07-25

Publications (2)

Publication Number Publication Date
WO1998004127A2 true WO1998004127A2 (fr) 1998-02-05
WO1998004127A3 WO1998004127A3 (fr) 1998-03-05

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1997/013160 WO1998004127A2 (fr) 1996-07-25 1997-07-25 Solutions au pyruvate pour greffons, et procedes de transplantation

Country Status (1)

Country Link
WO (1) WO1998004127A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000030442A1 (fr) * 1998-11-25 2000-06-02 Abbott Laboratories Solution de conservation d'organes contenant du pyruvate
WO2001052647A1 (fr) * 2000-01-20 2001-07-26 Res-Del International Limited Milieu physiologique destine a perfuser, a conserver et a stocker des echantillons de cellule, de tissu et d'organe isoles
US6846842B2 (en) 1999-10-07 2005-01-25 Beth Israel Deconess Medical Center, Inc. Pyruvate ester composition and method of use for resuscitation after events of ischemia and reperfusion

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0215138A1 (fr) * 1985-09-06 1987-03-25 Societe Des Produits Nestle S.A. Préservation des tissus vivants
WO1991009520A1 (fr) * 1989-12-21 1991-07-11 The Regents Of The University Of California Nouvelle technologie amelioree se rapportant a la conservation des organes destines a la transplantation
WO1992004826A1 (fr) * 1990-09-21 1992-04-02 Regents Of The University Of Minnesota Solutions de pyruvates utilisees dans le traitement d'insuffisance renale aigue
US5294641A (en) * 1991-11-27 1994-03-15 Montefiore - University Hospital Method for treating a medical patient for cardiac trauma
US5536751A (en) * 1994-05-09 1996-07-16 The United States Of America As Represented By The Secretary Of The Army Pharmaceutical alpha-keto carboxylic acid compositions method of making and use thereof
US5599659A (en) * 1993-03-11 1997-02-04 Breonics, Inc. Preservation solution for ex vivo, warm preservation of tissues, explants,organs and vascular endothelial cells comprising retinal-derived fibroblast growth factor, cyclodextrin and chondroitin sulfate

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1632427A1 (ru) * 1988-06-20 1991-03-07 Харьковский государственный университет им.А.М.Горького Среда дл предотвращени ишемического повреждени тканей при трансплантации органов

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0215138A1 (fr) * 1985-09-06 1987-03-25 Societe Des Produits Nestle S.A. Préservation des tissus vivants
WO1991009520A1 (fr) * 1989-12-21 1991-07-11 The Regents Of The University Of California Nouvelle technologie amelioree se rapportant a la conservation des organes destines a la transplantation
WO1992004826A1 (fr) * 1990-09-21 1992-04-02 Regents Of The University Of Minnesota Solutions de pyruvates utilisees dans le traitement d'insuffisance renale aigue
US5294641A (en) * 1991-11-27 1994-03-15 Montefiore - University Hospital Method for treating a medical patient for cardiac trauma
US5599659A (en) * 1993-03-11 1997-02-04 Breonics, Inc. Preservation solution for ex vivo, warm preservation of tissues, explants,organs and vascular endothelial cells comprising retinal-derived fibroblast growth factor, cyclodextrin and chondroitin sulfate
US5536751A (en) * 1994-05-09 1996-07-16 The United States Of America As Represented By The Secretary Of The Army Pharmaceutical alpha-keto carboxylic acid compositions method of making and use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIOLOGICAL ABSTRACTS, vol. 96, 1993 Philadelphia, PA, US; abstract no. 37299, S. KOJIMA ET AL.: "Simple 24-hour preservation of rabit hearts with hexanol and pyruvate cardioplegia." XP002049016 & J. MOL. CELL CARDIOL., vol. 25, no. 4, 1993, pages 453-458, *
DATABASE WPI Section Ch, Week 9205 Derwent Publications Ltd., London, GB; Class B05, AN 92-039875 XP002049017 & SU 1 632 427 A (UNIV KHARK) , 7 March 1991 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000030442A1 (fr) * 1998-11-25 2000-06-02 Abbott Laboratories Solution de conservation d'organes contenant du pyruvate
US6846842B2 (en) 1999-10-07 2005-01-25 Beth Israel Deconess Medical Center, Inc. Pyruvate ester composition and method of use for resuscitation after events of ischemia and reperfusion
WO2001052647A1 (fr) * 2000-01-20 2001-07-26 Res-Del International Limited Milieu physiologique destine a perfuser, a conserver et a stocker des echantillons de cellule, de tissu et d'organe isoles

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Publication number Publication date
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