WO1995034301A1 - Energy substrates - Google Patents

Energy substrates Download PDF

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Publication number
WO1995034301A1
WO1995034301A1 PCT/SE1995/000698 SE9500698W WO9534301A1 WO 1995034301 A1 WO1995034301 A1 WO 1995034301A1 SE 9500698 W SE9500698 W SE 9500698W WO 9534301 A1 WO9534301 A1 WO 9534301A1
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WO
WIPO (PCT)
Prior art keywords
alpha
ketoglutarate
organs
solution
providing
Prior art date
Application number
PCT/SE1995/000698
Other languages
English (en)
French (fr)
Inventor
Rolf Ekroth
Jan Wernerman
Original Assignee
Pharmacia & Upjohn Ab
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 Pharmacia & Upjohn Ab filed Critical Pharmacia & Upjohn Ab
Priority to AU27584/95A priority Critical patent/AU2758495A/en
Publication of WO1995034301A1 publication Critical patent/WO1995034301A1/en

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Classifications

    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine

Definitions

  • the present invention is directed to alpha-ketoglutarate containing infusible energy substrate preparations and the uses thereof.
  • the preparations are advantageous by their capacity in improving the ischemic tolerance of organs interrupted from their regular blood flow and in the improvement of the recovery of such organs.
  • Amino acid enriched cardioplegic solutions are described by e.g. the U.S. patent 4,988,515 wherein an improved glutamate/aspartate containing cardioplegic solution is described.
  • This document shows how a cardioplegic solution with a specific calcium ion concentration range and osmolality range improves cardiac recovery from ischemia after interrupting the blood flow to dogs' hearts.
  • Concentrated aqueous solutions of the amino acids, calcium ion and glucose are mixed with other standard additives and a cardioplegia compatible diluent or carrier, such as blood, stroma free haemoglobin, oxygenated plasma, crystalloids and fluorocarbons.
  • a cardioplegia compatible diluent or carrier such as blood, stroma free haemoglobin, oxygenated plasma, crystalloids and fluorocarbons.
  • HTK -s olution histidine-tryptophane-ketoglutarate
  • the HTK- solution is intended to be used clinically, immediately after aortic cross clamping when a cold solution (4 to 8°C) is infused into the coronary system for 6 to 10 min.
  • a cold solution (4 to 8°C)
  • the heart muscle will be arrested, the myocardial temperature decreases from 37°C to 10°C and the ⁇ 2-consumption decreases from about 7 to 0.1 ml/min/100 g.
  • the low content of alpha-ketoglutarate comprised in the HTK-solutions might be regarded as attempts to recreate the original intracellular conditions in the heart after it has been interrupted from its normal blood supply.
  • the German patent application DE 39 43424 teaches a parenteral composition of alpha-ketoacid analogues to certain essential amino acids to be used as a nutrient supply for patients with renal insufficiency that cannot tolerate amino acids.
  • the solutions can contain 15 g/1 of alpha-ketoglutarate.
  • a nutritional composition containing 5 to 25 g/litre of alpha-ketoglutarate is disclosed to improve the negative nitrogen balance and protein catabolism that occurs in postoperative and post traumatic states.
  • the International patent application WO 93/23027 discloses an infusible composition providing more than 0.25 g/kg body weight/ day of alpha-ketoglutarate to critically ill patients in order to improve the protein synthesis capacity and to maintain the energy level in skeletal muscle tissue.
  • the alpha-ketoglutarate amount exceeds 17.5 g/1, preferably more than 25 g/1 in a 1 1 amino acid solution per day dose, which for a 70 kg patient will correspond to more than 0.25 g/kg bw and day when administered with conventional total parenteral nutrition constituents.
  • This disclosure is generally directed to the treatment of such critically ill patients having more than a 50% depletion of their glutamine pool in the skeletal muscles, who suffer from severe complications like sepsis and multiple organ failure. It does, accordingly, not reveal anything about the specific energy substrate requirements in the post-traumatic heart or any other vital organs subjected to ischemia, for example, during bypass surgery or during preservation of organs for transplantation.
  • the heart metabolism is altered so that its substrate uptake is insufficient with respect to its oxygen consumption.
  • This condition seems to lead to a catabolic status where the myocardial tissue utilizes endogenous substrates such as glycogen and also, to a large extent amino acids rather than free fatty acids (FFA), glucose or lactate which are the normal substrates in the energy production of the heart.
  • FFA free fatty acids
  • glucose or lactate which are the normal substrates in the energy production of the heart.
  • the change in metabolism is most expressed during the first hours after the trauma, whereupon the metabolism is gradually normalised for about eight hours.
  • the present invention is directed to new highly concentrated alpha-ketoglutarate containing energy substrates, uses thereof as well as methods involving said compositions.
  • the preparations are especially useful for preventing the myocardial tissue from ischemic damages during cardiac surgery, thereby reducing the postoperative morbidity and the need for postoperative intensive care.
  • the present invention is related to compositions providing a total parenterally infused dosage of 5 to 250 gram alpha-ketoglutarate for improving the ischemic tolerance of vital organs interrupted from their regular blood flow and for improving the recovery and /or normal metabolism of such organs.
  • the compositions shall provide the patient with total amounts of between 5 to 50 g alpha-ketoglutarate, and more preferably from 10 to 30 g alpha-ketoglutarate.
  • compositions are intended to be used as energy substrates, useful for preventing organs from damages during surgery, or other critical conditions when the blood supply to a vital organ is interrupted, such as the first phase after a myocardial infarction or for perfusion and preservation of organs that shall be transplanted.
  • compositions of the according invention shall preferably be capable of providing an alpha-ketoglutarate level of about 5 to 100 mM in the fluid passing through the organ interrupted from its normal blood flow and more preferably about 10 to 50 mM. Uses of the compositions and methods of their clinical applications also are apparent from the appended claims.
  • compositions will preferably be in a dry powdered form, prepared by methods like lyophilisation or spray drying, that can be readily reconstituted to an administerable solution, just prior to the use. It is advantageous to provide such preparations in sterilizable multi-compartment packages or kits, wherein the solid alpha-ketoglutarate and the reconstitution solution are kept apart during the storage.
  • the person skilled in the art is familiar with numerous solutions to this type of technical problems which therefore not will be discussed in more detail.
  • the reconstitution solution will consist of a carrier or diluent that is suitable for a composition of the intended type of administration, that can be, for example, a cardioplegical solution, a solution to be administered to the heart just after a myocardial infarction, an infusion solution to be administered to other vital organs subjected to an insufficient blood flow, a solution to be used in connection with a surgical procedure of a vital organ, e.g. for peri- or postoperative administration and a solution useful in the storage and perfusion of organs to be transplanted.
  • a carrier or diluent that is suitable for a composition of the intended type of administration, that can be, for example, a cardioplegical solution, a solution to be administered to the heart just after a myocardial infarction, an infusion solution to be administered to other vital organs subjected to an insufficient blood flow, a solution to be used in connection with a surgical procedure of a vital organ, e.g. for peri- or postoperative
  • Each suitable carrier or diluent can further contain other specifically adapted, but conventional constituents in the form of energy substrates, such as carbohydrates, amino acids, polyols, buffering agents, electrolytes, stabilizers and certain trace elements, as will be disclosed in more detail below. It would also, of course, if necessary due to stability reasons, be possible to incorporate such constituents also in dry, reconstitutible form, either together with the alpha-ketoglutarate, or separately.
  • Suitable counter ions are tromethamine (2-amino-2- hydroxymethyl-l,3-propanediol or THAM), ornithine, lysine, histidine and arginine.
  • suitable conventionally used vehicles such as extracorporeal blood from the patient in blood cardioplegia, crystalloid solutions, oxygenated plasma and transfusion emulsions containing synthetic oxygen carriers.
  • the parenteral infusion rate of a solution containing a total dosage of 5 to 250 g alpha-ketoglutarate intended to prevent ischemic damages in an organ will vary considerably due to the condition it shall be used for and the desired length of the dosage.
  • the infusion rates will vary between 0.5 g/h and 100 g/h.
  • Solutions infused to patients subjected to cardiac surgery or during the first phase after a myocardial infarction shall supply a total amount of alpha-ketoglutarate of at least 5 to 250 g, preferably between 5 to 50 g, and more preferably from 10 to 30 g, either during intermittent or continuous administration.
  • a suitable solution for cardioplegic use can contain totally about 20 to 30 of alpha ketoglutarate and be diluted with extracorporeal blood and intermittently infused to the heart by the aorta during cardiac surgery.
  • the alpha-ketoglutarate containing solutions, for administration to organs interrupted from their regular blood flow, can, added to their carriers or diluents, contain suitable amounts of electrolytes such as sodium, potassium, and magnesium chloride, bicarbonates and phosphates; suitable carbohydrates, such as glucose, fructose, dextrose, ribose, mannitol and other polyols; amino acids, such as aspartate, glutamate, glutamine, histidine, tryptophane and branch chained amino acids can be included in the solution; as well as suitable buffering agents, such as citrate, acetate and tromethamine (tris buffer); and also certain other bioactive constituents, such as insulin, glutathione, adenosine and antibiotics, if desirable for a specific clinical application.
  • electrolytes such as sodium, potassium, and magnesium chloride, bicarbonates and phosphates
  • suitable carbohydrates such as glucose, fructose, dextrose, ribose,
  • Alpha-ketoglutarate containing solutions useful for perfusion and preservation of organs shall preferably comprise carriers suitable for such fluids like oxygen carrying emulsions. In addition they may comprise other suitable energy substrates, amino acids, electrolytes, carbohydrates, buffering agents, and stabilizers.
  • alpha-ketoglutarate has a surprisingly high capacity in making vital organs, like the heart, to withstand ischemic conditions, which can not only be explained by its property as an energy substrate, but must also be explained by an influence on the activity of the induced proteolysis and /or degradation of contractile elements in the damaged tissues.
  • Patients in the control group received blood cardioplegia comprising blood from the extracorporeal circuit (hematocrit 25%) and Plegisol ® (from Abbott) containing 15 mmol KC1/500 ml and 5 ml sodium bicarbonate 8.4%.
  • Blood and Plegisol® were mixed at a 4:1 ratio and delivered with a pump and a heat exchanger.
  • 1000 ml of the cardioplegic solution was delivered through a cannula in the aortic root at a rate of 260 ml/min.
  • Another dose of 500 ml blood cardioplegia was infused after the completion of each peripheral anastomosis.
  • the temperature of the blood cardioplegia was 8°C.
  • the final cardioplegia dose was given with the blood cardioplegia rewarmed to 30°C.
  • the terminal warm dose was given with at least 500 ml, or more, until the septal temperature reached 25°C.
  • the aortic cross-clamp was thereafter released so that the heart was reperfused in a normal manner.
  • alpha-ketoglutarate allocated patients, 30 grams of alpha- ketoglutarate were added to 500 ml Plegisol®, and delivered with the blood cardioplegia, which was delivered exactly as described with the control patients. Depending on the duration of the cardioplegic ischemia, this regimen resulted in that a total dose of 15 to 30 grams of alpha-ketoglutarate was delivered.
  • Figure 1 shows myocardial oxygen extraction (aerobic capacity) during cold (4 to 8) and warm (9) cardioplegia and after blood cardioplegia
  • FIG. 1 shows myocardial lactate release (mean ⁇ SEM) in control patients and in patients treated with alpha-ketoglutarate, during cold (4 to 8) and warm (9) cardioplegia and after blood cardioplegia (during reperfusion 10 to 12). The release of lactate, reflecting anaerobic oxidation, was greater in the alpha-ketoglutarate treated patients, as signified by a more negative value.
  • Figure 3 gives the blood concentration in arterial blood of ischemic marker CK-MB (representing myocardial dysfunction and membrane leak), means ⁇ SEM of the two study groups, during blood cardioplegia (2 to 9) and during 4 hours reperfusion (10 to 15).
  • CK-MB is used as a marker for myocardial ischemia.
  • the lower concentrations in the alpha-ketoglutarate group indicates that alpha-ketoglutarate protects the heart from ischemia to a higher degree.
  • Figure 4 gives similar data for troponine-t during blood cardioplegia and reperfusion.
  • Troponine-t is a highly cardiospecific substance signifying myocardial ischemic injury.
  • alpha ketoglutarate in the infused doses of totally 15 to 25 gram leads to a doubled myocardial aerobic capacity during blood cardioplegia and increased with 70% during the early reperfusion period.
  • the anaerobic metabolic capacity, represented by myocardial release of lactate is demonstrated to be doubled during cardioplegia and tripled during the early reperfusion if an alpha-ketoglutarate containing solution is infused.
  • the myocardial release of lactate had ceased within 1 hour when alpha- ketoglutarate in pharmacological doses had been added to the blood cardioplegia, while it was maintained in the control patients. This implies that aerobic metabolism was normalized quicker with alpha-ketoglutarate.
  • the r-values represent the correlation coefficients for the oxygen extraction and the lactate release of the myocardium, 5 minutes after reperfusion, when correlated to the arterial level 4 hours later.
  • troponine-t can be regarded as a marker of the induced activity of proteolytic enzymes during the ischemic events. This suggests that alpha- keto glutarate not only is active as an energy substrate for the myocardium, but also is active in inhibiting the catabolism during the ischemia by reducing the degradation of contractile elements in the myocardial tissue and /or inhibit proteolytic enzymes.
  • an alpha-ketoglutarate containing cardioplegic solution provides an improved myocardial protection during cardiac surgery and enhances the recovery of the heart, which is an important finding, since cardiac dysfunction is one of the major problems in cardiac surgery.
  • the invention is therefore likely to have significant clinical effects.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
PCT/SE1995/000698 1994-06-10 1995-06-09 Energy substrates WO1995034301A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU27584/95A AU2758495A (en) 1994-06-10 1995-06-09 Energy substrates

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9402027A SE9402027D0 (sv) 1994-06-10 1994-06-10 Energy substrates
SE9402027-8 1994-06-10

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5880098A (en) * 1996-04-12 1999-03-09 Pharmacia & Upjohn Aktiebolag Therapeutic treatment
US6207658B1 (en) 1996-01-11 2001-03-27 University Of Florida Research Foundation, Inc. Preservation of tissue during removal storage and implantation
WO2006016828A2 (en) * 2004-08-12 2006-02-16 Sgp & Sons Ab Use of alpha ketoglutarate for treating alzheimer, parkinson
WO2006127902A1 (en) * 2005-05-26 2006-11-30 Ben O'mar Arrington Preservation solution for organs and biological tissues
WO2007122190A1 (en) * 2006-04-21 2007-11-01 Sgp & Sons Ab Compositions comprising alpha-ketoglutarate and their use for modulating muscle performance
WO2009005464A1 (en) * 2007-07-02 2009-01-08 Entress Ab New use of known pharmacologically active chemical compounds
WO2017192413A1 (en) 2016-05-01 2017-11-09 The Regents Of The University Of California Glutarate compounds for treating ischemia-reperfusion injuries
US11998564B2 (en) 2018-12-14 2024-06-04 National Taiwan University Stable cardioplegic solution for cardiac surgery

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4415556A (en) * 1980-12-23 1983-11-15 Dr. Franz Kohler Chemie Gmbh Protective solution for heart and kidney and process for its preparation
WO1988001861A1 (en) * 1986-09-17 1988-03-24 Baxter Travenol Laboratories, Inc. Nutritional support or therapy for individuals at risk or under treatment for atherosclerotic, vascular, cardiovascular, and/or thrombotic diseases
WO1989003688A1 (en) * 1987-10-29 1989-05-05 Ab Erik Vinnars Amino acid composition for parenteral nutritional support and the use thereof
US4988515A (en) * 1988-01-28 1991-01-29 The Regents Of The Univ. Of Calif. Cardioplegic solution
DE3943424A1 (de) * 1989-12-30 1991-07-04 Nephro Medica Pharma Infusions- und injektionsloesung zur intravenoesen verabreichung
WO1993023027A1 (en) * 1992-05-20 1993-11-25 Ab Erik Vinnars Use of alpha-ketoglutarate

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4415556A (en) * 1980-12-23 1983-11-15 Dr. Franz Kohler Chemie Gmbh Protective solution for heart and kidney and process for its preparation
WO1988001861A1 (en) * 1986-09-17 1988-03-24 Baxter Travenol Laboratories, Inc. Nutritional support or therapy for individuals at risk or under treatment for atherosclerotic, vascular, cardiovascular, and/or thrombotic diseases
WO1989003688A1 (en) * 1987-10-29 1989-05-05 Ab Erik Vinnars Amino acid composition for parenteral nutritional support and the use thereof
US4988515A (en) * 1988-01-28 1991-01-29 The Regents Of The Univ. Of Calif. Cardioplegic solution
DE3943424A1 (de) * 1989-12-30 1991-07-04 Nephro Medica Pharma Infusions- und injektionsloesung zur intravenoesen verabreichung
WO1993023027A1 (en) * 1992-05-20 1993-11-25 Ab Erik Vinnars Use of alpha-ketoglutarate

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
STN, File Medline, Medline Accession No. 79021890, BAIRAMKULOV KhD et al., "Effect of Krebs Cycle Intermediates on the Blood Supply and Energy Metabolism of Ischemic Myocardium"; & BIULL. EKSP. BIOL. MED., (1978 Sep), 86 (9)317-9. *
STN, File MEDLINE, Medline Accession No. 91048991, TISHKIN V.S., "The Effect of Alpha-Ketoglutarate, Malate and Alpha-Glycero-Phosphate on Bioenergetic Processes in Ischemic Myocardium"; & UKR. BIOKHIM. ZH., (1990 Jul-Aug), 62(4), 93-7. *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207658B1 (en) 1996-01-11 2001-03-27 University Of Florida Research Foundation, Inc. Preservation of tissue during removal storage and implantation
US5880098A (en) * 1996-04-12 1999-03-09 Pharmacia & Upjohn Aktiebolag Therapeutic treatment
WO2006016828A2 (en) * 2004-08-12 2006-02-16 Sgp & Sons Ab Use of alpha ketoglutarate for treating alzheimer, parkinson
WO2006016828A3 (en) * 2004-08-12 2006-06-08 Sgp & Sons Ab Use of alpha ketoglutarate for treating alzheimer, parkinson
EP1887862A4 (en) * 2005-05-26 2012-06-06 Ben O'mar Arrington PRESERVATION SOLUTION FOR ORGANS AND BIOLOGICAL TISSUE
EP1887862A1 (en) * 2005-05-26 2008-02-20 Arrington, Ben O'Mar Preservation solution for organs and biological tissues
WO2006127902A1 (en) * 2005-05-26 2006-11-30 Ben O'mar Arrington Preservation solution for organs and biological tissues
WO2007122190A1 (en) * 2006-04-21 2007-11-01 Sgp & Sons Ab Compositions comprising alpha-ketoglutarate and their use for modulating muscle performance
WO2009005464A1 (en) * 2007-07-02 2009-01-08 Entress Ab New use of known pharmacologically active chemical compounds
WO2017192413A1 (en) 2016-05-01 2017-11-09 The Regents Of The University Of California Glutarate compounds for treating ischemia-reperfusion injuries
CN109417016A (zh) * 2016-05-01 2019-03-01 加州大学董事会 用于治疗缺血-再灌注损伤的戊二酸化合物
US10285962B2 (en) 2016-05-01 2019-05-14 The Regents Of The University Of California Glutarate compounds for treating ischemia-reperfusion injuries
US10500177B2 (en) 2016-05-01 2019-12-10 The Regents Of The University Of California Glutarate compounds for treating ischemia-reperfusion injuries
EP3453046A4 (en) * 2016-05-01 2020-01-08 The Regents of the University of California GLUTARATE COMPOUNDS FOR TREATING ISCHEMIC-RELATED REPERFUSION INJURIES
US11007163B2 (en) 2016-05-01 2021-05-18 The Regents Of The University Of California Glutarate compounds for treating ischemia-reperfusion injuries
US11998564B2 (en) 2018-12-14 2024-06-04 National Taiwan University Stable cardioplegic solution for cardiac surgery

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SE9402027D0 (sv) 1994-06-10
AU2758495A (en) 1996-01-05
ZA954775B (en) 1996-02-08

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