EP0098853A1 - Composition pharmaceutique pour la prevention et le traitement de degats cellulaires ischemiques et procedes d'utilisation et de preparation d'une telle composition pharmaceutique - Google Patents

Composition pharmaceutique pour la prevention et le traitement de degats cellulaires ischemiques et procedes d'utilisation et de preparation d'une telle composition pharmaceutique

Info

Publication number
EP0098853A1
EP0098853A1 EP83900363A EP83900363A EP0098853A1 EP 0098853 A1 EP0098853 A1 EP 0098853A1 EP 83900363 A EP83900363 A EP 83900363A EP 83900363 A EP83900363 A EP 83900363A EP 0098853 A1 EP0098853 A1 EP 0098853A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
physiologically acceptable
preventing
solution
cell damage
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Withdrawn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
EP83900363A
Other languages
German (de)
English (en)
Inventor
Jan Lennart Hultman
Gunnar Ronquist
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.)
Pfizer Health AB
Original Assignee
Pharmacia 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 AB filed Critical Pharmacia AB
Publication of EP0098853A1 publication Critical patent/EP0098853A1/fr
Withdrawn legal-status Critical Current

Links

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
    • A61K31/66—Phosphorus compounds
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition. More specificly, the invention relates to a pharmaceutical composition for preventing and treating ischemic cell damage. The invention also relates to a method for preventing and treating ischemic cell damage in mammals, including humans, or in organs removed therefrom.
  • Ischemic damage to the body cells of a mammal occurs when the flow of blood in a part of the body is impeded to such an extent that the supply of oxygen to the cells of said part of the body ceases or is greatly reduced.
  • the reason why the cell requires oxygen is because the predominant part (about 92 % ) of adenosine-5'-triphosphate (ATP), necessary to the survival of the cell, is formed by a mechanism which involves an aerobic oxida-tion.
  • ATP-content of the cell falls, the resultant injury to the cell being initially reversible, i.e. the damage can be stopped when the ATP content of the cell returns to more normal values, and in time becomes irreversible, resulting in the death of the cell and subsequently (with an increase in the number of dead cells) the death of the organ.
  • an introduction of relatively small quantities of ATP enables another substance, namely a salt of phosphoenolpyruvic acid, to be introduced into the cell in larger quantities simultaneously with ATP, where said substance then contributes to the conversion of adenosine diphosphate (ADP) present in the cell to ATP in one single reaction step which does not require the presence of oxygen.
  • ADP adenosine diphosphate
  • the present invention relates to a pharmaceutical composition for preventing and treating ischemic cell damage, said composition being characterized in that it includes a physiologically acceptable, watersoluble salt of phosphoenolpyruvic acid (which salt is hereinafter referred to as PEP) and a physiologically acceptable, water-soluble salt of adenosine-5'-triphosphoric acid (which salt. is hereinafter referred to as ATP) in a mutual ratio of 5:1 to 1000:1, preferably from 10:1 to 500:1, calculated on a molar basis.
  • PEP physiologically acceptable, watersoluble salt of phosphoenolpyruvic acid
  • ATP physiologically acceptable, water-soluble salt of adenosine-5'-triphosphoric acid
  • physiologically acceptable salts of the two compounds can be mentioned sodium salts, magnesium salts or ammonium salts and salts with physiologically acceptable organic amines, such as tris(hydroxymethyl)aminomethane (called tris), methyl glucamine, arginine, ornitine or histidirie.
  • physiologically acceptable organic amines such as tris(hydroxymethyl)aminomethane (called tris), methyl glucamine, arginine, ornitine or histidirie.
  • the molar ratio between PEP and ATP can, for example, be greater than 20:1, for example greater than 50:1, and can be lower than 400:1, e.g. lower than 300:1, e.g. lower than 200:1.
  • the pharmaceutical composition according to the invention comprises agents for establishing physiological conditions and, when necessary, water as a carrier.
  • the composition according to the invention is in the form of a sterile solution for parenteral administration and organ perfusion, but is preferably stored in a freeze-dried form because of the unfavourable stability properties of the solutions.
  • Agents for establishing physiological conditions are, for instance, buffer substances, ions for establishing correct osmolality and, when necessary, colloid-osmotically active substances, such as albumin and clinical dextrans, e.g. Dextran 40.
  • a physiologically acceptable salt solution or buffer solution such as a phosphate buffer solution or an infusion solution of conventional composition .
  • the pH can be adjusted with the use of bases or acids which provide physiologically acceptable salts, e.g. inorganic bases, preferably alkaline metal hydroxides, such as sodium hydroxide or potassium hydroxide, or organic bases, e.g. basic amino acids, such as arginine or ornitine or tris or methyl gl ucamine or histidine or..inorganic acids, such as HCl or organic acids, such as acetic acid. tion hereto in accordance with the aforegiven molar stoichi ometric rel ationshi ps .
  • bases or acids which provide physiologically acceptable salts e.g. inorganic bases, preferably alkaline metal hydroxides, such as sodium hydroxide or potassium hydroxide, or organic bases, e.g. basic amino acids, such as arginine or ornitine or tris or methyl gl ucamine or histidine or..inorganic acids, such as HCl or organic acids, such as
  • a sterile PEP and ATP in solid state are dry-mixed in the aforegiven mutual quantity ratio, whereafter the mixture is conveniently pre-packed in dosage units, such as bottles containing a quantity of the mixture corresponding to a normal dose.
  • a dosage quantity of the mixture is then dissolved in a given volume of a sterile, physiologically acceptable aqueous liquid, e.g. an isotonic buffer solution, such as a tris buffer solution or a phosphate buffer solution.
  • the composition may also contain magnesium ions, for example in a stoichiometric relationship of about 1:1 in relation to ATP.
  • These ions may be supplied, for example, by introducing a physiologically acceptable magnesium salt, preferably MgCl 2 , in a measured quantity at a suitable stage in the preparation process, e.g. added to a buffer solution in which a powderous mixture of PEP and ATP is dissolved, or by dissolving the magnesium salt in a physr ⁇ l ⁇ gtcally isotonic saline solution in conjunction with dissolving PEP and ATP therein.
  • a physiologically acceptable magnesium salt preferably MgCl 2
  • composition according to the invention is administered in the form of a sterile solution for parenteral administration and organ perfusion, to prevent and treat ischemic cell damage (preferably in humans but also in other mammals).
  • ischemic cell damage preferably in humans but also in other mammals.
  • An important area of application for the composition according to the invention is its use as a perfusion and preservation solution for organs, e.g. in open heart surgery, and organ transplantations.
  • Another important area of application is the use of the composition as an infusion solution for directed infusion through cathethers for treating ischemic brain and heart damage as result of. heart failure, drowning, an overdose of certain types of pharmaceutical preparations, such as soporifics etc.
  • the active substance concentration of the solutions intended for administration varies in dependence upon the distance from the site at which the solutions are administered to the location of the ischemic cell damage to be treated.
  • the concentration of the solution at the location of application remote from the location of the damage is such as to achieve an extracellular concentration of ATP at the injured location of an order of magnitude of 1 - 4 % , preferably 2 - 3 %, of the intracellular physiological concentration of ATP in the body cells.
  • concentration of such solutions with respect to PEP should be such that the organ (e.g. a heart) obtains during the whole of the perfusion period a total of, for example, 20 - 60 mmoles PEP.
  • the solution may contain for example 20 - 60 mmoles PEP per litre. If the solution volume totals two litres, the solution may correspondingly contain 10 - 30 mmoles PEP per litre.
  • the amount of ATP is selected in relation to the amount of PEP, so as to obtain the aforegiven mutual molar relationship.
  • the dosage may be, for example, 0.1-2, e.g. 0.5-1, mmole PEP per kilo body weight, the amount of ATP being selected in relation to the amount of PEP so as to fulfil the aforegiven molar stoi chi ometry.
  • the dosage may be, for example, 0.1-2, e.g. 0.5-1, mmole PEP per kilo body weight, the amount of ATP being selected in relation to the amount of PEP so as to fulfil the aforegiven molar stoi chi ometry.
  • PEP 1 mmole/kilo body weight
  • a patient obtains a total of 75 mmoles PEP (and ATP in relation thereto).
  • This can be administered with a 50 ml solution, the PEP concentration of which is 1500 mmoles per litre.
  • a higher concentration is suitably selected, to compensate for dilution and losses from the infusion site to the target organ.
  • composition according to the invention is administered will vary with the area of application.
  • the invention also relates to a method of preventing and treating ischemic cell damage in mammals, including humans, or in organs removed therefrom, the method being characterized by supplying to the mammal or to the organ a therapeutically effective dose of a pharmaceutical composition according to the invention.
  • the resultant composition is sterilized by sterile filtration, poured into 20 ml bottles and lyophilized, whereafter the bottles are sealed (all under aseptic conditions). Subsequent to dissolving the content of one bottle in a physiological aqueous solution, the resultant composition is suited for organ perfusion in experiments on rats.
  • EXAMPLE 2 The procedure described in Example 1 is followed but with 400 mmoles of monosodium phosphoenolpyruvate and 4 mmoles of di sodium-adenosi ne-5'-triphosphate.
  • the resultant composition is suitable for human use with directed infusion.
  • the ascending aorta of an excised rat heart was connec ted to the abdominal aorta of a living rat ("supporting rat") functioning as a heart-lung-machine for the excised rat heart by means of a tube ("pump tube”).
  • the coronary effluent from the excised heart was collected in a tempera ted water- jacketed funnel and retransfused to the supporting rat. After the ischemic period, a pulsatile blood flow was established from the supporting rat to the excised heart.
  • the temperature of th ⁇ supporting rat and the excised rat heart was kept at 37° ⁇ 1°C.
  • Rats intended for supporting function were anaesthetized by intraperi toneal administration of 5-sec.-butyl-5-ethyl 2-thiobarbituric acid (Inactin ® from Byk-Gulden Lomberg Chem. Fabrik GmbH, Konstanz, West Germany) 120 mg per kilo body weight. After tracheostomy the right carotis communis was cannulated for continuous blood pressure recording by an EMT 34 transducer (from Siemens-Elema AB, Solna, Sweden) and an M 34 recorder (from Siemens-Elema AB, Solna, Sweden). The right jugular vein was cannulated for transfusion. Heparin in a dose of 200 IU (international units) was administred intravenously. The supporting rat breathed air spontaneously.
  • Inactin ® from Byk-Gulden Lomberg Chem. Fabrik GmbH, Konstanz, West Germany
  • the abdominal aorta was cannulated and the cannula was fixed to the aorta by silk ligatures.
  • the cannula was cut close to the aorta and rejoined by a more flexible piece of si 1 icone rubber tubing, to permit easy clamping.
  • the connections permitted blood sampling and infusion.
  • the body temperature was recorded continuously in the abdominal cavity.
  • the heart donors were anaesthetized with ether. After 200 IU of heparin intravenously the blood was rapidly collected from the abdominal aorta. Subsequent thoracotomy and ligation of the aortic arch branches, the heart-archpreparation was excised. The time required for this pro cedure was 3 - 5 minutes.
  • the ascending aorta was attached to the ccinnula from the supporting rat. Electrodes for ECG-recording were placed at the apex, the right atrium and the aortic arch. During the ischemic period, the heart was kept in a water-jacketed funnel filled with plain saline solution at 37 - 38oC.
  • the retransfusion system consisted of a peristaltic roller pump (Mul ti perpl ex 2115 from LKB-Adapter AB, Bromma, Sweden), a temperature-controlled water bath and an air-bubble trap. All connections were of silicone rubber tubing. The system was primed with 20 ml of heparinized blood collected from the heart donor and an additional rat. The retransfusion of blood was adjusted to constant bloodpressure of the supporting rat by regulating the height of the bubble trap.
  • Normothermic ischemia was promoted by clamping the pump tube. After the ischemic period, the tube clamp was released and a pulsative blood-flow was re-established through the coronary arteries of the excised heart. All excised hearts were subjected to 15 minutes of complete global (37°C) ischemia, calculated from the time from excision of the heart to the start of reperfusion. Reperfusion with the pulsative arterial blood flow from the supporting rat was continued for 30 minutes, after which all hearts were immediately freeze-cl amped with a pair of chilled tongues (in liquid nitrogen) and transferred in liquid nitrogen. Freezing was instantaneous.
  • the excised hearts were stored at a temperature of -70oC and then freeze-dried at a temperature beneath -4°C.
  • HPLC High Performance Liquid Chromatography
  • adenylate charge potential in accordance with the Atkinson equation (see Atkinson, D.E.: "The energy charge of the adenylate pool as a regulatory parameter. Interaction with feedback modifiers”. Biochemistry 7 (1968) 4030-4038).
  • the enzyme creatine kinase (CK) efflux was followed as an indicator of tissue damage.
  • the principle for determining CK in serum was in accordance with recommendations from the Scandinavian Enzyme Committee, and the enzymatic activity was expressed in /ukat/l. (With respect to the HPLC-method applied, references were made to Hartwick, R.A. and Brown, P.R., "The performance of microparticle chemically bonded anionexchange. resins in the analysis of nucl eoti des.”, J. Chromatog. 112 (1979) 651 - 660).
  • n the number of hearts in the group.
  • the treated hearts in group 2 exhibited substantially improved contractibil ity when loaded than those in group 1, which had not been treated with the solution according to Example 1.

Abstract

Une composition pharmaceutique permettant la prévention et le traitement de dégâts cellulaires ischémiques contient un sel soluble dans l'eau, physiologiquement acceptable d'acide phosphoénolpyruvique et un sel soluble dans l'eau physiologiquement acceptable de l'acide adénosine-5'-triphosphorique dans un rapport mutuel de 5:1 à 1000:1, de préférence de 10:1 à 500:1, calculé sur une base molaire. Un procédé de prévention et de traitement de dégâts cellulaires ischémiques par administration d'une telle composition est également décrit ainsi qu'un procédé de préparation de cette composition par dissolution de ces sels dans un liquide aqueux physiologiquement acceptable, ajustement de la valeur du pH de la solution, stérilisation et, si besoin est, lyophilisation.
EP83900363A 1982-01-18 1983-01-14 Composition pharmaceutique pour la prevention et le traitement de degats cellulaires ischemiques et procedes d'utilisation et de preparation d'une telle composition pharmaceutique Withdrawn EP0098853A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8200252 1982-01-18
SE8200252A SE8200252L (sv) 1982-01-18 1982-01-18 Farmaceutisk komposition

Publications (1)

Publication Number Publication Date
EP0098853A1 true EP0098853A1 (fr) 1984-01-25

Family

ID=20345754

Family Applications (2)

Application Number Title Priority Date Filing Date
EP83850004A Withdrawn EP0085033A1 (fr) 1982-01-18 1983-01-14 Composition pharmaceutique
EP83900363A Withdrawn EP0098853A1 (fr) 1982-01-18 1983-01-14 Composition pharmaceutique pour la prevention et le traitement de degats cellulaires ischemiques et procedes d'utilisation et de preparation d'une telle composition pharmaceutique

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP83850004A Withdrawn EP0085033A1 (fr) 1982-01-18 1983-01-14 Composition pharmaceutique

Country Status (8)

Country Link
EP (2) EP0085033A1 (fr)
JP (1) JPS58502208A (fr)
DK (1) DK421283D0 (fr)
FI (1) FI833320A0 (fr)
NO (1) NO833257L (fr)
SE (1) SE8200252L (fr)
WO (1) WO1983002391A1 (fr)
ZA (1) ZA83130B (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE8403912D0 (sv) * 1984-07-30 1984-07-30 Pharmacia Ab Lekemedelssats eller -komposition
US4874882A (en) * 1986-03-25 1989-10-17 Ube Industries, Ltd. Process for preparing monosodium phosphoenolpyruvate
AU618723B2 (en) * 1986-10-06 1992-01-09 University Of Virginia Alumni Patents Foundation, The Use of an adenosine, hypoxanthine and ribose-containing solution for improved protection of the heart during surgery
US5070877A (en) * 1988-08-11 1991-12-10 Medco Research, Inc. Novel method of myocardial imaging
JP2770175B2 (ja) * 1988-09-27 1998-06-25 科学技術振興事業団 腎臓の庇護液
JP2914454B2 (ja) * 1989-03-29 1999-06-28 メドコー・リサーチ・インコーポレイテッド 血管診断助剤
FR2684381B1 (fr) * 1991-12-03 1995-05-05 Nicole Bru Composes presentant une liaison amide phosphorique ou une liaison phosphate d'enol pour leur application en tant que substance therapeutiquement active.
DE19603053A1 (de) * 1996-01-29 1997-07-31 Bayer Ag Verfahren zur Herstellung von Polymeren mit wiederkehrenden Succinyl-Einheiten
GB9624188D0 (en) 1996-11-21 1997-01-08 Itc Research Limited Pharmaceutical formulations
JPWO2008038417A1 (ja) * 2006-09-28 2010-01-28 興和株式会社 循環器官用薬
TW200824676A (en) * 2006-10-24 2008-06-16 Kowa Co Cardiovascular drug

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1083911A (en) * 1964-01-13 1967-09-20 Chugai Pharmaceutical Co Ltd Adenosine triphosphate salts of l-ornithine and process for preparing the same
FR3246M (fr) * 1964-02-06 1965-04-12 Pharmacodynamie Et Metabolisme Médicaments a base d'acide phospho-énol-pyruvique.
DE1939008A1 (de) * 1969-07-31 1971-02-11 Zander Dr Helmut Arzneimittelkombination zur Behandlung von Mangeldurchblutungen des Gehirns
US4216211A (en) * 1977-10-31 1980-08-05 The Procter & Gamble Company Therapeutic composition

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8302391A1 *

Also Published As

Publication number Publication date
JPS58502208A (ja) 1983-12-22
SE8200252L (sv) 1983-07-19
FI833320A (fi) 1983-09-16
DK421283A (da) 1983-09-15
FI833320A0 (fi) 1983-09-16
NO833257L (no) 1983-09-12
WO1983002391A1 (fr) 1983-07-21
EP0085033A1 (fr) 1983-08-03
DK421283D0 (da) 1983-09-15
ZA83130B (en) 1983-10-26

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