EP0188595A1 - Composition medicamenteuse ou medicament sous forme de kit utilises pour la prevention et le traitement de degats causes a des cellules ischemiques, et sa preparation - Google Patents

Composition medicamenteuse ou medicament sous forme de kit utilises pour la prevention et le traitement de degats causes a des cellules ischemiques, et sa preparation

Info

Publication number
EP0188595A1
EP0188595A1 EP19850903893 EP85903893A EP0188595A1 EP 0188595 A1 EP0188595 A1 EP 0188595A1 EP 19850903893 EP19850903893 EP 19850903893 EP 85903893 A EP85903893 A EP 85903893A EP 0188595 A1 EP0188595 A1 EP 0188595A1
Authority
EP
European Patent Office
Prior art keywords
drug
composition according
kit
drug kit
solution
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Withdrawn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
EP19850903893
Other languages
German (de)
English (en)
Inventor
Karl-Erik Arfors
Bengt Gerdin
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 EP0188595A1 publication Critical patent/EP0188595A1/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Withdrawn legal-status Critical Current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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • 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

  • a drug kit or drug composition for use in preventing and treating ischaemic cell damage and preparation thereof ischaemic cell damage and preparation thereof.
  • the present invention relates to a drug kit or drug compositi for use in preventing and treating ischaemic cell damage.
  • the present invention is based on the concept that incurable tissue damage can be caused as a result of unfavourable con ⁇ ditions created when re-establishing the blood circulation to a body organ.
  • the transportation of calcium into and out of -a cell is of great significance.
  • the transportation of calcium into and out of a cell normally takes place while maintaining externally of the cell a calciu concentration which is 1000 times greater than the calcium concentration inside the cell.
  • a deficiency in energy occurs as a result of ischaemia, the calcium gradient cannot be maintained, and calcium will consequently leak into the cel Calcium is taken up in the cell by the mitochondria, resultin in serious disturbances in energy production.
  • blood agai starts to flow, calcium will enter the cell in still greater quantities, while transportation of calcium from the cell is impaired due to the fact that the build-up of energy in the cell is inhibited by the high calcium content thereof.
  • the drug kit or drug composition according to the invention is characterized in that it comprises a) at least one plasma volume expander; b) at least one low molecular, physiologically acceptable hydroxyl radical scavenger; c) at least one physiologically acceptable and water soluble magnesium salt; and d) at least one calcium blocking organic compound dissolved in a-carrier, either per. se or in one or more co binations.
  • the invention is described hereinafter with reference to a drug kit intended for single-unit administration, although the invention also relates to different stock solutions which might come into question.
  • the plasma volume expander used may be a physiologically acceptable high molecular substance known per se in the exp sion of blood plasma volume. These substances have an avera molecular weight M Vv (weight average value) which is higher than 10,000 Daltons, e.g. higher than 15,000 and preferably higher than 30,000 and lower than 400,000 and preferably lower than 300,000 Daltons. It is well known in the art that the average molecular weight K ⁇ chosen depends on the high molecular substance used. Examples of such plasma expanders are plasma-albumin and substances based on dextran, starch derivatives or gelatine derivatives. The dextran products normally have an average molecular weight M ⁇ within the rang of 30,000 to 80,000 Daltons.
  • starch derivatives for this purpose include hydroxyethyl starch having an avera molecular weight within the range of 40,000 - 400,000 Daltons, e.g. in the order of 200,000 Daltons.
  • hydroxyethyl starch having an avera molecular weight within the range of 40,000 - 400,000 Daltons, e.g. in the order of 200,000 Daltons.
  • gelatine derivatives of varying average molecular weights 1 ⁇ are also used for this purpose.
  • the concentration of plasma volume expander in the solution in which it is present is chosen so that subsequent to being optionally mixed with one or more solutions incorporated in the kit, the solution injected into the patient will have a plasma-volume-expander concentration which is normal in the use of the substance in question.
  • the plasma volume expa solution-of the .invention usually- has a concentration of 1-1 100 ml,.such as'2-12 g/100 ml, for example 3-10 g/100 ml.
  • hydroxyl radical scavengers whic ⁇ can be used in accordance with the invention is that they are physiologically acceptable and have a molecular weight beneath 10,000 Daltons, preferably beneath 1,000 Daltons. Hydroxyl radical scavengers which have a molecular weight above 10,000 Daltons as a rule have a poor effect. A suitabl hydroxyl radical scavenger is soluble in water at physio ⁇ logical pH and ion strengths.
  • hydroxyl radical scavenger is advantageously selected from the group comprising physio ⁇ logically acceptable sugar alcohols, monosaccharides, ol-Lgo- saccharides, amino acids which contain mercapto groups, and methionine and histidine.
  • mannitol is the primary choice, because it is able to function simultaneously as a diuretic and an anti-oedema agent.
  • Other sugar alcohols of interest in this context are sorbitol and xylitol.
  • physiologically acceptable monosaccha ⁇ rides are glucose and fructose, and of oligosaccharides malto oligosaccharides and isomalto-oligosaccharides (which can be obtained by means of partial hydrolysis of starch and dextran respectively), e.g. maltose.
  • Cysteine is an example of amino acids which contain mercapto groups.
  • the hydroxyl scavenger, used is preferably a combination of at least one sugar alcohol and at least one amino acid accord to the above, particularly a combination of mannitol and L-methionine, or of mannitol, L-methionine and histidine.
  • the ' concentration of hydroxyl radical scavenger is determined by the specific substance in question and by the amount it is desired to administer. It is always so high as to enable a therapeutically active quantity to be administered when the kit is used.
  • the drug kit or drug composition according to the invention may thus contain from 1 g up to 150 g hydrox radical scavenger.
  • the range of 1-10 g is particularly appli ⁇ cable in the case of methionine and histidine and a range of 5-150 g in the case of sugar alcohols, calculated per occasio of treatment.
  • Magnesium salt present in the composition comprises one or more salts from the group water-soluble, pharmaceutically acceptable magnesium salts.
  • magnesium salts which are thus comtemplated are magnesium sulphate and magnesium chloride. .Magnesium chloride is particularly preferred.
  • Wate soluble magnesium salts are present in the composition according to the invention in quantities corresponding to 5-100 m ol Mg 2+, calculted per occasion of treatment.
  • the organic compounds acting as calcium blockers are normally of low molecular weight, with a molecular weight beneath — 2000 Daltons. They are defined by their ability to prevent the migration of calcium ions into cells.
  • Cf. "Calcium Blockers" (edited by Flai , S.P. et al; Urban-and Scharzen- berg.
  • the compounds in question may be of highly different structure, niphedipine, nimodipine verapamil,. diltiazem, lidoflazine, flunarazine and analogous compounds can be mentioned by way of example.
  • the calcium blockers used in accordance with the invention may be soluble in water and/or in fat.
  • Verapamil(5- f(3,4-dimethoxyphenyleth methylaminoj -2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile is an example of a water-soluble calcium blocker
  • an example of a fat-soluble calcium blocker is lidoflazine(4- [4,4-bis(4-fluorophenyl)butyl] -N-(2,6-dimethylphenyl)-1-piper azine acetamide) .
  • a fat soluble calcium blocker is used in accordance with the invention, it is advantageously in ⁇ cluded in the kit as a component separate from the plasma volume expander. According to one aspect of the invention, this enables lidoflazine to be administered in a separate in ⁇ jection when using the drug kit.
  • the fat-soluble calcium blocker may be dissolved in, for example, :
  • the mixture can be acidified, to increase solubility. It is essential in this respect that acidification of the mixture is adapted to the pH and buffer capacity of the remaining kit components to be used on the occasion of the treatment.
  • the mixture is advantageously acidified with acetic, acid, hydrochloric acid, or some other physiologically acceptable acid.
  • the mixture may also contain glycerol.
  • a usable product in this connection is retailed under the name Intralipi ⁇ -'Dy Apoteksvarucentralen Vi'trum AB, Sweden.
  • This product contains fractionated soya oil in an • amount of 100 or 200 mg/ml, fractionated egg-phospholipides (as stabilizer) in an amount of 12 mg/ml, and glycerol in an amount of 25 mg/ml, with the remainder sterile water.
  • the amount of calcium blocker included in the kit varies from substance to substance. Calculated per occasion of treatment it is normally included in amounts of from 1 to 300 mg; a particular value for lidoflazine. is from 10 to 200 mg.
  • the carrier or vehicle in which the active kit components can be dissolved is physiologically acceptable and contains water. It may optionally be buffered with a physiologically acceptable buffer substance to a pH-value and an ion strength such that the total effect of that intended to be administer is physiologically acceptable.
  • a physiologically acceptable buffer substance to a pH-value and an ion strength such that the total effect of that intended to be administer is physiologically acceptable.
  • buffer systems include trometamol buffers, carbonate buffers, phosphate buffers, histidine buffers, acetate buffers and combinations thereof.
  • a buffer system may be included as a solutio separate from the solution containing the plasma volume expander, hydroxyl radical scavenger, magnesium salt.
  • a se ⁇ parate buffer system shall be used when acidose is present. It shall be capable of restoring the blood of the patient in question to a pH-value of from 7.0 to 8.0, preferably the physiological pH-value 7.4.
  • the buffer capacity lies in the region of 25-300 mmol, preferably 50-200 mmol. In practice this means that a separate buffer system shall have a pH-valu in the range of 7.0 - 10.0, preferably 7.4 - 9.2.
  • the drug kit or composition according to the invention pre ⁇ ferably also includes a diuretic agent, particularly an osmotic diuretic agent, and/or an anti-oedema substance.
  • a diuretic agent particularly an osmotic diuretic agent
  • an anti-oedema substance since in addition to being an hydroxyl radical scavenger, mannitol is also able to fulfil the function of both a diuretic and an anti-oedema substance, mannitol is a pre ⁇ ferred substance in the present context. Sorbitol or gly- cerol can be used-as a diuretic agent, either instead of or together with mannitol.
  • the quantities in which a diuretic agent and anti-oedema substance is used is dependent on the substance utilized, and may thus vary within wide limits. In the case of an osmotic diuretic agent, the quantities use may lie within the range 5-150 g, otherwise 0.1-200 mg. In the case of
  • an xanthine oxidase inhibitor such as allopurinol for example, (50 mg - 5 g, de pending on which is chosen)
  • a superoxide radical scavenger such as superoxide dismutase for example
  • an hydrogen peroxide inactivator such as catalase for exampl and/or a substance which binds iron in a solid complex, such as desferrioxamine or diethylenetriamine-pentaacetic acid or ethylenediamine-di(o-hydroxyphenylacetic acid), or a phyti acid derivative.
  • the active components included in the drug kit or drug compo sition are present in the form of a single solution or a plu rality of solutions. Precisely how they are combined is de ⁇ termined, inter alia, on the grounds of solubility and sta ⁇ bility, even though for practical reasons the aim is to plac them in a common solution.
  • the plasma volume expander, hydr - xyl radical scavenger, magnesium salt and calcium blocker are selected so as to be compatible with one another in solu- bilized form and with the desired pH-value of the solution to be administered.
  • the embod ment most preferred has a solution (A) which contains plasma volume expander, hydroxyl radical scavenger and magnesium sal a solution (B) which contains a buffer system and a solution or dispersion (C) which contains a fat-soluble calcium blocke
  • A which contains plasma volume expander, hydroxyl radical scavenger and magnesium sal
  • B which contains a buffer system
  • C solution or dispersion
  • the remaining active components are place in one of the solutions A, B or C.
  • allopurino is chosen as the xanthine-oxidase inhibitor, it can be added to the buffer solution B for reasons of solubility. If the kit does not include such a solution, it may be necessary to choose another xanthine-oxidase inhibitor.
  • the various solutions included in a drug kit according to the invention may have the form of sterile storage solutions from which a suitable quantity of the separate solutions or dispersion is taken on each treatment occasion; preferably, however, the kit is made up with dosages suited to the purpos each dosage containing therapeutically active quantities of the substances in question.
  • a solution (A) according to the aforegoing can be packed into units of
  • the unit ' s can -be poured into plastic sachets, glass or plastic bottles, ampoules, syringes etc.. The exact choice varies from case to case,.-and is determined, inter alia, by practical conside ⁇ rations. It can be mentioned by way of example that the solu ⁇ tion C is advantageously placed in an ampoule or disposable syringe .
  • the concentration in which the active components are present are selected so as to maintain the mutual proportions., be- tween the aforementioned quantities.
  • the concentration of hydroxyl radical scavenger and magnesium salt corresponds to the aforemen ⁇ tioned quantities per 500 ml of solution.
  • the calcium blocker when it is incorporated in the same solution as these, two substances.
  • the calcium blocker concentration may be from 10 to 100 times greater than in the previous case, due among other things to the solubility conditions.
  • the kit components When calculated on the basis of a patient weighing 70 kg, the kit components are normally administered to the patient in a total solution volume of 500-600 ml.
  • this unit When using a drug kit according to the invention in which the calcium blocker is included as a separate unit (C) , this unit is the first to be injected into the patient. It is de ⁇ sirable that this injection can be given relatively quickly.
  • ⁇ solution.- " (B.) is ' used to correct the pH of the patient.
  • the solution (B) may be mixed with the solution (A) immediately or shortly before being ' ' used.
  • the mixture, or the solutions (A) and (B) each per se, is or are then administered to the patient as soon as possib after having injected the patient with (C) . In the absence of metabolic acidose, only solution (A) is administered.
  • a drug composition according to the invention in which a plasma volume expander, an hydroxyl radical scavenge magnesium salt and a calcium blocker are present in a common solution separate from a buffer solution (B) , this common solution is injected into the patient separately or in mixtu with (B) .
  • the solution (B) is only used in the case of meta ⁇ bolic acidose.
  • the drug kit according to the invention is intended for use primarily in acute resuscitation, such as in the event of a cardiac arrest or in other situations in which blood circu-ta- tion collaps>es and the brain is subjected to ischaemia.
  • the drug kit can also be used in various kinds of trauma in the central nervous system, cerebral haemmorrhage, apoplectic str kes, subarachnoidal bleeding, or in the case of intracranial vessel surgery, where blood vessels must be temporarily close
  • the drug kit can also be used with ischaemic conditions in ot body organs, such as the heart, kidneys, intestines and skel ton muscle, in conjunction with shock, trauma, embolies and heart attacks, and also in surgical operations, such as heart surgery, vessel reconstruction and organ transplantation.
  • the drug kit can also be used as a perfusion solution and pr serving solution for body organs in, for example, cardioplegy or organ transplantation.
  • the invention also relates to a process for the preparation o a drug kit or drug composition which process is characterized by the features set forth in claim 11.
  • the invention also relates to a method of treating the afore ⁇ said conditions.
  • the components of the ki are administered in any of the ways described above.
  • lidoflazine 80 mg lidoflazine were dissolved in 1.0 g ethanol (99.5%), 0.1 g concentrated acetic acid and 1.5 g glycerol, and was 10. diluted up to 10 ml with distilled water. The solution was sterilized by sterile filtration and poured into a l ⁇ .ml ampoule' under aseptic conditions.
  • the tests were carried out with a rat model, which gives an 20 incomplete cerebral ischaemia with a cortical flow ⁇ 5% of the normal flow, and a flow in the brain stem which is about 30% of the normal flow. This is effected by squeezing the two carotid arteries while simultaneously lowering the blood pressure to 50 mm Hg, by bleeding.
  • the method has been de- 25 scribed by Nordstrom C.H. and Siesj ⁇ B.K., Stroke j), 327-335 (1978).
  • Wistar-rats weighing 300-400 g and fasted overnight were used in the tests.
  • the rats were anaesthetized with 4% Fluothane ⁇ 5
  • the EEG was recorded continuously during this time period, an the ischaemic period was taken to commence when an isoelec- tric EEG was obtained. Subsequent to an ischaemic period of 10 mins, the infusion of lidoflazine in the treatment group was commenced. Of a total dosage of 1.0 mg in one ml of a physiological sodium-jchloride solution, half was administere during the ischaemia and the remainder after 5 minutes re- circulation. A corresponding volume of physiological sodium chloride- solution was administered to a control group.
  • the mortality of the con ⁇ trol group was 60%.
  • the corresponding figure in the group treated with a drug kit according to the invention was 20%. No significant differences were observed with regard to average arterial blood pressure, blood gas or blood sugar. With regard to the pH of the blood, it was observed that the blood-pH of the animals in the group treated with a drug kit according to the invention fell after the ischaemic period to a lesser extent than that of the animals in the control group, this being attributed to the buffer capacity of the drug kit according to the invention.

Abstract

Une composition médicamenteuse ou médicament sous forme de kit utilisés dans la prévention et le traitement de dégâts causés à des cellules ischémiques comprend: a) au moins un agent d'expansion du volume de plasma; b) au moins un co-precipitant à radical hydroxyle de faible poids moléculaire et physiologiquement acceptable; c) au moins un sel de magnésium soluble dans l'eau et physiologiquement acceptable; et d) au moins un composé organique actif tel un agent de blocage de calcium dissu dans un support, soit seul soit dans une ou plusieurs combinaisons.
EP19850903893 1984-07-30 1985-07-30 Composition medicamenteuse ou medicament sous forme de kit utilises pour la prevention et le traitement de degats causes a des cellules ischemiques, et sa preparation Withdrawn EP0188595A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE8403912A SE8403912D0 (sv) 1984-07-30 1984-07-30 Lekemedelssats eller -komposition
SE8403912 1984-07-30

Publications (1)

Publication Number Publication Date
EP0188595A1 true EP0188595A1 (fr) 1986-07-30

Family

ID=20356627

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19850903893 Withdrawn EP0188595A1 (fr) 1984-07-30 1985-07-30 Composition medicamenteuse ou medicament sous forme de kit utilises pour la prevention et le traitement de degats causes a des cellules ischemiques, et sa preparation

Country Status (6)

Country Link
EP (1) EP0188595A1 (fr)
JP (1) JPS61502821A (fr)
AU (1) AU4671385A (fr)
CA (1) CA1246449A (fr)
SE (1) SE8403912D0 (fr)
WO (1) WO1986000812A1 (fr)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4939146A (en) * 1987-01-29 1990-07-03 Kramer Richard S Method for alleviating ischemic-reperfusion injury
ES2007994A6 (es) * 1988-08-16 1989-07-01 Grino Boira Jose Maria Medio liquido para perfusion y preservacion de organos.
CH683485A5 (fr) * 1990-11-20 1994-03-31 Pasteur Merieux Serums Vacc Solutions de perfusion, de conservation et de reperfusion d'organes.
WO1994008612A1 (fr) * 1992-10-22 1994-04-28 Thomas Peter G Nouveau procede de protection du systeme nerveux central contre les lesions produites par l'alteration cerebrovasculaire ou neuronale
US6265385B1 (en) 1996-01-11 2001-07-24 Topo Target Aps Topoisomerase II poison and bis-dioxopiperazine derivative combination therapy
DE69724228T2 (de) * 1996-01-11 2004-06-09 Topotarget Aps Kombinationstherapie von topoisomerase ii toxinen und bis-dioxypiperazinderivaten
US5834178C1 (en) * 1997-07-09 2002-04-23 Univ Wayne State Flush-storage solution for donor organs
US6977140B1 (en) 1998-09-29 2005-12-20 Organ Recovery Systems, Inc. Method for maintaining and/or restoring viability of organs
CA2342944A1 (fr) * 1998-09-29 2000-04-06 Organ Recovery Systems, Inc. Dispositif et procede permettant de maintenir et/ou de restaurer la viabilite d'organes
US6485959B1 (en) * 1998-10-07 2002-11-26 Cedars Sinai Medical Center Cell preconditioning and cryopresevation medium
JP2001026536A (ja) * 1999-05-10 2001-01-30 Nikken Kasei Kk ラジカルスカベンジャー
US6492103B1 (en) 2000-01-31 2002-12-10 Organ Recovery Systems, Inc. System for organ and tissue preservation and hypothermic blood substitution
CN101400345A (zh) * 2006-03-15 2009-04-01 伯尔尼大学 心脏停搏液
PL2328593T3 (pl) * 2008-08-22 2015-08-31 Univ Bern Kardioplegiczny preparat

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Publication number Priority date Publication date Assignee Title
DE2532183C3 (de) * 1975-07-18 1982-03-04 Behringwerke Ag, 3550 Marburg Polyionische isotonische Salzlösung zur Konservierung von Erythrozyten oder zur Perfusion und zur Konservierung von zur Transplantion bestimmter Organen
CH639270A5 (de) * 1978-12-14 1983-11-15 Koehler Franz Dr Chemie Kg Protektive loesung fuer herz und niere.
FR2490963B1 (fr) * 1980-09-30 1986-04-18 Science Union & Cie Nouvelle composition therapeutique a action anti-ischemique contenant de la trimethoxy 2, 3, 4-benzyl 1-piperazine
ATE11736T1 (de) * 1980-12-23 1985-02-15 Dr. Franz Koehler Chemie Gmbh Protektive loesung fuer herz und niere und verfahren zu deren herstellung.
SE8200252L (sv) * 1982-01-18 1983-07-19 Pharmacia Ab Farmaceutisk komposition
GB8308126D0 (en) * 1983-03-24 1983-05-05 Bloch M Pharmaceutical compositions

Non-Patent Citations (1)

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Title
See references of WO8600812A1 *

Also Published As

Publication number Publication date
CA1246449A (fr) 1988-12-13
SE8403912D0 (sv) 1984-07-30
JPS61502821A (ja) 1986-12-04
AU4671385A (en) 1986-02-25
WO1986000812A1 (fr) 1986-02-13

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