US20130065218A1 - Medical fluid, a method of treatment and use of the fluid - Google Patents

Medical fluid, a method of treatment and use of the fluid Download PDF

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US20130065218A1
US20130065218A1 US13/697,839 US201113697839A US2013065218A1 US 20130065218 A1 US20130065218 A1 US 20130065218A1 US 201113697839 A US201113697839 A US 201113697839A US 2013065218 A1 US2013065218 A1 US 2013065218A1
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fluid
adrenaline
cocaine
organ
concentration
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Stig Steen
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XVIVO Perfusion AB
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Vivoline Medical AB
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Publication of US20130065218A1 publication Critical patent/US20130065218A1/en
Assigned to XVIVO PERFUSION AB reassignment XVIVO PERFUSION AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VIVOLINE MEDICAL AB
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    • 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 a method of handling an organ after harvesting, including a medical fluid and use of said fluid.
  • the organs After harvesting, the organs should be examined and evaluated for viability to be used for transplantation purpose.
  • the evaluation may be performed at a physiological temperature of about 37° C., such as between 30° C. and 40° C., or alternatively at a lower temperature.
  • the organs may be perfused by and/or surrounded by an evaluation fluid similar to blood.
  • the organs cannot be transplanted immediately, but a recipient should be found, which may take some time. Moreover, the organ to be transplanted should be transported to the recipient or the recipient be transported to the organ. Thus, the organs may be preserved for some hours or days, often at hypothermal conditions. During preservation, the organs may be perfused by and/or surrounded by a preservation fluid.
  • An evaluation fluid may operate at a physiological temperature of about 37° C. and provide support for metabolism of the organ, at least to a certain degree.
  • a fluid may be whole blood or a synthetic fluid operating similar to blood, or a combination.
  • a preservation fluid may be optimized for operation at low temperature, during which the metabolism of the organ is low.
  • WO2010077200A1 and WO2010077201A1 disclose fluids which are used for supporting body functions in a brain-dead body. The contents of these patent applications are incorporated in the present specification by reference.
  • an object of the present invention is to mitigate, alleviate or eliminate one or more of the above-identified deficiencies and disadvantages singly or in any combination.
  • a medical fluid for a harvested organ, tissue or parts thereof, for evaluation and/or preservation comprising: cocaine or a stimulating analogue thereof; adrenalin and/or noradrenalin; an oncotic agent; hormones; and electrolytes and optionally nutrients in substantially physiological concentrations in a physiologically acceptable medium.
  • Cocaine, noradrenaline, if present, and adrenaline, if present, may be in concentrations of about 0.010 ⁇ M to 0.100 ⁇ M.
  • the oncotic agent may be albumin or dextran or a combination thereof.
  • the hormones may be any one of thyroxin; triiodotyronine; or cortisone or a combination thereof.
  • the fluid may further comprise an oxygen carrier, such as erythrocytes.
  • the fluid may further comprise at least one of glucose; insulin; dopamine; hydrocortisone; methylprednisolone; and a vasopressor agent, such as desmopressin.
  • the cocaine or a stimulating analogue thereof; adrenalin; and noradrenaline may be present in concentration ratios of 1:1:1.
  • a method for treatment of a harvested organ for evaluation and/or preservation comprising: circulating a first fluid in the vascular system of the organ, and optionally partly or completely immersing said organ in a second fluid; said first fluid comprising cocaine or a stimulating analogue thereof; adrenalin and/or noradrenalin; an oncotic agent; hormones; and electrolytes and optionally nutrients in substantially physiological concentrations in a physiologically acceptable medium.
  • a fluid for a harvested organ, tissue or part thereof for evaluation and/or preservation wherein the fluid comprises the components mentioned above.
  • FIG. 1 is a schematic view of a nerve terminal.
  • cocaine analogue is intended to mean an analogue, which acts in the same or a similar way as cocaine in preserving organs after harvesting of the organs.
  • “Pharmaceutically acceptable” means a non-toxic material that does not decrease the effectiveness of the biological activity of the active ingredients.
  • physiologically acceptable solution means a solution that does not interfere substantially with the fluids in the body.
  • Such pharmaceutically acceptable buffers, carriers or excipients are well-known in the art, see for example Remington's Pharmaceutical Sciences, 18th edition, A.R. Gennaro, Ed., Mack Publishing Company (1990) and handbook of Pharmaceutical Excipients, 3rd edition, A. Kibbe, Ed., Pharmaceutical Press (2000).
  • An object of the below described embodiments is to improve the outcome of organs harvested from a donor and transplanted to a recipient.
  • a hypothesis is that the outcome of organs after transplantation may be improved by use of a fluid comprising adrenaline (epinephrine) and/or nor-adrenaline (nor-epinephrine).
  • adrenaline epinephrine
  • nor-adrenaline nor-epinephrine
  • Adrenaline and noradrenaline are neurotransmitters which influence upon alfa- and beta-receptors, and have numerous actions in the body.
  • Adrenaline and nor-adrenaline may as well be regarded as hormones because they are secreted by the adrenal medulla into the blood stream in the living (mammal) body.
  • Normal human secretion in the adrenal medulla of adrenaline may be 0.2 ⁇ g per kg and min and of nor-adrenaline 0.05 ⁇ g per kg and min.
  • Normal plasma adrenaline concentration is about 0.05 to 0.5 mg per liter in a living human body. In certain conditions, the plasma adrenaline concentrations may be increased more than ten times.
  • noradrenaline is produced in the pre-synaptic adrenergic nerve terminal from tyrosine, which is an amino acid present all over the body in large quantities.
  • FIG. 1 is a schematic and simplified view showing a nerve terminal of the sympathetic nerve system.
  • the nerve terminal ends in a presynaptic adrenergic varicosity 11 having a cell membrane 12 .
  • a postsynaptic effector cell membrane 14 is positioned a short distance from the cell membrane 12 . The distance is called the synaptic cleft and may be about 20 nm in a chemical synapse.
  • Tyrosine is transported into the varicosity 11 via a transporter 15 and into the cytoplasm, wherein the tyrosine is converted to DOPA under the influence of an enzyme; Tyrosine Hydroxylase (TH). This step is considered to be the rate-limiting step in the synthesis of nor-adrenaline and adrenaline.
  • TH Tyrosine Hydroxylase
  • DOPA is transformed to dopamine in the cytoplasm under the influence of an enzyme; Aromatic L-amino acid decarboxylase (AAADC).
  • AAADC Aromatic L-amino acid decarboxylase
  • Dopamine is taken up into vesicles 16 via an active transporter 17 called VMAT-2 (Vesicular Monoamine Transporter), which is relatively non-specific and can transport different catecholamines, such as nor-adrenaline and dopamine, and other substances. Only about 50% of the dopamine produced is normally transported into the vesicles 16 ; the rest is metabolized in the cell by an enzyme called MAO (Monoamine Oxidase), see further below. There are a great number of vesicles in the nerve terminal.
  • VMAT-2 Vascular Monoamine Transporter
  • any nor-adrenaline present inside the varicosity 11 is transported into the vesicle 16 by the same transporter 17 , VMAT-2. In this way, nor-adrenaline is reused. A portion of the nor-adrenaline inside the varicosity does not enter the vesicle 16 but is metabolized by the enzyme MAO. Thus, there is a competition between the enzyme MAO and the active transporter 17 VMAT-2, both with regard to dopamine and nor-adrenaline.
  • the concentration of nor-adrenaline inside the vesicle is very high. A concentration in the range of 1 mole/liter has been reported.
  • VAMPs proteins associated with the vesicular membrane
  • SNAPs membrane of the varicosity
  • the nor-adrenaline passes into the synaptic cleft and may interact with alfa- and beta-receptors present at the effector cell membrane, as shown by arrows in FIG. 1 . Since the concentration of nor-adrenaline in the vesicle is extremely high and because the concentration of nor-adrenaline in the synaptic cleft normally is very low, and because the distance across the synaptic cleft is very small, some 20 nm, the nor-adrenaline will more or less explode when released from the vesicle due to the high concentration gradient and rapidly reaches the receptors at the effector cell membrane. The entire process comprising receipt of a depolarization voltage, inflow of calcium and exocytosis of nor-adrenaline takes often less than one tenth of a second.
  • the released nor-adrenaline may also interact with presynaptic receptors of alfa-2-type and beta-type.
  • the alfa-2-receptor may influence directly on the vesicle and diminish the release of nor-adrenaline.
  • the beta-receptor may facilitate the release of nor-adrenaline. The mechanism is not clearly understood for such direct influence of the release of the nor-adrenaline.
  • nor-adrenaline attached to the receptors is released from the receptors in the synaptic cleft.
  • This transporter has a high affinity for nor-adrenaline.
  • NET removes free nor-adrenaline from the synaptic cleft, often within 0.1 seconds. However, a small portion of the free nor-adrenaline in the synaptic cleft passes out to the surrounding interstitial fluid and subsequently to the vascular blood circulation. Circulating nor-adrenaline is rapidly metabolized in the liver, normally within a few minutes.
  • the distance from the synaptic cleft to the blood circulation may be in the range of about 0.1 ⁇ m to several millimeters and is thus larger than the synaptic cleft.
  • a nor-adrenaline plasma concentration in the living body of about 1.5 mg per liter (about 9 ⁇ M) is required in order to observe a physiological change.
  • the corresponding plasma concentration for adrenaline is about 0.05 mg per liter (0.3 ⁇ M).
  • Adrenaline is produced from nor-adrenaline by an extra enzymatically driven step in the adrenal medulla.
  • the enzyme is called phenylethanolamine N-methyltransferase (PNMT) and converts nor-adrenaline to adrenaline.
  • PNMT phenylethanolamine N-methyltransferase
  • This enzyme is present essentially only in the adrenal medulla.
  • the adrenal medulla comprises nerve terminals similar to the adrenergic varicosity shown in FIG. 1 but lacks a postsynaptic portion. Instead, the exocytosis takes place directly into the blood stream. Normally, the adrenal medulla excretes about 80% adrenaline and 20% nor-adrenaline into the blood.
  • Circulating adrenaline and noradrenaline are metabolized by the liver and have a half-life of approximately a few minutes when circulating in blood. Other metabolization paths are also known.
  • nor-adrenaline may cause myocardial ischemia and/or desensitization of the beta-adrenergic signaling pathway.
  • Administration of nor-adrenaline may further desensitize the myocardial beta-adrenergic signaling.
  • the recovery potential of BAR remains unknown, but may have an impact on organ function.
  • the organ When an organ has been harvested, the organ may be evaluated for suitability for transplantation. Such evaluation may involve administration of a medical fluid to the vascular system of the organ during physiological temperature.
  • the evaluation may involve measurement of the organs ability to pump fluid. If the organ is the lungs, the organs ability to add oxygen and remove carbon dioxide may be measured. For other organs, the organs ability to operate as required may be assessed.
  • a medical fluid used for such purpose may be for example Steen Solution disclosed in WO 2002/35929 A1, the contents of which are incorporated in the present specification by reference.
  • Such medical fluid may comprise salts and nutrients as well as serum albumin and for example dextran compounds.
  • erythrocytes may be added for oxygen supply.
  • the evaluation fluid is able to support oxygenation and nutrition of the cells.
  • the evaluation fluid comprises oncotic agents, there is a risk that the organ forms edema.
  • a hypothesis is that the vascular system of the organ may have lost its vasotonus. The reason may be that the nerves are at least partly denervated and no activation signals are received by the nerve terminals. Consequently, the nerve terminals do not emit nor-adrenaline into the synaptic cleft.
  • adrenal medulla is no longer connected to the organ.
  • the organ does not receive adrenaline and noradrenaline.
  • Depletion of nor-adrenaline may results for example in that the vascular system of the organ loses its vasotonus, and the vascular bed becomes vasodilatated.
  • the endothelial cells may be unable to resist outflow of fluid into the interstitial volume, resulting in edema formation and/or organ swelling.
  • Depletion of adrenaline may result in down-regulation of beta adrenergic cardiac receptors (BAR), i.e. a reduction of BAR density, which potentially may result in poor transplant outcome.
  • BAR beta adrenergic cardiac receptors
  • adrenaline may be included in the medical fluid in concentrations lower or similar to those normally encountered in the blood.
  • the added adrenaline interacts with beta-receptors to promote for example cardiac output.
  • Adrenaline has numerous other actions in the organs as is well known to the skilled person.
  • nor-adrenaline may be included in the medical fluid in concentrations sufficient to cause diffusion from the blood to the synaptic cleft and to the receptors present therein, for example alfa-receptors, in order to interact with for example alfa-receptors to cause vasoconstriction for at least partly maintaining vasotonus.
  • Nor-adrenaline has numerous other actions in the organs as is well known to the skilled person.
  • nor-adrenaline is normally produced and normally acts at sites different from the vascular system. This fact may be a cause to different results when adding nor-adrenaline to fluids entered into the vascular system, as reported in the literature.
  • One mechanism which may decrease the action of the nor-adrenaline circulating in the vascular system and diffusing to the synaptic cleft may be the fact that any nor-adrenaline reaching the synaptic cleft will be rapidly taken up by the NET transporter and be entered into the presynaptic nerve terminal.
  • the NET transporter will compete with the activation of the effector cell receptors and decrease the action of the nor-adrenaline present in the vascular system and diffusing to the synaptic cleft.
  • nor-adrenaline tends to be absorbed or soaked up by the nerve terminals.
  • the inventor has found that the addition of cocaine together with nor-adrenaline would permit the use of lower levels of nor-adrenaline in the vascular system than normally found in the living body, and still obtain the desired effects of at least partly maintained vasotonus.
  • the cocaine acts as NET inhibitor, which is previously known.
  • the NET transporter will no longer compete with the alfa-receptor and the nor-adrenaline diffusing from the vascular system to the synaptic cleft may cause the desired action and at least partly maintain vasotonus.
  • Other explanations may be relevant in combination.
  • any negative effect of high concentration of nor-adrenaline in the vascular system can be counteracted.
  • cocaine may interact with adrenaline for preserving the BAR receptors, and possibly prevent down-regulation of BAR receptors and may have other beneficial effects.
  • the medical fluid may comprise both adrenaline and nor-adrenaline and in addition cocaine.
  • cocaine (benzoylmethyl ecgonine) has been used.
  • Cocaine acts as a NET inhibitor of nor-adrenaline and dopamine.
  • Cocaine may also or alternatively act via further mechanisms not known or appreciated today, and may have a beneficial effect for preserving organs after harvesting.
  • Cocaine analogues may operate in the same way.
  • Analogues may be any analogue as defined above. It is believed that it is the stimulant effect of cocaine that is active.
  • cocaine analogues mean cocaine analogues with stimulating effect.
  • Cocaine-analogues with both stimulant & local anesthetic effects are for example: Dimethocaine or larocaine (DMC) ((3-diethylamino-2,2-dimethylpropyl)-4-aminobenzoate); and 3-(p-Fluorobenzoyl)tropane ((1R,5S)-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-fluorobenzoate).
  • DMC dimethocaine or larocaine
  • 3-(p-Fluorobenzoyl)tropane ((1R,5S)-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-fluorobenzoate).
  • Cocaine-analogues for stimulant effects with local anesthetic effects removed are for example: ⁇ -CIT (methyl (1R,2S,3S,5S)-3-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate); ⁇ -CPPIT (3 ⁇ -(4′-Chlorophenyl)-2 ⁇ -(3′-phenylisoxazol-5′-yl)tropane); FE- ⁇ -CPPIT (N-(2′-Fluoroethyl)-3 ⁇ -(4′-chlorophenyl)-2 ⁇ -(3′-phenylisoxazol-5′-yl)nortropane); FP- ⁇ -CPPIT (N-(3′-Fluoropropyl)-3 ⁇ -(4′-chlorophenyl)-2 ⁇ -(3′-phenylisoxazol-5′-yl)nortropan
  • the medical fluid according to embodiments may be used for any organ, tissue or parts thereof and will have beneficial effects, for example reduced edema formation.
  • the heart will benefit by the medical fluid, which in addition seems to decrease cardiac irritability.
  • pulmonary edema may decrease by the use of the medical fluid, which will improve the result of subsequent pulmonary transplantation.
  • the medical fluid may in addition to cocaine or a stimulating analogue thereof, adrenaline and/or noradrenaline, further contain additional components such as at least one of: an oncotic agent, such as dextran; hormones, such as thyroxin (T4), triiodotyronine (T3), cortisone; electrolytes and optionally nutrients in substantially physiological concentrations in a physiologically acceptable medium; albumin; and an oxygen carrier, such as erythrocytes; further hormones or substances, such as insulin; dopamine; hydrocortisone; methylprednisolone; and a vasopressor agent, such as desmopressin, or Minirin.
  • an oncotic agent such as dextran
  • hormones such as thyroxin (T4), triiodotyronine (T3), cortisone
  • electrolytes and optionally nutrients in substantially physiological concentrations in a physiologically acceptable medium albumin
  • an oxygen carrier such as erythrocytes
  • the oncotic agent may be Dextran 40 in a concentration of 0% to 6.0%.
  • Albumin also acts as an oncotic agent and if albumin is present, Dextran 40 may be reduced or eliminated. If no albumin is present, the concentration of Dextran 40 should be in the higher range.
  • Albumin may be replaced by recombinant serum albumin or bovine serum albumin.
  • Dextran 40 may be partly or entirely replace by Dextran 70 or another Dextran compound and/or derivatives thereof.
  • the ratio between the cocain:adrenaline:nor-adrenaline may be about 1:1:1.
  • the adrenaline and/or nor-adrenaline may be partly or entirely replaced by an equivalent substance.
  • phenylephrine is an alfa-1-agonist and may replace nor-adrenaline. It seems that phenylephrine is about 5 times less potent as nor-adrenaline.
  • Erythrocytes may be replaced by synthetic oxygen carriers.
  • Dopamine may be added in quantities corresponding to an infusion of less than about 0.01 mg/kg/min.
  • Hormones should be added as required. It has been found that the levels of the hormones thyroxin (T4), triiodotyronine (T3), and cortisone are reduced rapidly in the harvested organ, and may be replaced and included in the medical fluid. Further hormones may be added as needed, such as insulin. Vasopressin may also be rapidly reduced in the harvested organ and may be included in the medical fluid, for example Desmopressin or Minirin.
  • Electrolytes and optionally nutrients are included in the medical fluid. Electrolytes are for example those included in Kreb's solution. Nutrients may be physiologically acceptable carbohydrates, such as glucose, fatty acids and amino acids or any combinations thereof.
  • the medical fluid comprises cocaine or a stimulating analogue, and in addition adrenaline, nor-adrenaline, cortisone, thyroxin, triiodotyronine, desmopressin, electrolytes and albumin. Erythrocytes are added before use.
  • the embodiments also relate to a medical fluid comprising the composition as defined above dissolved in a pharmaceutical acceptable medium.
  • acceptable mediums are physiological sodium chloride solution, Hartmann's solution and Ringer's (acetate) solution or sterile, non-ionic water, i.e. pure H 2 O.
  • the basis is a Kreb's solution, comprising for example NaCl, 110-135 mM; NaHCO 3 , 15-35 mM; KCl, 2.5-4.6 mM; MgCl 2 , 1.0-2.6 mM; CaCl 2 , 1.5-2.4; NaH 2 PO 4 , 1.0-2.0 mM; Glucose 1-15%, such as about 10%.
  • KCl may be 15-25 mM or as high as 125 mM if a cardioplegic fluid is required.
  • Albumin between 2.0% and 5.5%, such as 5.0%, or between 2.0% and 4.5%, such as 4.0%,
  • Dextran 40 between 0% and 5.0%, such as 0.5%
  • Cocaine and adrenaline and noradrenaline each about 0.001 to 0.1 ⁇ M, such as 0.01 ⁇ M.
  • cocaine and nor-adrenaline are included in the mentioned concentrations.
  • cocaine and adrenaline are included in the mentioned concentrations.
  • Erythrocytes may be replaced by synthetic oxygen carriers.
  • Dextran 40 may be partly or entirely replace by Dextran 70 or another Dextran compound and/or derivatives thereof.
  • the organ When the organ has been evaluated by any known method and using the medical fluid, the organ may be preserved awaiting transplantation. Such preservation often takes place in a hypothermic condition, such as a temperature below 20° C., for example below 15° C., such as about 10° C. During hypothermic conditions, the metabolism of the cells of the organ is reduced.
  • a hypothermic condition such as a temperature below 20° C., for example below 15° C., such as about 10° C.
  • a preservation fluid may not require all components of the medical fluid.
  • One embodiment of the medical fluid may have the same composition as the above-mentioned fluid, except:
  • Dextran 40 between 1% and 5.0%, such as 4%
  • the preservation fluid does not comprise albumin and erythrocytes, it is less expensive, but will still maintain the organ in a good condition for subsequent transplantation.
  • the Dextran concentration will be sufficient for maintaining an oncotic pressure, which will prevent edema formation, in addition to cocaine/adrenaline/nor-adrenaline.
  • the medical fluid may be provided without erythrocytes, which are added shortly before use.
  • the medical fluid may be provided without an oncotic agent, which is added shortly before use, such as a combination of albumin and Dextran 40.
  • a medical fluid may be provided, which is suitable for preservation. If the solution should be used for evaluation, certain additions are made before use, such as addition of albumin, Dextran 40 and erythrocytes.
  • the evaluation and preservation may take place by arranging the organ in a device, such as the device disclosed in WO2009136838A1, the contents of which are incorporated in the present specification by reference.
  • the organ may be partly or completely immersed in the fluid.
  • the fluid may be introduced into the vascular system of the organ and be circulated there through.
  • hypothermic preservation Since the evaluation may take place at a physiological temperature, hormones and other substances may be consumed, and need to be replaced intermittent or continuously to maintain the concentration thereof. During hypothermic preservation, replacement may not be required.
  • the circulation may not be required, but the preservation fluid may be present inside the vascular system.
  • the organ may be partly or completely immersed in the preservation fluid.
  • the fluid may be arranged to drip onto the organ, which is surrounded by cloths, so that the organ is kept moist.
  • the organ may be arranged in a moist atmosphere.
  • preservation fluid there is no strict distinction between a preservation fluid and an evaluation fluid.
  • evaluation fluid there is no strict distinction between a preservation fluid and an evaluation fluid.
  • the same medical fluid may be used for evaluation and preservation purposes.
  • first fluid may comprise erythrocytes and/or albumin
  • second fluid may lack erythrocytes and/or albumin
  • the evaluation at the same time comprises preservation, since the evaluation takes some time during which the organ needs to be preserved.
  • the corresponding plasma concentration for adrenaline is about 0.05 mg per liter (0.3 ⁇ M). Also for adrenaline, the cocaine seems to have a potentiating effect so that low concentrations of adrenaline still results in a favorable effect.

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EP2568805A1 (fr) 2013-03-20
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EP2568805A4 (fr) 2013-12-11
SE534862C2 (sv) 2012-01-24
CA2799318A1 (fr) 2011-11-17
US20160338343A1 (en) 2016-11-24
US10271540B2 (en) 2019-04-30
SE1000518A1 (sv) 2011-11-15
TR201910329T4 (tr) 2019-08-21
EP2568805B1 (fr) 2019-05-01
WO2011142705A1 (fr) 2011-11-17
DK2568805T3 (da) 2019-07-22

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