GB2270614A - Solution for the perfusion, preservation and reperfusion of organs - Google Patents
Solution for the perfusion, preservation and reperfusion of organs Download PDFInfo
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- GB2270614A GB2270614A GB9319264A GB9319264A GB2270614A GB 2270614 A GB2270614 A GB 2270614A GB 9319264 A GB9319264 A GB 9319264A GB 9319264 A GB9319264 A GB 9319264A GB 2270614 A GB2270614 A GB 2270614A
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- 230000010410 reperfusion Effects 0.000 title claims abstract description 16
- 230000010412 perfusion Effects 0.000 title claims abstract description 11
- 210000000056 organ Anatomy 0.000 title description 15
- 238000004321 preservation Methods 0.000 title description 9
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims abstract description 69
- 108010024636 Glutathione Proteins 0.000 claims abstract description 31
- 229960003180 glutathione Drugs 0.000 claims abstract description 27
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000001301 oxygen Substances 0.000 claims abstract description 19
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 19
- 238000003860 storage Methods 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 60
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 229930195712 glutamate Natural products 0.000 claims description 6
- 229940099584 lactobionate Drugs 0.000 claims description 6
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 claims description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- 150000003841 chloride salts Chemical class 0.000 claims description 3
- 239000000470 constituent Substances 0.000 claims description 3
- 229960000958 deferoxamine Drugs 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 239000001103 potassium chloride Substances 0.000 claims description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Inorganic materials [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 3
- 235000011164 potassium chloride Nutrition 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 2
- 239000002738 chelating agent Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 239000004033 plastic Substances 0.000 claims description 2
- 229920003023 plastic Polymers 0.000 claims description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical group CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 6
- 229960004308 acetylcysteine Drugs 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 208000028867 ischemia Diseases 0.000 description 6
- 230000002107 myocardial effect Effects 0.000 description 6
- 238000002054 transplantation Methods 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000008280 blood Substances 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 239000002516 radical scavenger Substances 0.000 description 3
- 102000003992 Peroxidases Human genes 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 206010063837 Reperfusion injury Diseases 0.000 description 2
- 102000019197 Superoxide Dismutase Human genes 0.000 description 2
- 108010012715 Superoxide dismutase Proteins 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008148 cardioplegic solution Substances 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 230000002631 hypothermal effect Effects 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- 108040007629 peroxidase activity proteins Proteins 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GZFOMNDCXQBAAX-BQBZGAKWSA-N (2s)-2-amino-5-[[(2r)-1-[(2-methoxy-2-oxoethyl)amino]-1-oxo-3-sulfanylpropan-2-yl]amino]-5-oxopentanoic acid Chemical compound COC(=O)CNC(=O)[C@H](CS)NC(=O)CC[C@H](N)C(O)=O GZFOMNDCXQBAAX-BQBZGAKWSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 102000016938 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 101100366137 Mesembryanthemum crystallinum SODCC.1 gene Proteins 0.000 description 1
- 101100096142 Panax ginseng SODCC gene Proteins 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- GLEVLJDDWXEYCO-UHFFFAOYSA-N Trolox Chemical compound O1C(C)(C(O)=O)CCC2=C1C(C)=C(C)C(O)=C2C GLEVLJDDWXEYCO-UHFFFAOYSA-N 0.000 description 1
- 108700042768 University of Wisconsin-lactobionate solution Proteins 0.000 description 1
- VEUACKUBDLVUAC-UHFFFAOYSA-N [Na].[Ca] Chemical group [Na].[Ca] VEUACKUBDLVUAC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000001101 cardioplegic effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940105657 catalase Drugs 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
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- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- -1 glutathione Chemical class 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002357 osmotic agent Substances 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940072417 peroxidase Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 101150017120 sod gene Proteins 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
- A01N1/0205—Chemical aspects
- A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
- A01N1/0226—Physiologically active agents, i.e. substances affecting physiological processes of cells and tissue to be preserved, e.g. anti-oxidants or nutrients
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N1/00—Preservation of bodies of humans or animals, or parts thereof
- A01N1/02—Preservation of living parts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
Abstract
Single solution for perfusion, storage and reperfusion, essentially having the following composition: <IMAGE> Water (quantity for one litre readjusted to pH 7.30 +/- 0.10 at +20 DEG C> Theoretical osmolality 360 mOsm/kg Glutathione (reduced GSH) or equivalent 0.5 to 10 mmol/l, (preferably 3) Reduced glutathione, or equivalent, being in solution under reduced or zero partial pressure of oxygen and being essentially kept at this value up to the time of use.
Description
2270614 Solution for the perfusion, preservation and reperfusion of
organs.
The present invention relates to solutions f or the perfusion, preservation (or storage) and reperfusion of organs, including for heart transplantations. It also relates to a process f or using these solutions applied to the different phases of a transplantation.
One of the principal causes of failure of heart transplantations results f rom the risks of degradation, or even necrosis, of the transplant which manifest themselves during reoxygenation of the transplanted organ and which are linked to the generally prolonged ischaemia between the beginning of the explantation in the donor and the end of the implantation in the recipient.
An ischaemia of four to five hours constitutes, f or example in the case of the heart. the tolerable upper limit and does not exclude numerous complications.
To limit this risk, many authors have proposed and used protective solutions, both for the perfusion of the organ to be explanted, and for its preservation at low temperature, and its reperfusion during the transplantation.
Examples of these solutions are the solutions:
Bretschneider ETK COLLINS ST THOMAS UW Stanford.
However. these solutions have only limited advantages and at best offer only a partial protection against the risks which appear during reperfusion and which are partly attributed to the metabolic production of oxygen free radicals which are produced in large quantities, especially during reoxygenation of the ischaemic organ.
The risk of cellular and membrane oxidative degradations resulting from the production of these radicals has been the subject of several studies in the field of myocardial protection by cardioplegia. These
2 different studies have suggested introducing antioxidants into the protecting solutions used. Various compounds have -been proposed, some, such as deferoxamine, allopurinol, catalase and peroxidase, as being capable of preventing the production of free radicals, others, such as superoxide dismutase, being capable of destroying these radicals, still others, such as vitamin Eor equivalents (Trolox) being capable of "neutralizing" the free radicals.
Among these latter compounds are also molecules carrying thiol groups such as N-acetylcysteine or reduced glutathione (GSH), the latter having been considered as scavenger for free radicals. However. the literature is divided on the usefulness of glutathione. See:
is - G.W. Standeven et al., J. Thorac. Cardiovasc.
Surg. 1979, 78, 893-907 Cold-Blood potassium cardio plegia; _ M. Bernier et al., Reperf us ion- induced Arrhyth mias and Oxygen-derived Free Radicals, Circulation Research, Vol. 58, No. 3, March 1986, 331-340; i.C. Chatham et al., Depletion of Myocardial Glutathione; Its effects on heart function and metabolism during ischaemia and reperfusion, Cardiovascular Research, 1988. 22, 833-839; - A. Blaustein et al.,, Myocardial Glutathione Depletion Impairs Recovery After Short Periods of Ischaemia, Circulation, Vol. 80. No. 5. November 1989; - A. Singh et al.. Relation Between Myocardial Glutathione Content and Extent of Ischaemia Reperfusion Injury, Circulation, Vol. 80, No. 6, December 1989, 1795-1803; - W.N. Wicomb et al., Role of Glutathione in 24-hour Heart Storage by Microperfusion Using a New Polyethylene Glycol Solution. J. Mol. Cell Cardiol. 22 (supplement V) 1990, p. 82; - V. Kantamnen! et al., Extended Preservation of Canine Myocardium Using UW Solution, J. Mol. Cell Cardiol. 1990 (Suppl. V); 22: 22 (Abstr.).
The addition of N-acetylcysteine is studied by M-B. Forman, Glutathione Redox Pathway and Reperfusion injury, Circulation, Vol. 78, No. 1, July 1988, 202-213. He suggests that a treatment with N-acetylcysteine (NAC) before the reperfusion can improve postischaemic 5 recovery.
While it may therefore appear advantageous to use substances which act against the production or the effect of free radicals in myocardium within the framework of cardioplegic protection, the choice of compound and the modes of application did not appear to be obvious and the addition of these compounds, including glutathione, into the solutions for myocardial perfusion and reperfusion in daily hospital procedure had not made it possible to arrive at conclusive results.
Ph. Menasch6 et al., in Pi6geurs de Radicaux Libres dans la Protection Myocardique en Chirurgie Cardiaque [Scavengers for Free Radicals in Myocardial Protection in Heart Surgery], Ann. Cardiol. Ang6iol; 1986r 35 (No. 7A), 747-752, conclude however that the preservation of the postischaemic left ventricular function, due to a given cardioplegic solution, could be -significantly improved by the addition of antioxidants capable of preventing the formation of free radicals or of destroying or neutralizing them. On the other hand, the choice of the most effective antioxidant among the many candidates, including superoxide dismutase SOD, peroxidase and glutathione, was not obvious, without mentioning the possible side or toxic effects. A fortiori when instead of the field of cardioplegia, in which the durations of ischaemia are relatively short, the field of transplantation is considered, the literature provided no real applicable indication on the choice and ways of using really effective protective solutions. Ph. Menasch6 et al. then described, in Belgian 35 Patent Application BE-A-009101067, solutions for the perfusion and preservation And/or reperfusion of organs, including the heart organ, characterized by the inclusion of at least one antioxidant compound, which compound may be especially a scavenger for oxygen free radicals, 4 especially glutathione in the reduced state, or an ana logue, such as N-acetylcysteine, or by a zero or highly reduced partial pressure of oxygen and being essentially kept at this reduced value up to the time of use.
However, the various solutions known are unsuit able f or use both f or perfusion and storage, and f or reperfusion, such that. in practice, surgical teams are obliged to use at least two different solutions. one for reperfusion and then storage of the explanted organ, the other for reperfusion of the organ during implantation.
The present invention aims to resolve these problems and to provide protecting solutions which are remarkably ef f ective f or the preservation of organs. with a view to surgical operations and in particular transis plantation. The organs of interest comprise the heart, as well as-the other organs and, especially the liver, the lungs and the kidneys.
The subject of the present invention is therefore a single solution for perfusion, storage and reperfusion, 20 essentially having the following compo.sition:
- Constituent (for example Concentration in 1 or 21 bags) g/1 mmol/litre K+ is 5% Ne 100 10% Mg' 13 5% Ca' 0.25 5% Chlorides 41.5 5% - calcium chloride, 2H20 0.037 - potassium chloride 1.118 5% - magnesium chloride 2.642 Histidine (base) 4.650 30 10% Mannitol 10.930 60 5% Lactobionate (acid) 28.664 80 5% Glutamate (acid) 2.942 20 10% Water (quantity for one litre readjusted to pE 7.30 0.10 at +20C) Theoretical osmolality 360 mOsm/kg Glutathione (reduced GSH) or equivalent 0.5 to 10 mmol/1, (preferably 3) Reduced glutathione, or equivalent, being in solution under reduced or zero partial pressure of oxygen and being essentially kept at this value up to the time of use.
This solution may be used for all the phases of a transplantation, for example as cardioplegic solution for stopping the heart of the donor, as storage solution for the transportation and hypothermic storage of the organ during reimplantation, either in the form of a colloidal solution or, preferably, after dilution with blood.
In this solution, the prevention of calcium excess in the cells is ensured by the presence of the glutamate component which has the capacity to activate ATP under anaerobic conditions, t he low concentration of 35 calcium which reduces transfer by passive diffusion, the high concentration of sodium which limits sodium-calcium exchange, the electric potential -dependent transfer of calcium by the channels being limited by the low concentration of potassium as well as by the magnesium content. This. extracellular type ionic formulation is made possible by the simultaneous presence of effective imper- meabilizers. Mannitol has the dual capacity of behaving as an osmotic agent and as a scavenger for free radicals. Lactobionate ensures a more effective prevention of cellular swelling than mannitol alone and the total concentration of impermeabilizers is equivalent to that of intracellular proteins and non-transferable anions which exert a pressure from the outside towards the inside of the cells.
The pH is preferably weakly acidic (7.20-7.40) because of the fact that it has been discovered that this value further improves the prevention of calcium excess and, furthermore, that. contrary o more alkaline values, it improves the protection of cells during the hypothermic ischaemic arrest. The solution is advantageously buffered with histidine because it has been discovered that among the buffers which can be used in man, histidine is the only one which remains really effective at low temperatures.
Of course, the various components of the solution can be replaced with equivalents, provided that the latter ensure practically the same functions.
Among the glutathione equivalents in the reduced state (GSH) are its precursors or related substances, its analogues, especially glutathione monoester and N-acetylcysteine. However, other compounds with a thiol func- tional group which might manifest the same properties could be used.
The solutions conforming to the invention may be designed for storage in the form of a single ready-foruse preparation and simultaneously containing all the components of the solution.
In this case, and in conformity with the invention, the solutions are prepared and kept protected from atmospheric oxygen, by being for example prepared in degassed solutions, preferably under a nitrogen atmosphere. The storage and the preservation of the solutions according to the invention are performed in air-tight containers such as air-tight bottles or pref erably bags made f rom plastic material, f or example f rom 5 laminated composites of a type known per se.
However, in another embodiment of the invention, the solution according to the invention may be stored in the form of two separate preparations, namely a solution containing reduced glutathione, prepared and kept protected from atmospheric oxygen, for example in a syringe, and a solution for the other components, which does not necessarily have to be kept protected from atmospheric oxygen and which can therefore be contained in normal bags.
is Preferably, the solution containing reduced glutathione GSH has the following composition (per litre):
Glutathione (reduced GSH) 185.4 g/1 600 10% mmol/1 Histidine 4.650 g/1 30 10% mmol/1 In this case,, the solution is advantageously provided in the form of a kit comprising:
- a solution containing, in a bag or other container, for example a two-litre bag, the different anions and cations, mannitol, lactobionate, glutamate and, preferably, histidine, - a solution contained in a container sealed from atmospheric oxygen, preferably a syringe. and containing reduced glutathione or an analogue, and preferably histidine at the same concentration.
- and instructions to ensure, during use, the mixing or injection of the separate solution containing the glutathione into the solution containing the other components.
In this latter case, if the solution containing the other components is not itself at a reduced or zero oxygen pressure, the instruction leaflet advantageously specifies that the final solution, now ready for use, 8 should be used within a short period of a few hours, for example three or four hours.
Advantageously, the solutions according to the invention may also contain, in addition to reduced glutathione, a compound which prevents the formation of radicals such as metal chelators and in particular deferoxamine (DCI).
Reduced value of oxygen concentration in conformity with the invention is understood to mean, preferably, a maximum dissolved oxygen concentration of less than 0.1 ppm.
In order to produce, by way of example, a solution according to the invention, a composition having the following content is prepared in a sterilized pyrogen- free aqueous medium:
Constituent Concentration g/1 mmol/litre V' 15 Ne 100 Mg' 13 Ca' 0.25 Chlorides 41.5 - calcium chloride, 2H20 0.037 - potassium chloride 1.118 magnesium chloride 2.642 Histidine (base) 4.650 30 Mannitol 10.930 60 Lactobionate (acid) 28.664 80 Glutamate (acid) 2.942 20 Water (quantity for one litre readjusted to pE 7.30) Theoretical osmolality 360 mOsmlkg In a degassed sterile pyrogen-free aqueous medium, and under conditions protected from atmospheric oxygen, a solution having the following content is prepared, per litre 9 - Concentration g/1 mmol/litre Glutathione (reduced GSH) 185.4 600 Histidine 4.650 30 This solution is packaged in the f orm of syringes protected from atmospheric oxygen and capable of holding ml of solution for a two-litre bag or 5 ml for a one-litre bag.
-Preferably, the whole is provided in the form of a kit containing, on the one hand, a solution in a two-litre bag and, on the other hand, a syringe with a content of 10 ml.
For use, the contents of the syringe are injected into the bag so as to dilute the contents of the syringe is in the bag and this results in a reduced glutathione concentration of the order of 3 mmol/1.
The solution thus prepared is rapidly used in order to ensure the perfusion of the organ to be explanted in order to obtain the cardiac arrest. A sufficient volume of identical solution prepared in the same manner is used for preserving the organ.
During the implantation, an identical solution is again used for the reperfusion procedures, the solution being advantageously mixed with the patient's blood.
Claims (7)
1 Single solution for perf usion, storage and reperfusion, essentially having the following composition:
Constituent Concentration g/1 mmol/litre K+ is 5% Ne 100 10% Mg++ 13 5% C&+ 0.25 5% Chlorides 41.5 5% - calcium chloride, 2H20 0.037 - potassium chloride 1.118 5% - magnesium chloride 2.642 Histidine (base) 4.650 30 10% Mannitol 10.930 60 5% Lactobionate (acid) 28.664 80 5% Glutamate (acid) 2.942 20 10% Water (quantity for one litre readjusted to pE 7.30 0.10 at +20OC) 20 Theoretical osmolality 360 mOsmlkg Glutathione (reduced GSH) or equivalent 0.5 to 10 mmol/1, (preferably 3) Reduced glutathione, or equivalent, being in solution under. reduced or zero partial pressure of oxygen and being essentially kept at this value up to the time of use.
2. Solution according to Claim 1 in the f orm, of a single preparation ready for use and containing all the components, prepared and kept protected from atmospheric oxygen in air-tight containers such as air-tight bottles or bags made from plastic material.
3. Solution according to Claim 1, prepared and stored in the form of two separate preparations, namely a preparation containing reduced glutathione, prepared and kept protected f rom atmospheric oxygen, and a preparation containing the other components in solution.
4. Solution according to Claim 3, characterized in that the preparation containing reduced glutathione GSH has the following composition (per-litre):
Glutathione (reduced GSH) 185.4 g/1 600 10% mmol/1 Histidine 4.650 g/1 30 10% mmol/1.
5. Solution according to one of Claims 3 and 4 characterized in that the preparation containing the reduced glutathione is packaged in an airtight syringe, especially with a content of 10 ml.
6. Solution according to Claim 5, characterized.in that it is provided in the form of a kit containing:
- a preparation containing, in a bag or other container, the different anions and cations, mannitol, lactobionate, glutamate and histidine, - a preparation contained in a syringe sealed from atmospheric oxygen. containing reduced glutathione or an analogue, and histidine, - and instructions to ensure, during use,, the mixing or injection of the separate solution containing the glutathione into the solution containing the other components.
7. Solution according to one of Claims 1 to 6, characterized in that it contains, in addition to reduced glutathione, a compound which prevents the formation of radicals such as metal chelators and especially in particular deferoxamine (DCI).
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US94607392A | 1992-09-18 | 1992-09-18 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB9319264D0 GB9319264D0 (en) | 1993-11-03 |
| GB2270614A true GB2270614A (en) | 1994-03-23 |
| GB2270614B GB2270614B (en) | 1996-03-20 |
Family
ID=25483919
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9319264A Expired - Lifetime GB2270614B (en) | 1992-09-18 | 1993-09-17 | Solution for the perfusion, preservation and reperfusion of organs |
Country Status (9)
| Country | Link |
|---|---|
| AT (1) | AT407216B (en) |
| BE (1) | BE1007500A3 (en) |
| CA (1) | CA2106249C (en) |
| CH (1) | CH686870A5 (en) |
| DE (1) | DE4331711C2 (en) |
| ES (1) | ES2070089B1 (en) |
| FR (1) | FR2695827B1 (en) |
| GB (1) | GB2270614B (en) |
| IT (1) | IT1272638B (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999002034A1 (en) * | 1997-07-09 | 1999-01-21 | Wayne State University | Flush-storage solution for donor organs |
| CN1057192C (en) * | 1997-09-10 | 2000-10-11 | 上海长征医院 | Method for preparing preservation liquid for various kinds of living organs and the prepns. thereof |
| EP1647186A1 (en) * | 2004-10-12 | 2006-04-19 | Nipro Corporation | Cell-preservation liquid |
| WO2007128866A2 (en) * | 2006-05-09 | 2007-11-15 | Novobion Oy | Novel chemical compositions |
| US7510823B2 (en) | 2000-11-22 | 2009-03-31 | The Leeds Teaching Hospitals Nhs Trust | Flush preservation solution |
| WO2014176224A1 (en) * | 2013-04-24 | 2014-10-30 | Somahlution, Llc | Organ and tissue preservation solutions having increased oxygen-content, stability and shelf life |
| WO2014179113A1 (en) * | 2013-04-29 | 2014-11-06 | Somahlution, Llc | Formulations containing poly (0-2-hydroxyethyl) starch for increasing the oxygen-content, stability and shelf life of an organ and tissue preservation solution |
| US11291201B2 (en) | 2013-11-22 | 2022-04-05 | Marizyme, Inc. | Solutions for increasing the stability and shelf life of an organ and tissue preservation solution |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19527734A1 (en) * | 1995-07-28 | 1997-01-30 | Hubert Verhaag | Method and device for preserving tissues and organs, in particular transplant tissues and organs |
| US5880098A (en) * | 1996-04-12 | 1999-03-09 | Pharmacia & Upjohn Aktiebolag | Therapeutic treatment |
| SE9601396D0 (en) * | 1996-04-12 | 1996-04-12 | Dieter Haeussinger | New therapeutic treatment 2 |
| DE19706111C2 (en) * | 1997-02-17 | 1999-02-18 | Fresenius Medical Care De Gmbh | Solution for storage of organs |
| DE19834087C1 (en) * | 1998-07-29 | 2000-03-30 | Mirzaie Sedaposhteh Massoud | Aqueous preservative solution for storage of animal tissue, especially porcine heart valves, contains sodium, potassium, magnesium and calcium salts, glucose and chelate former |
| FR2785501B1 (en) | 1998-11-10 | 2001-01-05 | Centre Nat Rech Scient | PERFUSION AND / OR PRESERVATION AND / OR REPERFUSION SOLUTION DURING ORGAN TRANSPLANTATION |
| CN115720893B (en) * | 2022-08-08 | 2024-02-23 | 四川大学华西医院 | Parathyroid gland external preservation solution and preservation method |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4798824A (en) * | 1985-10-03 | 1989-01-17 | Wisconsin Alumni Research Foundation | Perfusate for the preservation of organs |
| US4879283A (en) * | 1985-10-03 | 1989-11-07 | Wisconsin Alumni Research Foundation | Solution for the preservation of organs |
| ES2007994A6 (en) * | 1988-08-16 | 1989-07-01 | Grino Boira Jose Maria | Liquid medium for infusion and preservation of organs. |
| US4920044A (en) * | 1988-11-08 | 1990-04-24 | The Cleveland Clinic Foundation | Intracellular flush solution for preserving organs |
| US4938961A (en) * | 1989-04-28 | 1990-07-03 | Geoffrey Collins | Organ preservation solution containing pokyethylene gycol and method of performing cardioplegia |
| US5104787A (en) * | 1990-03-05 | 1992-04-14 | Lindstrom Richard L | Method for apparatus for a defined serumfree medical solution useful for corneal preservation |
| US5145771A (en) * | 1990-04-12 | 1992-09-08 | The University Of North Carolina At Chapel Hill | Rinse solution for organs and tissues |
| GB9021325D0 (en) * | 1990-10-01 | 1990-11-14 | Geistlich Soehne Ag | Chemical composition |
| CH683485A5 (en) * | 1990-11-20 | 1994-03-31 | Pasteur Merieux Serums Vacc | infusion solutions, preservation and organ perfusion. |
-
1993
- 1993-09-14 BE BE9300965A patent/BE1007500A3/en not_active IP Right Cessation
- 1993-09-14 FR FR9310926A patent/FR2695827B1/en not_active Expired - Lifetime
- 1993-09-14 CH CH02760/93A patent/CH686870A5/en not_active IP Right Cessation
- 1993-09-15 CA CA002106249A patent/CA2106249C/en not_active Expired - Lifetime
- 1993-09-16 IT ITMI931994A patent/IT1272638B/en active IP Right Grant
- 1993-09-17 GB GB9319264A patent/GB2270614B/en not_active Expired - Lifetime
- 1993-09-17 ES ES09301971A patent/ES2070089B1/en not_active Expired - Fee Related
- 1993-09-17 DE DE4331711A patent/DE4331711C2/en not_active Expired - Lifetime
- 1993-09-20 AT AT0189793A patent/AT407216B/en not_active IP Right Cessation
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999002034A1 (en) * | 1997-07-09 | 1999-01-21 | Wayne State University | Flush-storage solution for donor organs |
| CN1057192C (en) * | 1997-09-10 | 2000-10-11 | 上海长征医院 | Method for preparing preservation liquid for various kinds of living organs and the prepns. thereof |
| US7510823B2 (en) | 2000-11-22 | 2009-03-31 | The Leeds Teaching Hospitals Nhs Trust | Flush preservation solution |
| US8236486B2 (en) | 2000-11-22 | 2012-08-07 | The Leeds Teaching Hospital NHS Trust | Flush preservation solution |
| EP1647186A1 (en) * | 2004-10-12 | 2006-04-19 | Nipro Corporation | Cell-preservation liquid |
| WO2007128866A2 (en) * | 2006-05-09 | 2007-11-15 | Novobion Oy | Novel chemical compositions |
| WO2007128866A3 (en) * | 2006-05-09 | 2011-04-21 | Novobion Oy | Chemical compositions for hypothermic storage of cells and organ |
| WO2014176224A1 (en) * | 2013-04-24 | 2014-10-30 | Somahlution, Llc | Organ and tissue preservation solutions having increased oxygen-content, stability and shelf life |
| WO2014179113A1 (en) * | 2013-04-29 | 2014-11-06 | Somahlution, Llc | Formulations containing poly (0-2-hydroxyethyl) starch for increasing the oxygen-content, stability and shelf life of an organ and tissue preservation solution |
| US11291201B2 (en) | 2013-11-22 | 2022-04-05 | Marizyme, Inc. | Solutions for increasing the stability and shelf life of an organ and tissue preservation solution |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2695827B1 (en) | 1995-07-28 |
| FR2695827A1 (en) | 1994-03-25 |
| AT407216B (en) | 2001-01-25 |
| GB9319264D0 (en) | 1993-11-03 |
| DE4331711C2 (en) | 2001-05-03 |
| ATA189793A (en) | 2000-06-15 |
| CH686870A5 (en) | 1996-07-31 |
| ITMI931994A0 (en) | 1993-09-16 |
| ITMI931994A1 (en) | 1995-03-16 |
| ES2070089B1 (en) | 1995-12-16 |
| CA2106249A1 (en) | 1994-03-19 |
| CA2106249C (en) | 2009-04-14 |
| IT1272638B (en) | 1997-06-26 |
| GB2270614B (en) | 1996-03-20 |
| DE4331711A1 (en) | 1994-03-24 |
| BE1007500A3 (en) | 1995-07-18 |
| ES2070089A1 (en) | 1995-05-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732E | Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977) | ||
| PE20 | Patent expired after termination of 20 years |
Expiry date: 20130916 |