ITFI20110206A1 - PLEGIC SOLUTION CONTAINING A RECOMBINANT HUMAN ISOFORM OF MANGANESE SUPEROXIDE DISMUTASE (RMNSOD) FOR THE CONSERVATION OF TRANSPLANT ORGANS. - Google Patents
PLEGIC SOLUTION CONTAINING A RECOMBINANT HUMAN ISOFORM OF MANGANESE SUPEROXIDE DISMUTASE (RMNSOD) FOR THE CONSERVATION OF TRANSPLANT ORGANS. Download PDFInfo
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- ITFI20110206A1 ITFI20110206A1 IT000206A ITFI20110206A ITFI20110206A1 IT FI20110206 A1 ITFI20110206 A1 IT FI20110206A1 IT 000206 A IT000206 A IT 000206A IT FI20110206 A ITFI20110206 A IT FI20110206A IT FI20110206 A1 ITFI20110206 A1 IT FI20110206A1
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- Italy
- Prior art keywords
- rmnsod
- chloride
- potassium
- superoxide dismutase
- liter
- Prior art date
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- 210000000056 organ Anatomy 0.000 title claims description 20
- 102000019197 Superoxide Dismutase Human genes 0.000 title claims description 10
- 108010012715 Superoxide dismutase Proteins 0.000 title claims description 10
- 102000001708 Protein Isoforms Human genes 0.000 title claims description 5
- 108010029485 Protein Isoforms Proteins 0.000 title claims description 5
- 239000000243 solution Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 12
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 10
- 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 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- 150000001413 amino acids Chemical group 0.000 claims description 8
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- 239000001103 potassium chloride Substances 0.000 claims description 8
- 235000011164 potassium chloride Nutrition 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- 229960004799 tryptophan Drugs 0.000 claims description 8
- 239000008215 water for injection Substances 0.000 claims description 7
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 6
- 229960002337 magnesium chloride Drugs 0.000 claims description 6
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- 229930091371 Fructose Natural products 0.000 claims description 4
- 239000005715 Fructose Substances 0.000 claims description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 229930010555 Inosine Natural products 0.000 claims description 4
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 claims description 4
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 4
- 229960003786 inosine Drugs 0.000 claims description 4
- GHOKWGTUZJEAQD-UHFFFAOYSA-N pantothenic acid Chemical compound OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 claims description 4
- 229940024606 amino acid Drugs 0.000 claims description 3
- 235000001014 amino acid Nutrition 0.000 claims description 3
- 239000002773 nucleotide Substances 0.000 claims description 3
- 125000003729 nucleotide group Chemical group 0.000 claims description 3
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- 235000000346 sugar Nutrition 0.000 claims description 3
- 150000008163 sugars Chemical class 0.000 claims description 3
- QZNNVYOVQUKYSC-JEDNCBNOSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CN=CN1 QZNNVYOVQUKYSC-JEDNCBNOSA-N 0.000 claims description 2
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims description 2
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 claims description 2
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- 239000004471 Glycine Substances 0.000 claims description 2
- 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 claims description 2
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- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 2
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- 229930195722 L-methionine Natural products 0.000 claims description 2
- 229930182821 L-proline Natural products 0.000 claims description 2
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 claims description 2
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 2
- 239000004473 Threonine Substances 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 229960003767 alanine Drugs 0.000 claims description 2
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 2
- 229960005261 aspartic acid Drugs 0.000 claims description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229960002713 calcium chloride Drugs 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 claims description 2
- 229940052299 calcium chloride dihydrate Drugs 0.000 claims description 2
- 229960003178 choline chloride Drugs 0.000 claims description 2
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical compound [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims description 2
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- VTYGSWGUBDXCRA-UHFFFAOYSA-L dipotassium;2-oxopentanedioate Chemical compound [K+].[K+].[O-]C(=O)CCC(=O)C([O-])=O VTYGSWGUBDXCRA-UHFFFAOYSA-L 0.000 claims description 2
- 229960000304 folic acid Drugs 0.000 claims description 2
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- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 2
- 229960000367 inositol Drugs 0.000 claims description 2
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims description 2
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- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 claims description 2
- 235000020778 linoleic acid Nutrition 0.000 claims description 2
- 229940050906 magnesium chloride hexahydrate Drugs 0.000 claims description 2
- DHRRIBDTHFBPNG-UHFFFAOYSA-L magnesium dichloride hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[Cl-].[Cl-] DHRRIBDTHFBPNG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 2
- XTCZBVVKDHLWKU-UHFFFAOYSA-M potassium;5-hydroxy-4,5-dioxopentanoate Chemical compound [K+].OC(=O)C(=O)CCC([O-])=O XTCZBVVKDHLWKU-UHFFFAOYSA-M 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 229960002429 proline Drugs 0.000 claims description 2
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- 235000019192 riboflavin Nutrition 0.000 claims description 2
- 239000002151 riboflavin Substances 0.000 claims description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 claims description 2
- 229960001153 serine Drugs 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
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- 229960004295 valine Drugs 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 1
- 230000000302 ischemic effect Effects 0.000 description 2
- 230000010410 reperfusion Effects 0.000 description 2
- ZWGNFOFTMJGWBF-VZSHSMSCSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;(2s)-2-amino-3-(1h-indol-3-yl)propanoic acid;2-oxopentanedioic acid Chemical compound OC(=O)CCC(=O)C(O)=O.OC(=O)[C@@H](N)CC1=CN=CN1.C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 ZWGNFOFTMJGWBF-VZSHSMSCSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/44—Oxidoreductases (1)
- A61K38/446—Superoxide dismutase (1.15)
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/0004—Oxidoreductases (1.)
Description
DOMANDA DI BREVETTO PER INVENZIONE INDUSTRIALE DAL TITOLO: PATENT APPLICATION FOR INDUSTRIAL INVENTION WITH THE TITLE:
Soluzione plegica contenente una isoforma umana ricombinante di Manganese Superossido Dismutasi (rMnSOD) per la conservazione di organi da trapianto Hemiplegic solution containing a recombinant human isoform of Manganese Superoxide Dismutase (rMnSOD) for the preservation of transplant organs
Campo dell’invenzione Field of invention
La presente invenzione riguarda il campo delle soluzioni per la conservazione di organi da trapiantare The present invention relates to the field of solutions for the conservation of organs to be transplanted
Stato dell’arte State of the art
Il trapianto di un organo à ̈ spesso il solo modo per curare un gran numero di malattie ma la disponibilità di organi da trapianto risulta sempre inferiore alla domanda. Organ transplantation is often the only way to cure a large number of diseases but the availability of organs for transplant is always lower than the demand.
La fase ischemica e quella della ri-perfusione sono le due fasi fondamentali che svolgono un ruolo decisivo per il destino di un organo espiantato da un donatore e trapiantato ad un ricevente. The ischemic phase and that of re-perfusion are the two fundamental phases that play a decisive role in the fate of an organ explanted from a donor and transplanted to a recipient.
Le soluzioni utilizzate per la conservazione degli organi durante il trasporto dal donatore al ricevente debbono soprattutto assicurare il mantenimento della funzionalità dell’organo da trapiantare. Purtroppo, al momento le soluzioni impiegate riescono ad assicurare la conservazione degli organi solo per un tempo limitato (6 ore) e ciò à ̈ causa non solo della inutilizzazione di organi che potrebbero essere trapiantati e che invece vengono distrutti, ma anche il vero motivo della lunga lista di attesa che un paziente deve sopportare prima di ricevere un trapianto. The solutions used to preserve the organs during transport from the donor to the recipient must above all ensure the maintenance of the functionality of the organ to be transplanted. Unfortunately, at the moment the solutions used are able to ensure the conservation of the organs only for a limited time (6 hours) and this is due not only to the non-use of organs that could be transplanted and which are instead destroyed, but also the real reason for the long waiting list that a patient has to endure before receiving a transplant.
Numerose solo le soluzioni plegiche (anche ampiamente diversificate a seconda degli organi da conservare) riportate in letteratura vedi in proposito ad esempio: WO 2004/019968 (e stato dell’arte ivi citato pag. 1 l.14 – 16), EP 1339 279, EP – 54635) ma tutto ciò non ha migliorato le prospettive ed i tempi di conservazione, cosicché à ̈ indispensabile trovare nuovi metodi per la conservazione degli organi che assicurino anche una migliore loro sopravvivenza ed à ̈ quindi essenziale poter disporre di un presidio farmacologico che consenta di mantenere un organo da trapiantare per un periodo più lungo e in condizioni migliori. There are only numerous hemiplegic solutions (also widely diversified according to the organs to be conserved) reported in the literature, see for example: WO 2004/019968 (and state of the art cited therein page 1 l.14 - 16), EP 1339 279, EP â € “54635) but all this has not improved the prospects and storage times, so it is essential to find new methods for organ conservation that also ensure a better survival and it is therefore essential to be able to have a pharmacological device that allows to keep an organ to be transplanted for a longer period and in better conditions.
Sommario Summary
La presente invenzione si riferisce a soluzioni plegiche in cui ai normali componenti che costituiscono dette soluzioni à ̈ aggiunta una opportuna quantità di una isoforma umana ricombinante di Manganese Superossido Dismutasi (rMnSOD) avente sequenza aminoacidica come riportata in Seq ID No.1. The present invention refers to hemiplegic solutions in which a suitable quantity of a recombinant human isoform of Manganese Superoxide Dismutase (rMnSOD) having an amino acid sequence as reported in Seq ID No. 1 is added to the normal components that make up said solutions.
Descrizione dettagliata dell’invenzione Detailed description of the invention
E’ stato ora sorprendentemente trovato che l’aggiunta di Manganese Superossido Dismutasi (rMnSOD) avente sequenza aminoacidica come riportata in Seq ID No. 1 alle normali soluzioni plegiche utilizzate per la conservazione degli organi consente di prolungarne la vita in modo significativo. It has now been surprisingly found that the addition of Manganese Superoxide Dismutase (rMnSOD) having an amino acid sequence as reported in Seq ID No. 1 to the normal hemiplegic solutions used for organ preservation allows to significantly prolong their life.
Seq ID No.1 Seq ID No.1
ASMTGGQQMG RGSEFMLSRA VCGTSRQLAP ALGYLGSRQK HSLPDLPYDY GALEPHINAQ IMQLHHSKHH AAYVNNLNVT EEKYQEALAK GDVTAQALQP ALKFNGGGHIN HSIFWTNLSP NGGGEPKGEL LEAIKRDFGS FDKFKEKLTA ASVGVQGSGW GWLGFNKERG HLQIAACPNQ DPLQGTTGLI PLLGIDVWEH AYYLQYKNVR PDYLKAIWNV INWENVTERY MACKNKNSC ASMTGGQQMG RGSEFMLSRA VCGTSRQLAP ALGYLGSRQK HSLPDLPYDY GALEPHINAQ IMQLHHSKHH AAYVNNLNVT EEKYQEALAK GDVTAQALQP ALKFNGGGHIN HSIFWTNLSP NGGGEPKGEL LEAIKRDFGS FDKFKEKLTA ASVGVQGSGW GWLGFNKERG HLQIAACPNQ DPLQGTTGLI PLLGIDVWEH AYYLQYKNVR PDYLKAIWNV INWENVTERY MACKNKNSC
In tutti i casi osservati, gli organi hanno mantenuto una integrità strutturale ed ultrastrutturale, suggerendo una corrispondente potenzialità funzionale. In all the cases observed, the organs maintained a structural and ultrastructural integrity, suggesting a corresponding functional potential.
La proteina penetrando nelle cellule e negli spazi interstiziali rende tutte le cellule dell’organo capaci di resistere prontamente agli attacchi dei radicali liberi che si formano sia nella fase ischemica, sia in quella della riperfusione. The protein penetrating into the cells and interstitial spaces makes all the cells of the organ capable of readily resisting the attacks of free radicals that are formed both in the ischemic phase and in that of reperfusion.
Ciò suggerisce che il pretrattamento di tutto il paziente donatore con dosi di rMnSOD, prima che avvenga l’espianto, riuscirebbe addirittura ad allungare ancora di più il tempo della conservazione dell’organo. This suggests that the pretreatment of the entire donor patient with doses of rMnSOD, before the explantation takes place, would even be able to extend the organ conservation time even more.
Allo stesso modo, pretrattando anche il paziente ricevente con la rMnSOD, si abiliterebbero gli organi del ricevente a resistere alla fase di riperfusione. Similarly, pre-treating the recipient patient with rMnSOD would enable the recipient's organs to resist the reperfusion phase.
Le soluzioni plegiche secondo l’invenzione sono come detto quelle note contenenti normalmente sali (ad esempio cloruro di sodio, cloruro di potassio, ketoglutarato di potassio, cloruro di magnesio, cloruro di calcio), aminoacidi (come istidina, triptofano), nucleotidi (come l’inosina), zuccheri (come mannitolo, fruttosio, ribosio) ed hanno normalmente un’osmolarità compresa fra 300 e 350 mosm ed un pH compreso fra 6,6 e 7, 6. The hemiplegic solutions according to the invention are as mentioned those known normally containing salts (for example sodium chloride, potassium chloride, potassium ketoglutarate, magnesium chloride, calcium chloride), amino acids (such as histidine, tryptophan), nucleotides ( such as inosine), sugars (such as mannitol, fructose, ribose) and normally have an osmolarity between 300 and 350 mosm and a pH between 6.6 and 7, 6.
Un esempio particolare di soluzione plegica secondo l’invenzione à ̈ descritta in EP 54635 ed ha la seguente composizione espressa in millimoli per litro di acqua per iniezioni: A particular example of a hemiplegic solution according to the invention is described in EP 54635 and has the following composition expressed in millimoles per liter of water for injections:
Cloruro di sodio 15 8 Sodium chloride 15 8
Cloruro di potassio 10 8 Potassium chloride 10 8
Cloruro di magnesio 10 2 Magnesium chloride 10 2
alpha-cetoglutatato acido di potassio o sodio 4 3 potassium or sodium acid alpha-cetoglutatate 4 3
Triptofano 2 1 Tryptophan 2 1
Istidina 150 100 Histidine 150 100
Istidina cloridrato 16 11 Histidine hydrochloride 16 11
Mannitolo 50 50 Mannitol 50 50
Fruttosio 50 50 Fructose 50 50
Ribosio 50 50 Ribosio 50 50
Inosina 50 50 Inosine 50 50
La quantità di Manganese Superossido Dismutasi (rMnSOD) avente sequenza aminoacidica come riportata in Seq ID No. 1 aggiunta alle soluzioni plegiche note à ̈ normalmente compresa fra 100 – 170 pmol/litro. The quantity of Manganese Superoxide Dismutase (rMnSOD) having an amino acid sequence as reported in Seq ID No. 1 added to known hemiplegic solutions is normally between 100 - 170 pmol / liter.
Esempio 1 Example 1
Ad una soluzione plegica (Custodiol<®>) costituita da (in acqua per iniezioni): componenti g/litro To a hemiplegic solution (Custodiol <®>) consisting of (in water for injections): components g / liter
Cloruro di calcio anidro 0,1245 Anhydrous calcium chloride 0.1245
Solfato di rame•5H2O 0,0000025 Copper sulphateâ € ¢ 5H2O 0.0000025
Solfato ferroso•7 H2O 0,000834 Ferrous sulphateâ € ¢ 7 H2O 0.000834
Cloruro di magnesio (anidro) 0,046659 Magnesium chloride (anhydrous) 0.046659
Solfato di magnesio (anidro) 0,02528 Magnesium sulphate (anhydrous) 0.02528
Cloruro di potassio 0,305 Potassium chloride 0.305
Fosfato monobasico di potassio 0,06124 Monobasic potassium phosphate 0.06124
Cloruro di sodio 7,517 Sodium chloride 7.517
Fosfato dibasico anidro 0,1324 Anhydrous dibasic phosphate 0.1324
Solfato di zinco•7 H2O 0,000863 Zinc sulphateâ € ¢ 7 H2O 0.000863
L-Alanina 0,018 L-Alanine 0.018
L-Arginina 0,422 L-Arginine 0.422
L-Asparagina•H2O 0,03 L-Asparagineâ € ¢ H2O 0.03
L-Acido aspartico 0,026 L-Aspartic acid 0.026
L-Cisteina•HCl•H2O 0,07026 L-Cysteineâ € ¢ HClâ € ¢ H2O 0.07026
L-Acido glutammico 0,03 L-Glutamic acid 0.03
L-Glutamina 0,292 L-Glutamine 0.292
Glicina 0,016 Glycine 0.016
L-Histidina•HCl•H2O 0,042 L-Histidinaâ € ¢ HClâ € ¢ H2O 0.042
L-Isoleucina 0,0078 L-Isoleucine 0.0078
L-Leucina 0,0262 L-Leucine 0.0262
L-Lisina•HCl 0,073 L-Lysineâ € ¢ HCl 0.073
L-Metionina 0,009 L-Fenilalanina 0,01 L-Methionine 0.009 L-Phenylalanine 0.01
L-Prolina 0,07 L-Proline 0.07
L-Serina 0,021 L-Serine 0.021
L-Treonina 0,0238 L-Threonine 0.0238
L-Triptofano 0,004 L-Tryptophan 0.004
L-Tirosina•2Na•2H2O 0,01586 L-Tyrosineâ € ¢ 2Naâ € ¢ 2H2O 0.01586
L-Valina 0,0234 L-Valine 0.0234
D-Biotina 0,0000073 D-Biotin 0.0000073
Cloruro di colina 0,01396 Choline chloride 0.01396
Acido folico 0,00132 Folic acid 0.00132
mio-Inositolo 0,01802 Niacinamide 0,00004 myo-inositol 0.01802 Niacinamide 0.00004
D-Acido pantotenico 0,000238 Piridoximina•HCl 0,00006 Riboflavina 0,00004 Tiamina•HCl 0,000337 D-Pantothenic acid 0.000238 Pyridoximineâ € ¢ HCl 0.00006 Riboflavin 0.00004 Thiamineâ € ¢ HCl 0.000337
Vitamina B-12 0,00136 Vitamin B-12 0.00136
D-Glucosio 1,802 D-Glucose 1.802
Hipoxantina 0,00404 Hipoxanthin 0.00404
Acido linoleico 0,00009 Linoleic acid 0.00009
Vermelho di fenolo•Na 0,00125 Putrescina•2HCl 0,000161 Phenol vermelhoâ € ¢ Na 0.00125 Putrescineâ € ¢ 2HCl 0.000161
Acido piruvico•Na 0,22 Pyruvic acidâ € ¢ Na 0.22
DL-6,8-Acido tiotico 0,000206 DL-6,8-Thiotic acid 0.000206
Timidina 0,0007 Thymidine 0.0007
Mannitolo 5,5 rManganseSupeOssido Dismutasi (rMnSOD) Seq ID No.1 0,003 Mannitol 5.5 rManganseSupe Oxide Dismutase (rMnSOD) Seq ID No.1 0.003
La soluzione così ottenuta ha mostrato un potere conservativo fino al 100% maggiore (fino a 12 ore) rispetto alla soluzione di partenza (6 ore). The solution thus obtained showed a preservative power up to 100% greater (up to 12 hours) than the starting solution (6 hours).
Esempio 2 Example 2
Risultati analoghi a quelli ottenuti nell’esempio 1 si sono ottenuti con una soluzione secondo l’invenzione avente la seguente composizione (in acqua per iniezioni): Results similar to those obtained in example 1 were obtained with a solution according to the invention having the following composition (in water for injections):
0,8766 gr di Cloruro di Sodio 15,0 mmol/litro 0,6710 gr di Cloruro di potassio 9,0 “ 0,8766 gr of Sodium Chloride 15,0 mmol / liter 0,6710 gr of Potassium Chloride 9,0 â € œ
0,1842 gr di Potassio idrogeno 2-ketoglutarato 1,0 “ 0,8132 gr di Cloruro di Magnesio esaidrato 4,0 “ 3,7733 gr di Istidina –HCl –idrato 18,0 “ 27,9289 gr di Histidina 180,0 “ 0,4085 gr di Triptofano 2,0 “ 5,4651 gr di mannitolo 30,0 “ 0,0022 gr di Cloruro di Calcio biidrato 0,015 “ 0.1842 g of potassium hydrogen 2-ketoglutarate 1.0 â € œ 0.8132 g of magnesium chloride hexahydrate 4.0 â € œ 3.7733 g of histidine â € “HCl â €“ hydrate 18.0 â € œ 27.9289 grams of Histidina 180.0 â € œ 0.4085 grams of Tryptophan 2.0 â € œ 5.4651 grams of mannitol 30.0 â € œ 0.0022 grams of calcium chloride dihydrate 0.015 â € œ
3- 5 µgr di rMnSOD 100 -170 pmol./litro Disciolti in 1000 cc di acqua per iniezioni 3- 5 µgr of rMnSOD 100 -170 pmol./litro Dissolved in 1000 cc of water for injections
Osmolarità = 310 millosm./litro Osmolarity = 310 millosm./l
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| Application Number | Priority Date | Filing Date | Title |
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| IT000206A ITFI20110206A1 (en) | 2011-09-23 | 2011-09-23 | PLEGIC SOLUTION CONTAINING A RECOMBINANT HUMAN ISOFORM OF MANGANESE SUPEROXIDE DISMUTASE (RMNSOD) FOR THE CONSERVATION OF TRANSPLANT ORGANS. |
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| Application Number | Priority Date | Filing Date | Title |
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| IT000206A ITFI20110206A1 (en) | 2011-09-23 | 2011-09-23 | PLEGIC SOLUTION CONTAINING A RECOMBINANT HUMAN ISOFORM OF MANGANESE SUPEROXIDE DISMUTASE (RMNSOD) FOR THE CONSERVATION OF TRANSPLANT ORGANS. |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5540911A (en) * | 1985-11-22 | 1996-07-30 | Bio-Technology General Corp. | Methods of use of human manganese superoxide dismutase |
| WO1999058547A1 (en) * | 1998-05-08 | 1999-11-18 | Webb-Waring Institute For Biomedical Research | A genetically modified manganese superoxide dismutase for treating oxidative damage |
| US6326003B1 (en) * | 1986-10-14 | 2001-12-04 | Chiron Corporation | Manganese superoxide dismutase cloning and expression in microorganisms |
-
2011
- 2011-09-23 IT IT000206A patent/ITFI20110206A1/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5540911A (en) * | 1985-11-22 | 1996-07-30 | Bio-Technology General Corp. | Methods of use of human manganese superoxide dismutase |
| US6361772B1 (en) * | 1985-11-22 | 2002-03-26 | Bio-Technology General Corp. | Human manganese superoxide dismutase DNA, its expression and method of recovering human manganese superoxide dismutase |
| US6326003B1 (en) * | 1986-10-14 | 2001-12-04 | Chiron Corporation | Manganese superoxide dismutase cloning and expression in microorganisms |
| WO1999058547A1 (en) * | 1998-05-08 | 1999-11-18 | Webb-Waring Institute For Biomedical Research | A genetically modified manganese superoxide dismutase for treating oxidative damage |
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