TW201632178A - 移植器官植活促進劑 - Google Patents
移植器官植活促進劑 Download PDFInfo
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- TW201632178A TW201632178A TW105118232A TW105118232A TW201632178A TW 201632178 A TW201632178 A TW 201632178A TW 105118232 A TW105118232 A TW 105118232A TW 105118232 A TW105118232 A TW 105118232A TW 201632178 A TW201632178 A TW 201632178A
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- Taiwan
- Prior art keywords
- iron
- organ
- sodium
- compound
- transplantation
- Prior art date
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- 210000000056 organ Anatomy 0.000 title claims abstract description 223
- 230000004083 survival effect Effects 0.000 title abstract description 5
- 239000003623 enhancer Substances 0.000 title description 24
- 150000002506 iron compounds Chemical class 0.000 claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 41
- -1 pentyl ester Chemical class 0.000 claims abstract description 27
- JHYAVWJELFKHLM-UHFFFAOYSA-H tetrasodium;2-hydroxypropane-1,2,3-tricarboxylate;iron(2+) Chemical compound [Na+].[Na+].[Na+].[Na+].[Fe+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O JHYAVWJELFKHLM-UHFFFAOYSA-H 0.000 claims abstract description 10
- 238000002054 transplantation Methods 0.000 claims description 120
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 50
- 150000001875 compounds Chemical class 0.000 claims description 29
- 229910052742 iron Inorganic materials 0.000 claims description 25
- 230000006058 immune tolerance Effects 0.000 claims description 20
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 210000004027 cell Anatomy 0.000 claims description 13
- 210000002865 immune cell Anatomy 0.000 claims description 12
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- 230000006698 induction Effects 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 150000003863 ammonium salts Chemical class 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910000358 iron sulfate Inorganic materials 0.000 claims description 6
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 6
- GIPOFCXYHMWROH-UHFFFAOYSA-L 2-aminoacetate;iron(2+) Chemical compound [Fe+2].NCC([O-])=O.NCC([O-])=O GIPOFCXYHMWROH-UHFFFAOYSA-L 0.000 claims description 5
- YNVZDODIHZTHOZ-UHFFFAOYSA-K 2-hydroxypropanoate;iron(3+) Chemical compound [Fe+3].CC(O)C([O-])=O.CC(O)C([O-])=O.CC(O)C([O-])=O YNVZDODIHZTHOZ-UHFFFAOYSA-K 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
- 229920002307 Dextran Polymers 0.000 claims description 4
- 102000008857 Ferritin Human genes 0.000 claims description 4
- 108050000784 Ferritin Proteins 0.000 claims description 4
- 238000008416 Ferritin Methods 0.000 claims description 4
- PMVSDNDAUGGCCE-TYYBGVCCSA-L Ferrous fumarate Chemical compound [Fe+2].[O-]C(=O)\C=C\C([O-])=O PMVSDNDAUGGCCE-TYYBGVCCSA-L 0.000 claims description 4
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 4
- 102000010445 Lactoferrin Human genes 0.000 claims description 4
- 108010063045 Lactoferrin Proteins 0.000 claims description 4
- 102000004338 Transferrin Human genes 0.000 claims description 4
- 108090000901 Transferrin Proteins 0.000 claims description 4
- OOIOHEBTXPTBBE-UHFFFAOYSA-N [Na].[Fe] Chemical compound [Na].[Fe] OOIOHEBTXPTBBE-UHFFFAOYSA-N 0.000 claims description 4
- FRHBOQMZUOWXQL-UHFFFAOYSA-L ammonium ferric citrate Chemical compound [NH4+].[Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O FRHBOQMZUOWXQL-UHFFFAOYSA-L 0.000 claims description 4
- 229930002875 chlorophyll Natural products 0.000 claims description 4
- 235000019804 chlorophyll Nutrition 0.000 claims description 4
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 claims description 4
- VEPSWGHMGZQCIN-UHFFFAOYSA-H ferric oxalate Chemical compound [Fe+3].[Fe+3].[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O.[O-]C(=O)C([O-])=O VEPSWGHMGZQCIN-UHFFFAOYSA-H 0.000 claims description 4
- CADNYOZXMIKYPR-UHFFFAOYSA-B ferric pyrophosphate Chemical compound [Fe+3].[Fe+3].[Fe+3].[Fe+3].[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O CADNYOZXMIKYPR-UHFFFAOYSA-B 0.000 claims description 4
- 239000011640 ferrous citrate Substances 0.000 claims description 4
- 235000019850 ferrous citrate Nutrition 0.000 claims description 4
- 239000011773 ferrous fumarate Substances 0.000 claims description 4
- 235000002332 ferrous fumarate Nutrition 0.000 claims description 4
- 229960000225 ferrous fumarate Drugs 0.000 claims description 4
- 239000004222 ferrous gluconate Substances 0.000 claims description 4
- 235000013924 ferrous gluconate Nutrition 0.000 claims description 4
- 229960001645 ferrous gluconate Drugs 0.000 claims description 4
- 150000003278 haem Chemical class 0.000 claims description 4
- 239000004313 iron ammonium citrate Substances 0.000 claims description 4
- 235000000011 iron ammonium citrate Nutrition 0.000 claims description 4
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 4
- ATEAWHILRRXHPW-UHFFFAOYSA-J iron(2+);phosphonato phosphate Chemical compound [Fe+2].[Fe+2].[O-]P([O-])(=O)OP([O-])([O-])=O ATEAWHILRRXHPW-UHFFFAOYSA-J 0.000 claims description 4
- PVFSDGKDKFSOTB-UHFFFAOYSA-K iron(3+);triacetate Chemical compound [Fe+3].CC([O-])=O.CC([O-])=O.CC([O-])=O PVFSDGKDKFSOTB-UHFFFAOYSA-K 0.000 claims description 4
- APVZWAOKZPNDNR-UHFFFAOYSA-L iron(ii) citrate Chemical compound [Fe+2].OC(=O)CC(O)(C([O-])=O)CC([O-])=O APVZWAOKZPNDNR-UHFFFAOYSA-L 0.000 claims description 4
- VRIVJOXICYMTAG-IYEMJOQQSA-L iron(ii) gluconate Chemical compound [Fe+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O VRIVJOXICYMTAG-IYEMJOQQSA-L 0.000 claims description 4
- CSSYQJWUGATIHM-IKGCZBKSSA-N l-phenylalanyl-l-lysyl-l-cysteinyl-l-arginyl-l-arginyl-l-tryptophyl-l-glutaminyl-l-tryptophyl-l-arginyl-l-methionyl-l-lysyl-l-lysyl-l-leucylglycyl-l-alanyl-l-prolyl-l-seryl-l-isoleucyl-l-threonyl-l-cysteinyl-l-valyl-l-arginyl-l-arginyl-l-alanyl-l-phenylal Chemical compound C([C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CC=CC=C1 CSSYQJWUGATIHM-IKGCZBKSSA-N 0.000 claims description 4
- 229940078795 lactoferrin Drugs 0.000 claims description 4
- 235000021242 lactoferrin Nutrition 0.000 claims description 4
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims description 4
- XJDIIQYURGDWCL-UHFFFAOYSA-K sodium;iron(3+);2-oxidopropane-1,2,3-tricarboxylate Chemical compound [Na+].[Fe+3].[O-]C(=O)CC([O-])(C([O-])=O)CC([O-])=O XJDIIQYURGDWCL-UHFFFAOYSA-K 0.000 claims description 4
- 239000012581 transferrin Substances 0.000 claims description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- BVEUYZRNNURYFB-DFWYDOINSA-N azanium (4S)-4-amino-5-(dicarboxymethoxy)-5-oxopentanoate Chemical compound N[C@@H](CCC(=O)[O-])C(=O)OC(C(=O)O)C(=O)O.[NH4+] BVEUYZRNNURYFB-DFWYDOINSA-N 0.000 claims description 3
- MDXRFOWKIZPNTA-UHFFFAOYSA-L butanedioate;iron(2+) Chemical compound [Fe+2].[O-]C(=O)CCC([O-])=O MDXRFOWKIZPNTA-UHFFFAOYSA-L 0.000 claims description 3
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- HWVFSIHLBZDKFK-DFWYDOINSA-M sodium (4S)-4-amino-5-(dicarboxymethoxy)-5-oxopentanoate Chemical compound N[C@@H](CCC(=O)[O-])C(=O)OC(C(=O)O)C(=O)O.[Na+] HWVFSIHLBZDKFK-DFWYDOINSA-M 0.000 claims description 3
- MKWYFZFMAMBPQK-UHFFFAOYSA-J sodium feredetate Chemical compound [Na+].[Fe+3].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O MKWYFZFMAMBPQK-UHFFFAOYSA-J 0.000 claims description 3
- OESFSXYRSCBAQJ-UHFFFAOYSA-M sodium;3-carboxy-3,5-dihydroxy-5-oxopentanoate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.OC(=O)CC(O)(C(O)=O)CC([O-])=O OESFSXYRSCBAQJ-UHFFFAOYSA-M 0.000 claims description 3
- YPFNIPKMNMDDDB-UHFFFAOYSA-K 2-[2-[bis(carboxylatomethyl)amino]ethyl-(2-hydroxyethyl)amino]acetate;iron(3+) Chemical compound [Fe+3].OCCN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O YPFNIPKMNMDDDB-UHFFFAOYSA-K 0.000 claims description 2
- RUTXIHLAWFEWGM-UHFFFAOYSA-H iron(3+) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 claims description 2
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- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims 1
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Abstract
本發明提供一種不使用現有之免疫抑制劑，而可抑制排斥反應之移植器官植活促進劑，或可維持自供體摘出後之器官之新鮮度之器官保存液等。本發明調製一種以5-胺基乙醯丙酸(ALA)或者其衍生物或其鹽、及鐵化合物作為有效成分之移植器官植活促進劑、或器官保存液。作為上述ALA類，可較佳地例示ALA、及ALA甲酯、ALA乙酯、ALA丙酯、ALA丁酯、ALA戊酯等各種酯類，及該等之鹽酸鹽、磷酸鹽、硫酸鹽等，作為鐵化合物，可較佳地例示檸檬酸亞鐵鈉。
Description
本發明係關於一種含有5-胺基乙醯丙酸(以下亦稱作「ALA(aminolevulinic acid)」)或者其衍生物或該等之鹽與鐵化合物等含金屬之化合物之移植器官植活促進劑，或含有該移植器官植活促進劑之自供體摘出後之器官之防腐劑等。
器官移植中，本來保護活體免受細菌或病毒等侵害之免疫機制將移植器官識別為「異物」，從而引起排斥反應。可以說能以何種程度控制排斥反應關係到移植醫療之成敗。作為控制排斥反應之方法，一般認為有局部控制移植器官之排斥反應之方法與控制全身之排斥應答本身之方法，目前主要應用之方法為後者，環孢靈、他克莫司等鈣調神經磷酸酶抑制劑或類固醇系之藥劑之投予廣泛應用於抑制移植後之排斥反應，但眾所周知副作用亦較多。
近年來，為減少投予藥劑量，作為人工誘導免疫耐受性之方法，業界正開發出自供體或受體採取T細胞、與特殊之抗體混合培養並轉移回體內之方法。例如，有以下提議：於存在抗CD80抗體、或其抗原結合性片段與抗CD86抗體、或其抗原結合性片段之情況下，藉由以腎臟之供體之同種抗原刺激自接受腎移植之受體採取之T細胞而獲得之含有源自上述受體之T細胞作為有效成分之腎移植排斥反應抑制劑(例如，參照專利文獻1)；包括下述步驟之用以降低移植物抗宿主病之影響之方法：自人類供體採取含有包含CD4+CD25+控制性T細胞之周邊
血液單核細胞之試樣的步驟，藉由濃縮上述試樣中之上述CD4+CD25+控制性T細胞而生成濃縮CD4+CD25+控制性T細胞之步驟，使上述經濃縮之CD4+CD25+控制性T細胞之群增殖之步驟，將上述經增殖之CD4+CD25+控制性T細胞之一部分投予至人類而治療移植物抗宿主病之步驟(例如，參照專利文獻2)；包括下述過程之誘導受體細胞以減輕移植排斥反應之方法：a)將周邊單核血液細胞自受體及供體單離，b)於體外混合供體及受體之細胞，c)以調節組合物處理該細胞，d)使該細胞增殖，e)將該細胞導入該受體中(例如，參照專利文獻3)；等。
又，已知有含有類黃酮糖苷之器官保存液(例如，參照專利文獻4)、含有1,5-脫水果糖或其衍生物之器官防腐劑(例如，參照專利文獻5)、含有富勒烯類之器官防腐劑(例如，參照專利文獻6)、含有肝細胞增殖因子(HGF，hepatocyte growth factor)之器官保存液(例如，參照專利文獻7)、含有卵磷脂化超氧化物歧化酶之器官保存液(例如，參照專利文獻8)、含有葡糖基-L-抗壞血酸或其鹽而成之器官防腐劑(例如，參照專利文獻9)等。
另一方面，ALA作為廣泛存在於動物、植物或菌類中之四吡咯生物合成路徑之中間物而為人所知，通常係藉由5-胺基乙醯丙酸合成酶，自琥珀醯基輔酶A與甘胺酸而生物合成。業界亦開發出使用ALA之光線力學療法或光動力學治療(以下亦稱作「ALA-PDT(5-Aminolevulinic Acid Photodynamic Therapy)」)，作為侵襲性較低、QOL(Quality of life，生活品質)得以保證之治療法而備受關注，報告有使用ALA等之腫瘤診斷、治療劑等。又，亦已知ALA用作成人病、癌、男性不孕之預防改善劑或治療劑(例如，參照專利文獻10~12)。
[專利文獻1]日本專利特開2007-131598號公報
[專利文獻2]日本專利特表2011-505378號公報
[專利文獻3]日本專利特表2003-530101號公報
[專利文獻4]日本專利特開2009-221128號公報
[專利文獻5]日本專利特開2008-115089號公報
[專利文獻6]日本專利特開2006-316000號公報
[專利文獻7]日本專利特開2005-306749號公報
[專利文獻8]日本專利特開2002-60301公報
[專利文獻9]日本專利特開2000-191401號公報
[專利文獻10]國際公開WO2010/050179
[專利文獻11]日本專利特開2011-16753號公報
[專利文獻12]國際公開WO2009/139156
為防止作為移植後之移植器官之功能衰竭之最大原因的排斥反應，一般認為必需長期服用免疫抑制劑。然而，業界擔心長期投予免疫抑制劑會引起傳染病或腎損傷、糖尿病、淋巴組織增殖症、惡性腫瘤、心血管系併發症等嚴重之副作用，要求進行嚴格管理。上述之採取T細胞、與特殊之抗體混合培養而轉移回體內之方法等人工免疫耐受性誘導方法，雖可實現免疫抑制劑之減量，但細胞培養時間需要數週，程序較為繁雜，或可觀察到脫髮等副作用，因此尚未普及。除此以外，亦雖實驗性地開發出各種耐受性誘導系統，但幾乎無實際地進行臨床應用者。
本發明之課題在於提供一種安全且與先前之藥劑之作用機制不同之可促進器官移植中之移植器官之植活的移植器官植活促進劑，及可維持自供體摘出後之器官之新鮮度之器官保存液等。
本發明者等人持續對ALA之於醫療中之應用進行各種研究，於抑制研究器官移植之排斥反應時，發現ALA具有促進移植器官之植活之作用。又，本發明者等人偶然發現，相對於先前之器官移植之免疫抑制劑僅投予至受體之情況，於移植手術前向供體單獨投予ALA或投予含有ALA類與鐵化合物之組合物，並亦對移植有自該供體摘出之器官之受體進行投予，藉此，移植器官之植活率顯著上升。進而發現，於將該器官移植後之受體之脾臟細胞投予至其他受體同時移植自供體摘出之器官之情形時，產生無需投予ALA亦促進移植器官之植活之二次免疫耐受性誘導作用。並且又發現，ALA作為自供體摘出後之器官之防腐劑較為有效。
又，亦發現鐵化合物協動ALA，增強移植器官之植活促進作用、二次免疫耐受性誘導作用、或自供體摘出後之器官之新鮮度保持作用。於鐵化合物充分存在之情形，或另行攝取鐵化合物之情形時，會有單獨投予ALA並無問題之情形。對瘦肉之攝取量少於各外國之日本人而言，礦物質中鐵常常不足。因此，為日本人時之實施例之一部分同時添加鐵化合物，但以儲存鐵充分之人為對象之情形時則無需添加。又，眾所周知，ALA經代謝為卟啉並藉由光照射而表現出PDT、PDD(Photodynamic Diagnosis，光動力診斷)活性，但於本發明之移植器官植活促進劑而言並不需要光。
本發明者等人進而對投予方法及投予量反覆進行銳意研究，確定單獨以ALA類、或以ALA類與鐵化合物作為有效成分之移植器官植活促進劑，從而完成本發明。
即，本發明係關於下述者：(1)一種移植器官植活促進劑，其含有下述式(I)所表示之化合物或其鹽：
(式中，R1表示氫原子或醯基，R2表示氫原子、直鏈或分支狀烷基、環烷基、芳烷基或芳基)；(2)如上述(1)之移植器官植活促進劑，其中R1及R2為氫原子；(3)如上述(1)或(2)之移植器官植活促進劑，其進而含有鐵化合物；(4)如上述(3)之移植器官植活促進劑，其中鐵化合物為選自氯化鐵、三氧化二鐵、硫酸鐵、焦磷酸亞鐵、檸檬酸亞鐵、檸檬酸鐵鈉、檸檬酸亞鐵鈉、檸檬酸鐵銨、焦磷酸鐵、乳酸鐵、葡萄糖酸亞鐵、二伸乙基三胺五乙酸鐵鈉、二伸乙基三胺五乙酸鐵銨、乙二胺四乙酸鐵鈉、乙二胺四乙酸鐵銨、二羧基甲基麩胺酸鐵鈉、二羧基甲基麩胺酸鐵銨、反丁烯二酸亞鐵、乙酸鐵、草酸鐵、琥珀酸亞鐵、琥珀酸檸檬酸鐵鈉、血紅素鐵、葡聚糖鐵、三伸乙基四胺鐵、乳鐵蛋白鐵、轉鐵蛋白鐵、葉綠素鐵鈉、鐵蛋白鐵、含糖氧化鐵、及硫化甘胺酸鐵中之1種或2種以上之化合物；(5)如上述(3)之移植器官植活促進劑，其中鐵化合物為檸檬酸亞鐵鈉；(6)一種器官移植中之移植器官植活促進方法，其特徵在於：其係將如上述(1)至(5)中任一項之移植器官植活促進劑投予至器官移植前及/或後之受體；(7)一種器官移植中之移植器官植活促進方法，其特徵在於：其係將如上述(1)至(5)中任一項之移植器官植活促進劑投予至器官移植前之供體及器官移植前及/或後之受體；
(8)一種移植器官植活促進套組，其包括a)上述式(I)所表示之化合物或其鹽、與b)鐵化合物；(9)一種移植器官植活促進方法，其特徵在於：其係同時或相繼將a)上述式(I)所表示之化合物或其鹽與b)鐵化合物投予至對象；(10)一種移植器官植活促進劑之組合，其包括：a)上述式(I)所表示之化合物或其鹽、b)鐵化合物、與c)器官移植免疫抑制藥；(11)一種移植器官植活促進劑之組合，其包括：a)如上述(1)至(5)中任一項之移植器官植活促進劑、與b)器官移植免疫抑制藥；(12)一種經單離之免疫細胞，其特徵在於：其係源自對器官移植前及/或後之受體投予如上述(1)至(5)中任一項之移植器官植活促進劑而得之受體；(13)一種經單離之免疫細胞，其特徵在於：其係源自對器官移植前之供體及器官移植前及/或後之受體投予如上述(1)至(5)中任一項之移植器官植活促進劑而得之受體；(14)如上述(12)或(13)之經單離之免疫細胞，其係控制性T細胞；(15)一種二次免疫耐受性之誘導方法，其特徵在於：其係將如上述(12)至(14)中任一項之免疫細胞投予至採取該細胞之同一及/或不同之受體；(16)一種移植用器官之保存方法，其特徵在於：其係對自供體摘出後之器官或該器官之保存液投予如上述(1)至(5)中任一項之移植器官植活促進劑；(17)如上述(16)之保存方法，其中該器官係源自預先對器官移植前之供體投予如上述(1)至(5)中任一項之移植器官植活促進劑而得之供體；(18)一種自供體摘出後之器官之防腐劑，其特徵在於：其包含如上述(1)至(5)中任一項之移植器官植活促進劑；
(19)一種上述式(I)所表示之化合物或其鹽，其係用以提高移植器官之植活率；(20)一種上述式(I)所表示之化合物或其鹽、及鐵化合物，其係用以提高移植器官之植活率；(21)一種上述式(I)所表示之化合物或其鹽之用途，其係用於製造移植器官植活促進劑；(22)一種上述式(I)所表示之化合物或其鹽、及鐵化合物之用途，其係用於製造移植器官植活促進劑；(23)一種上述式(I)所表示之化合物或其鹽，其用於自供體摘出後之器官之防腐劑；(24)一種上述式(I)所表示之化合物或其鹽、及鐵化合物，其用於自供體摘出後之器官之防腐劑；(25)一種上述式(I)所表示之化合物或其鹽之用途，其係用於製造自供體摘出後之器官之防腐劑；(26)一種上述式(I)所表示之化合物或其鹽、及鐵化合物之用途，其係用於製造自供體摘出後之器官之防腐劑。
藉由本發明之移植器官植活促進劑，可保護移植器官免受應激反應損害，維持其新鮮度，抑制伴隨器官移植之排斥反應，提高移植器官之植活率。本發明與現有之免疫抑制劑、或採取T細胞而與特殊之抗體混合培養並轉移回體內之方法等人工免疫耐受性誘導方法之機制完全不同，幾乎無副作用，亦無需長時間服用藥劑，作為器官移植中之移植器官之植活促進劑極其有效。又，由於與先前之免疫抑制劑等之作用機制不同，故業界亦期待藉由與現有藥品併用而更提高效果。又，本發明之器官之防腐劑可保持自供體摘出後之器官之新鮮度。
圖1(a)、(b)表示不同系統小鼠心臟移植實驗之圖表之例。
圖2為表示使用本發明之移植器官植活促進劑之不同系統小鼠心臟移植及移植後之經過之概要的圖。縱軸表示心臟搏動率。
圖3為表示使用本發明之移植器官植活促進劑之其他態樣之不同系統小鼠心臟移植及移植後之經過之概要的圖。縱軸表示心臟搏動率。
圖4為表示對同一系統受體小鼠進行不同系統小鼠心臟移植時之移植心臟之植活率之結果的圖，該同一系統受體小鼠移植有源自對器官移植前之供體小鼠及受體小鼠、與器官移植後之受體小鼠投予本發明之移植器官植活促進劑而得之受體之脾臟細胞。
圖5為表示對同一系統受體小鼠進行不同系統小鼠皮膚移植時之照片的圖，該同一系統受體小鼠移植有源自對器官移植前之供體小鼠及受體小鼠、與器官移植後之受體小鼠投予本發明之移植器官植活促進劑而得之受體之脾臟細胞。
圖6為表示脾臟細胞中之控制性T細胞數之測定結果的圖，該脾臟細胞係源自對器官移植前之供體小鼠及受體小鼠、與器官移植後之受體小鼠投予本發明之移植器官植活促進劑而得之受體。
圖7為表示藉由保存過程中停止搏動之心臟藉由移植而再次開始搏動為止之時間(second)研究自供體摘出後之器官之含有ALA之防腐劑之有效性之結果的圖。
作為本發明之移植器官植活促進劑，若為含有上述式(I)所表示之化合物或其鹽(以下亦有將該等總稱為「ALA類」之情形)作為有效成分者，則並無特別限制，較佳為除ALA類以外含有鐵化合物者。將上述本發明之移植器官植活促進劑尤其是含有ALA類與鐵化合物之移植器官植活促進劑除投予至人類以外，亦投予至家畜、家禽類或寵物等對象，藉此可進行器官移植中之移植器官植活促進。又，本發明中，
所謂移植器官之植活促進，係指抑制器官移植(包括組織移植)中之排斥反應，提高經移植之器官(組織)於活體中繼續發揮功能之比率即植活率。
作為本發明之移植器官植活促進套組，若為以ALA類與鐵化合物為有效成分、作為個別藥劑而含有之套組，則並無特別限制，若使用該移植器官植活促進套組，可進行除人類以外，家畜、家禽類或寵物等對象之器官移植中之移植器官植活促進。上述移植器官植活促進套組中可包含操作說明書等隨附文件。
作為上述經移植之器官，若為可進行移植之器官，則並無特別限制，不僅可為自供體摘出之器官，且可為於活體外製作之移植物或細胞、藉由再生醫療技術而人工構築之組織、器官，除此以外，亦可為由萬能細胞製作之器官等。又，作為器官之種類，可例示：腎臟、肝臟、心臟、胰腺、肺、小腸、眼球、角膜、毛髮、皮膚等，其中，可較佳地例示：腎臟、肝臟、心臟、胰腺、肺、小腸。
作為本發明之移植器官植活促進劑之組合，若為上述本發明之移植器官植活促進劑與器官移植免疫抑制藥之組合，或ALA類、鐵化合物與器官移植免疫抑制藥之組合，則並無特別限制，藉由投予該等組合，可進行移植器官之植活促進。作為上述器官移植免疫抑制藥，可列舉：硫唑嘌呤、巰嘌呤、甲胺喋呤、麥考酚酸、來氟米特等代謝拮抗劑，或環磷醯胺等烷化劑，或環孢靈、他克莫司等鈣調神經磷酸酶抑制劑，或類固醇劑等醫藥品。由於本發明之移植器官植活促進劑或移植器官植活促進套組與現有之器官移植免疫抑制藥之作用機制不同，因此，若使用本發明之移植器官植活促進劑之組合，則可期待累加性之視情況為協同性之效果。
作為可用作本發明之移植器官植活促進劑之有效成分之化合物，可以式(I)所表示之化合物或其鹽(以下亦有將該等總稱為「ALA類」
之情形)而例示。亦稱作δ-胺基乙醯丙酸之ALA為式(I)之R1及R2同為氫原子之情形，為胺基酸之1種。作為ALA衍生物，可列舉式(I)之R1為氫原子或醯基，式(I)之R2為氫原子、直鏈或分支狀烷基、環烷基、芳基或芳烷基之除ALA以外之化合物。
上述ALA類之中，可較佳地例示式(I)之R1及R2同為氫原子之情形即ALA或其鹽。ALA為亦稱作δ-胺基乙醯丙酸之胺基酸之1種。又，作為ALA衍生物，可列舉：式(I)之R1為氫原子或醯基，式(I)之R2為氫原子、直鏈或分支狀烷基、環烷基、芳基或芳烷基之除ALA以外之化合物。
作為式(I)中之醯基，可列舉：甲醯基、乙醯基、丙醯基、丁醯基、異丁醯基、戊醯基、異戊醯基、特戊醯基、己醯基、辛醯基、苄基羰基等直鏈或分支狀之碳數1~8之烷醯基，或苯甲醯基、1-萘甲醯基、2-萘甲醯基等碳數7~14之芳醯基。
作為式(I)中之烷基，可列舉：甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、新戊基、己基、庚基、辛基等直鏈或分支狀之碳數1~8之烷基。
作為式(I)中之環烷基，可列舉：環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環十二烷基、1-環己烯基等可存在飽和、或部分不飽和鍵之碳數3~8之環烷基。
作為式(I)中之芳基，可列舉：苯基、萘基、蒽基、菲基等碳數6~14之芳基。
作為式(I)中之芳烷基，芳基部分可例示與上述芳基相同者，烷基部分可例示與上述烷基相同者，具體而言，可列舉：苄基、苯乙基、苯基丙基、苯基丁基、二苯甲基、三苯甲基、萘基甲基、萘基乙基等碳數7~15之芳烷基。
作為上述ALA衍生物，較佳為R1為甲醯基、乙醯基、丙醯基、丁
醯基等之化合物，或上述R2為甲基、乙基、丙基、丁基、戊基等之化合物，可較佳地例示上述R1與R2之組合為甲醯基與甲基、乙醯基與甲基、丙醯基與甲基、丁醯基與甲基、甲醯基與乙基、乙醯基與乙基、丙醯基與乙基、丁醯基與乙基之組合等。
ALA類可於活體內以式(I)之ALA或其衍生物之狀態作為有效成分而發揮作用，根據投予之形態，可以用以提高溶解性之各種鹽、酯、或經活體內之酶分解之前驅藥(前驅物)而投予。例如，作為ALA及其衍生物之鹽，可列舉：藥理學上容許之酸加成鹽、金屬鹽、銨鹽、有機胺加成鹽等。作為酸加成鹽，例如可例示：鹽酸鹽、氫溴酸鹽、氫碘酸鹽、磷酸鹽、硝酸鹽、硫酸鹽等各無機酸鹽，甲酸鹽、乙酸鹽、丙酸鹽、甲苯磺酸鹽、琥珀酸鹽、草酸鹽、乳酸鹽、酒石酸鹽、乙醇酸鹽、甲磺酸鹽、丁酸鹽、戊酸鹽、檸檬酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、蘋果酸鹽等各有機酸加成鹽。作為金屬鹽，可例示：鋰鹽、鈉鹽、鉀鹽等各鹼金屬鹽，鎂、鈣鹽等各鹼土金屬鹽，鋁、鋅等各金屬鹽。作為銨鹽，可例示：銨鹽、四甲基銨鹽等烷基銨鹽等。作為有機胺鹽，可例示：三乙基胺鹽、哌啶鹽、啉鹽、甲苯胺鹽等各鹽。再者，使用該等鹽時，亦可用作溶液。
以上之ALA類之中，較理想者為ALA、及ALA甲酯、ALA乙酯、ALA丙酯、ALA丁酯、ALA戊酯等各種酯類，及該等之鹽酸鹽、磷酸鹽、硫酸鹽，可尤佳地例示ALA鹽酸鹽或ALA磷酸鹽。
上述ALA類可藉由化學合成、利用微生物進行之生產、利用酶進行之生產中之任一公知之方法而製造。又，上述ALA類可形成水合物或溶劑合物，又，可單獨使用任一者或適當組合2種以上而使用。
作為上述鐵化合物，可為有機鹽，亦可為無機鹽，作為無機鹽，可列舉：氯化鐵、三氧化二鐵、硫酸鐵、焦磷酸亞鐵，作為有機鹽，可列舉：羧酸鹽例如羥基羧酸鹽，檸檬酸亞鐵、檸檬酸鐵鈉、檸檬酸
亞鐵鈉、檸檬酸鐵銨等檸檬酸鹽，或焦磷酸鐵、乳酸鐵、葡萄糖酸亞鐵、二伸乙基三胺五乙酸鐵鈉、二伸乙基三胺五乙酸鐵銨、乙二胺四乙酸鐵鈉、乙二胺四乙酸鐵銨、二羧基甲基麩胺酸鐵鈉、二羧基甲基麩胺酸鐵銨、反丁烯二酸亞鐵、乙酸鐵、草酸鐵、琥珀酸亞鐵、琥珀酸檸檬酸鐵鈉等有機酸鹽，或血紅素鐵、葡聚糖鐵、三伸乙基四胺鐵、乳鐵蛋白鐵、轉鐵蛋白鐵、葉綠素鐵鈉、鐵蛋白鐵、含糖氧化鐵、硫化甘胺酸鐵，其中較佳為檸檬酸亞鐵鈉或檸檬酸鐵鈉。
上述鐵化合物可分別單獨使用，亦可混合2種以上使用。作為鐵化合物之投予量，相對於ALA類之投予量(ALA換算)，只要以莫耳比計為0.01~100倍即可，較佳為0.05倍~10倍，更佳為0.1倍~8倍。
本發明之移植器官植活促進劑可於不產生過量徵候之範圍內，進而含有其他金屬化合物代替鐵化合物，或除鐵化合物以外進而含有其他金屬化合物。作為該金屬化合物，可列舉：鎂化合物、鋅化合物、鎳化合物、釩化合物、鈷化合物、銅化合物、鉻化合物、鉬化合物等。
本發明之移植器官植活促進方法中，較佳為一併投予ALA類及鐵化合物。於該情形時，可以含有ALA類與鐵化合物之組合物，或者分別單獨同時或相繼投予。分別單獨投予之情形時較佳為同時投予，分別單獨相繼投予之情形時，較佳為以ALA類與鐵化合物之投予可發揮累加性效果、較佳為協同性效果之方式投予。
亦可僅將本發明之移植器官植活促進劑投予至移植有自供體摘出之器官、將自供體摘出之器官暫時保管於保存液中之後之器官、使用再生醫療技術來用於自體移植而製作之器官、或將該等器官浸漬於ALA類中之後之器官等後之受體，但就提高植活率之方面而言，較佳為亦一併投予摘出器官前之供體。如上所述，本發明之較大之特徵在於藉由將本發明之移植器官植活促進劑或移植器官植活促進套組投予至器官移植前之供體及器官移植後或移植前後之受體，從而提高植活
率。
視需要而使源自對器官移植前及/或後之受體投予本發明之移植器官植活促進劑或移植器官植活促進套組而得之受體之經單離之免疫細胞、或源自對器官移植前之供體及器官移植前及/或後之受體投予本發明之移植器官植活促進劑或移植器官植活促進套組而得之受體之經單離之免疫細胞增殖，並投予採取該免疫細胞之同一及/或不同之受體，藉此，即便未對投予有該免疫細胞之受體投予本發明之移植器官植活促進劑或移植器官植活促進套組，於個體水平上亦誘導促進免疫耐受性(二次免疫耐受性之誘導促進)。該二次免疫耐受性之誘導促進顯示移植器官植活促進依賴於免疫耐受性誘導，可應用於過繼免疫療法。例如，若自免疫耐受性經誘導之人類採取免疫細胞並將其暫時保管，則於解除免疫耐受性時(例如，不接受移植器官時等)，即便不投予本發明之移植器官植活促進劑，藉由移植該細胞，亦可使免疫耐受性之狀態恢復。該二次免疫耐受性之誘導促進係本發明之尤其大之特徵。
作為上述免疫細胞，除脾臟細胞以外，可列舉：巨噬細胞、樹狀細胞、T細胞、B細胞、NK細胞、嗜中性球、嗜酸性球、骨髓衍生抑制細胞(MDSC，myeloid-derived suppressor cells)等，較佳為控制性T細胞或脾臟細胞。
作為本發明之移植器官植活促進劑、或移植器官植活促進套組之各成分之投予路徑，可列舉亦包括舌下投予之經口投予，或滴鼻投予、吸入投予、包括點滴之靜脈內投予、利用敷劑等進行之經皮投予、藉由栓劑、或使用經鼻胃管、經鼻腸管、胃瘺管或腸瘺管之強制性經腸營養法進行之投予等非經口投予等，較佳為經口投予。
作為本發明之移植器官植活促進劑、或移植器官植活促進套組之各成分之劑型，可根據上述投予路徑而適當決定，可列舉：注射劑、
滴鼻劑、點滴劑、片劑、膠囊劑、細粒劑、散劑、液劑、溶解於糖漿等中而成之水劑、敷劑、栓劑等。本發明之移植器官植活促進劑、或移植器官植活促進套組之各成分除醫藥用途以外，亦可以片劑或膠囊劑之補充品之形態投予。又，尤其是對於難以咽下之高齡者或嬰幼兒等而言，較佳為於口中表現出迅速之崩解性之崩解片之形態、或適於經鼻胃管投予之液劑之形態。
為調製本發明之移植器官植活促進劑、移植器官植活促進套組，亦可視需要而添加於藥理學上可容許之載體、賦形劑、稀釋劑、添加劑、崩解劑、結合劑、被覆劑、潤滑劑、滑走劑、滑澤劑、調味劑、甜味劑、助溶劑、溶劑、膠化劑、營養劑等，具體而言，可例示：水、生理鹽水、動物性脂肪及油、植物油、乳糖、澱粉、明膠、晶質纖維素、橡膠、滑石、硬脂酸鎂、羥丙基纖維素、聚伸烷基二醇、聚乙烯醇、甘油。再者，將本發明之移植器官植活促進劑或移植器官植活促進套組調製為水溶液之情形時，為防止ALA類之分解，必需注意避免水溶液成為鹼性，於成為鹼性之情形時，亦可藉由除去氧而防止分解。
本發明之移植器官植活促進劑於可抑制將所摘出之供體之器官移植至受體之情形時引起之受體側之免疫應答、抑制伴隨器官移植之排斥反應、且可提高移植器官之植活率之方面而言較為有用，除可用作自供體摘出後之器官之防腐劑以外，添加至現有之器官保存液中，可增強器官移植中之移植器官植活促進效果。作為上述排斥反應，可列舉：器官移植後之超急性排斥反應、急性排斥反應、慢性排斥反應。
所謂上述超急性排斥反應，一般認為係多見於異種器官移植中、於剛結束移植起至移植後24小時以內發生之激烈之排斥反應，可以將縫合血管、血液再次開始流動後於數分鐘至數小時以內，例如於移植器官之動脈中是否形成血栓作為超急性排斥反應之有無之判斷基準，於心臟移植之情形時，可以剛結束移植起至移植後24小時以內之搏動
之停止作為判斷基準。所謂上述急性排斥反應，一般認為係自移植後3天起至1週前後之間發生之排斥反應，於心臟移植之情形時，可以移植後24小時以後之搏動之停止作為急性排斥反應之有無之判斷基準。所謂上述慢性排斥反應，一般認為係於移植後3個月以後發生之排斥反應，詳細之機制尚不明確，於心臟移植之情形時，亦可以搏動之停止作為慢性排斥反應之有無之判斷基準。
作為本發明中之供體及/或受體，可列舉：人類、狒狒、牛、豬、狗、貓、兔、大鼠、小鼠等哺乳動物，作為使用本發明之移植器官植活促進劑而進行之器官移植之態樣，只要為可實現自供體至受體之器官之移植之態樣，則並無特別限制，可列舉自小鼠至小鼠、自大鼠至大鼠、自兔至兔、自狗至狗、自貓至貓、自豬至豬、自猴至猴、自狒狒至狒狒、自人類至人類等同種器官移植，或自豬至人類、自牛至人類、自猴至人類、自狒狒至人類等異種器官移植。
使用本發明之移植器官植活促進劑之器官移植可藉由常法而進行，可為摘除受體之對應器官而將由供體等提供之器官移植至受體中之相同部位之正位器官移植，亦可為殘留受體之器官而直接將由供體等所提供之器官移植至受體之其他部位之異位器官移植。
必需將本發明之移植器官植活促進劑投予至器官經移植後之受體，作為具體之投予時間，例如可列舉移植當天之次日~10天後，較佳可列舉移植當天之次日~15天後，更佳可列舉移植當天之次日~1個月後，尤佳可列舉移植當天之次日~充分確認移植器官之植活之日期，視需要亦可持續長時間投予，亦可自早於移植當天起投予。
如上所述，為提高植活率，較佳為將本發明之移植器官植活促進劑預先投予至摘出器官之供體。然而，尤其是於腦死亡移植等時等無足夠時間投予足量於供體之情形時，對自供體摘出之器官直接投予，或將該器官浸漬於含有本發明之移植器官植活促進劑之溶液中，或於
保管該器官之保管液中添加本發明之移植器官植活促進劑等，藉由於摘出後之器官中之投予亦可獲得相同之效果。使用利用再生醫療技術用於自體移植而製作之器官之情形時，亦可採用於該器官之保管液中添加之方法。如上所述，本發明之自供體摘出後之器官之防腐劑可含有移植器官植活促進劑，作為粉末、顆粒、片劑等固體型或液體型而構成。於固體型之情形時，可視需要而調配分散劑、溶解劑、pH值調節劑。於液體型之情形時，較佳為具有緩衝能力者。又，於液體型之情形時，亦可製成濃縮保存液，於使用時以生理鹽水等稀釋而使用。
對本發明中之供體投予本發明之移植器官植活促進劑之情形時，必需於摘出器官前之特定時間投予，作為具體之投予時間，可列舉器官之摘出手術當天之1週前~摘出當天，較佳可列舉5天前~摘出當天，更佳可列舉3天前~摘出當天，進而較佳可列舉2天前~摘出當天，於器官之摘出手術後必需運輸器官等之情形時，較佳為採取將本發明之移植器官植活促進劑保管於保存液中等措施。
如上所述，本發明之移植器官植活促進劑或移植器官植活促進套組，除人類以外，亦可使用於家畜、家禽類或寵物等獸醫領域。關於該移植器官植活促進劑等之投予量、頻度、時間，於對象為人類之情形時，根據年齡、體重、症狀等而有所不同，作為ALA類之投予量，以ALA莫耳換算計，可列舉每個成人為0.1~12mmol/天，較佳可列舉0.2~9mmol/天，更佳可列舉0.3~6mmol/天，進而較佳可列舉0.35mmol/天~4mmol/天，作為投予頻度，可例示一天一次~數次之投予或利用點滴等進行之連續性投予。投予時間亦可由該技術領域之藥理學者或臨床醫生根據已知之方法而決定。
作為將本發明之移植器官植活促進劑用作器官保存液之情形時之ALA類的濃度，可列舉0.1μM~100mM，較佳為1μM~10mM，更佳為5μM~5mM，最佳為10μM~1mM。
本發明之移植器官植活促進劑亦可與其他現有之器官移植免疫抑制方法組合使用。作為現有之器官移植免疫抑制方法，可列舉利用CD2、CD3、CD4、CD7、CD25、CD28、CD45、B7等抗體之免疫抑制性單株抗體之免疫耐受性誘導方法。由於一般認為該等藥劑或方法分別與ALA之關於器官移植免疫抑制效果之機制在根本上不同，因此可期待累加性之視情況為協同性之效果。又，亦可期待藉由減少現有之器官移植免疫抑制劑之投予量而減輕副作用之效果。
以下藉由實施例對本發明進行更具體之說明，但本發明之技術範圍並不限定於該等例示。
作為提供移植之心臟之供體小鼠，使用B10小鼠(雄性、平均10週齡、體重20~25g)。作為移植自供體取出之心臟之受體小鼠，使用CBA小鼠(雄性、平均10週齡、體重20~25g)。小鼠異位同種心臟移植之順序係按照器官移植實驗指南(秀潤公司)、第1章第2部2-1-5「小鼠異位心臟移植」之記載。概要如以下所示。
將供體小鼠麻醉後開胸，使用添加肝素之冰生理食鹽水1mL充分灌注後將心臟摘出，將摘出之心臟保存至添加肝素之冰生理食鹽水中。將受體小鼠麻醉後剖腹，將自供體小鼠摘出之心臟移植至腹部大靜脈上，製成異位心臟移植模型小鼠。
將上述異位心臟移植模型小鼠分為如以下之表1之(1)~(4)所示之各群的投予模式，進行本發明之移植器官植活促進劑之經口投予實驗。受檢小鼠除攝取投予組合物以外，於麻醉處置前及自麻醉中蘇醒後可自由地攝取食物或水。將實驗之概要示於圖1。
組(1)~(4)之投予結果如以下所示。又，將經過天數與心臟搏動率之關係示於圖2。
於對供體小鼠、受體小鼠雙方投予殺菌水之組(1)中，至第9天全部個體之移植心臟停止搏動，不存在長期搏動個體。更詳細而言，移植後第6天1隻、第7天2隻、第8天2隻、第9天1隻之移植心臟停止搏動。
於僅對供體小鼠投予ALA(100mg/kg)+SFC(115mg/kg)(SFC為檸檬酸亞鐵鈉之簡稱，以下同)之組(2)中，至第8天全部個體之移植心臟停止搏動或個體死亡，不存在長期搏動個體。第7天4隻、第8天2隻之移植心臟停止搏動。
於僅對受體小鼠投予ALA(100mg/kg)+SFC(115mg/kg)之組(3)中，發現長期搏動個體。更詳細而言，第12天2隻之移植心臟停止搏動。存在1隻移植心臟持續搏動至經過66天時之個體，存在1隻移植心臟持續搏動至經過70天時之個體。
於對供體小鼠、受體小鼠雙方投予ALA(100mg/kg)+SFC(115mg/kg)之組(4)中，持續長期搏動個體之數目顯著較多。更詳細而言，第8天1隻之移植心臟停止搏動。各存在2隻移植心臟持續搏動至經過
66、76天時之個體，各存在1隻移植心臟持續搏動至經過96、106天時之個體。
本實驗模型可於某種程度上預測為實施侵襲性較大之手術而引起因應激反應導致之個體死亡之情況，該情況與ALA類及鐵化合物之投予之有無無關。然而，可確認於對移植前之供體、及移植後之受體經口投予ALA類與鐵化合物之情形時，持續長期搏動個體之數目較多，藉由投予ALA類與鐵化合物，器官之植活率顯著提高。組(3)之小鼠亦存在長期搏動個體，可確認僅對移植後之受體進行投予時，本發明之移植器官植活促進劑亦具有效果。
將上述之異位同種心臟移植模型小鼠分為如以下之表2之組(a)~(e)所示之各群的投予模式，研究本發明之移植器官植活促進劑之鐵化合物之含量之多少引起之效果之不同。受檢小鼠除投予組合物之攝取以外，可於麻醉處置前及自麻醉中蘇醒後自由地攝取食物或水。
組(a)~(e)之投予結果如以下所示。又，將經過天數與心臟搏動率之關係示於圖3。
於對供體小鼠、受體小鼠雙方投予殺菌水之組(a)中，至第9天全部個體之移植心臟停止搏動，不存在長期搏動個體。更詳細而言，於移植後第6天2隻、第7天5隻、第8天2隻之移植心臟停止搏動。
於對供體小鼠、受體小鼠雙方投予ALA(100mg/kg)之組(b)中，至第8天全部個體之移植心臟停止搏動，不存在長期搏動個體。更詳細而言，第7天2隻、第8天3隻之移植心臟停止搏動。
於對供體小鼠、受體小鼠雙方投予ALA(100mg/kg)+SFC(11.5mg/kg)之組(c)中，存在長期搏動個體。更詳細而言，於移植後第8天1隻、第12天1隻之移植心臟停止搏動，但存在1隻移植心臟持續搏動至經過25天時之個體，存在2隻移植心臟持續搏動至經過29天時之個體。
於對供體小鼠、受體小鼠雙方投予ALA(100mg/kg)+SFC(115mg/kg)之組(d)中，持續長期搏動個體之數目顯著較多，生存時間較長之個體較多。更詳細而言，各存在2隻移植心臟持續搏動至經過63、73天時之個體。各存在1隻移植心臟持續搏動至經過93天、103天時之個體。
於僅對受體小鼠投予ALA(100mg/kg)+SFC(115mg/kg)之組(e)中，存在長期搏動個體。更詳細而言，於第15天1隻之移植心臟停止搏動，但存在2隻移植心臟持續搏動至經過29天時之個體。
藉由組(b)與組(c)及(d)之比較，可確認對移植前之供體與移植後之受體投予ALA類之情形時，與單獨投予ALA類相比，組合投予ALA與鐵化合物顯著增大免疫抑制效果，提高受體之生存率。又，可確認作為鐵化合物之添加量，投予檸檬酸亞鐵鈉115mg/kg之組(d)之成績較佳。又，組(e)之小鼠亦存在長期搏動個體，可確認僅對移植後之受體進行投予時，本發明之移植器官植活促進劑亦具有效果。
自心臟移植2天前起至移植日為止，將ALA(100mg/kg)+SFC(115mg/kg)投予至供體小鼠、受體小鼠雙方，心臟移植後僅對受體小鼠繼續以一天一次之方式投予直至第11天，單離源自長期植活(>100天)之一次移植受體小鼠(CBA)之脾臟細胞，以腹腔內注射之方式向其他受體系統小鼠(CBA)注射該脾臟細胞，同時將與一次移植時相同之系統之供體小鼠(B10)之心臟移植至上述受體系統小鼠(CBA)內。將結果示於圖4。其結果，藉由經歷ALA+SFC投予心臟移植之脾臟細胞移植，而促進心臟二次移植之植活率(二次免疫耐受性之誘導)。即，將源自進行一次移植之受體系統小鼠(CBA)之脾臟細胞與供體小鼠(B10)之心臟同時移植之小鼠(耐受；n=5)與將源自未進行一次移植之受體系統小鼠(CBA)之脾臟細胞與供體小鼠(B10)之心臟同時移植之小鼠(未處理；n=5)相比，提高心臟之植活率。該結果顯示，移植器官植活之機理為免疫耐受性。
自心臟移植2天前起至移植日為止，將ALA(100mg/kg)+SFC(115mg/kg)投予至供體小鼠、受體小鼠雙方，心臟移植後僅對受體小鼠繼續以一天一次之方式投予直至第11天，單離源自長期植活(>100天)之一次移植受體小鼠(CBA)之脾臟細胞，以腹腔內注射向其他受體系統小鼠(CBA)注射該脾臟細胞，同時將與一次移植時相同之系統之供體小鼠(B10)之皮膚移植至上述受體系統小鼠(CBA)上。將皮膚移植30天後之結果示於圖5。其結果，藉由經歷ALA+SFC投予心臟移植之脾臟細胞移植，可觀察到皮膚移植之植活。該結果顯示，移植器官植活小鼠於個體水平產生免疫耐受性。
藉由流式細胞儀測定受體系統小鼠(CBA)之脾臟中之控制性T細胞數。供試者如下：1)群為僅投予殺菌水之受體系統小鼠(n=6)；2)群為投予ALA(100mg/kg)+SFC(115mg/kg)之受體系統小鼠(n=6)；3)群為以腹腔內注射之方式注射有源自對供體小鼠、受體小鼠雙方投予殺菌水之一次心臟移植受體小鼠(CBA)之脾臟細胞之其他受體系統小鼠(n=6)；4)群為以腹腔內注射之方式注射有脾臟細胞之其他受體系統小鼠(n=6)，該脾臟細胞係源自自心臟移植2天前起至移植日為止向供體小鼠、受體小鼠雙方投予ALA(100mg/kg)+SFC(115mg/kg)、心臟移植後僅對受體小鼠以一天一次之方式繼續投予直至第11天之一次心臟移植受體小鼠(CBA)。將結果示於圖6。其結果，可知4)群之受體系統小鼠中之控制性T細胞數顯著多於3)群中者，脾臟中之控制性T細胞之比率會增加。該結果顯示，ALA+SFC投予誘導免疫耐受性。
關於器官之新鮮度保持，研究自供體摘出後之器官之含有ALA之防腐劑之有效性。藉由保存過程中停止搏動之心臟藉由移植而開始再次搏動為止之時間(second)即複跳時間(Re-beating time)而研究器官之新鮮度保持。作為提供保存、移植之心臟之供體小鼠，係使用B10小鼠(雄性、7~10週齡、體重20~25g)。
作為保存液，供試者如下：於含有氯化鉀、碳酸氫鈉、磷酸氫二鉀、磷酸二氫鉀、及葡萄糖之基本溶液中，以用最終濃度計ALA達到100μM、硫酸鐵達到5μM之方式添加而成之保存液G6(+)；及於上述基本溶液中，以用最終濃度計硫酸鐵達到5μM之方式添加而成之保存液G6(-)。作為上述ALA，係使用ALA鹽酸鹽。該等供試保存液之滲透壓為326~363Osm/kg。又，作為對照，使用市售之器官保存液(Astellas Pharma股份有限公司製造之「ViaSpan」；保存液UW)。將該等保存液
之溫度設為冰浴冷卻，保存時間設為24小時。
複跳時間之測定時，供試者為保存液G6(+)、保存液G6(-)及保存液UW。又，複跳時間之測定係按照器官移植實驗指南(秀潤公司)、第1章第2部2-1-5「小鼠異位心臟移植」之記載，及European Heart Journal(2011)32,509-516之記載。概要如以下所示。
將供體小鼠麻醉後開胸，使用供試保存液1mL充分灌注後將心臟摘出，將摘出之心臟保存於供試保存液中。將受體小鼠麻醉後剖腹，將自供體小鼠摘出並保存之心臟移植至腹部大靜脈上，製成異位心臟移植模型小鼠。此時，測量自血液向心臟之再灌注之開始起至心臟之複跳開始為止之時間，作為複跳時間。
將移植用小鼠之心臟於保存液G6(+)、保存液G6(-)及保存液UW中保存24小時後，進行異位同種心臟移植，測定複跳時間(second)。將結果示於圖7。其結果，含有ALA(100μM)+硫酸鐵(5μM)溶液之保存液G6(+)之複跳時間(秒)之平均值為108秒，含有硫酸鐵(5μM)溶液之保存液G6(-)之複跳時間(秒)之平均值為145秒，對照保存液UW之複跳時間(秒)之平均值為229秒。如上所述，可知若使用保存液G6(+)，則與使用保存液UW之情形相比，可顯著縮短複跳時間(t檢驗；p=0.0244)。
本發明之移植器官植活促進劑可有利地用於醫藥、醫療之領域。
Claims (9)
- 一種由源自受體之樣品於活體外所單離之免疫細胞的用途，其係用以製造二次免疫耐受性之誘導促進劑，其特徵在於：該受體係於器官移植前及/或後經投予下述式(I)所示之化合物或其藥理學上容許之酸加成鹽、金屬鹽、銨鹽、或有機胺鹽、與鐵化合物之組合，且於投予該化合物或其藥理學上容許之酸加成鹽、金屬鹽、銨鹽、或有機胺鹽、與鐵化合物之組合後不進行光照射：
- 一種由源自受體之樣品於活體外所單離之免疫細胞的用途，其係用以製造二次免疫耐受性之誘導促進劑，其特徵在於：供體於器官移植前、以及該受體於器官移植前及/或後經投予下述式(I)所示之化合物或其藥理學上容許之酸加成鹽、金屬鹽、銨鹽、或有機胺鹽、與鐵化合物之組合，且於投予該化合物或其藥理學上容許之酸加成鹽、金屬鹽、銨鹽、或有機胺鹽、與鐵化合物之組合後不進行光照射：
- 如請求項1之用途，其中免疫細胞係控制性T細胞。
- 如請求項2之用途，其中免疫細胞係控制性T細胞。
- 如請求項1至4中任一項之用途，其中R1及R2為氫原子。
- 如請求項1至4中任一項之用途，其中鐵化合物為選自氯化鐵、三 氧化二鐵、硫酸鐵、焦磷酸亞鐵、檸檬酸亞鐵、檸檬酸鐵鈉、檸檬酸亞鐵鈉、檸檬酸鐵銨、焦磷酸鐵、乳酸鐵、葡萄糖酸亞鐵、二伸乙基三胺五乙酸鐵鈉、二伸乙基三胺五乙酸鐵銨、乙二胺四乙酸鐵鈉、乙二胺四乙酸鐵銨、二羧基甲基麩胺酸鐵鈉、二羧基甲基麩胺酸鐵銨、反丁烯二酸亞鐵、乙酸鐵、草酸鐵、琥珀酸亞鐵、琥珀酸檸檬酸鐵鈉、血紅素鐵、葡聚糖鐵、三伸乙基四胺鐵、乳鐵蛋白鐵、轉鐵蛋白鐵、葉綠素鐵鈉、鐵蛋白鐵、含糖氧化鐵、及硫化甘胺酸鐵中之1種或2種以上之化合物。
- 如請求項5之用途，其中鐵化合物為選自氯化鐵、三氧化二鐵、硫酸鐵、焦磷酸亞鐵、檸檬酸亞鐵、檸檬酸鐵鈉、檸檬酸亞鐵鈉、檸檬酸鐵銨、焦磷酸鐵、乳酸鐵、葡萄糖酸亞鐵、二伸乙基三胺五乙酸鐵鈉、二伸乙基三胺五乙酸鐵銨、乙二胺四乙酸鐵鈉、乙二胺四乙酸鐵銨、二羧基甲基麩胺酸鐵鈉、二羧基甲基麩胺酸鐵銨、反丁烯二酸亞鐵、乙酸鐵、草酸鐵、琥珀酸亞鐵、琥珀酸檸檬酸鐵鈉、血紅素鐵、葡聚糖鐵、三伸乙基四胺鐵、乳鐵蛋白鐵、轉鐵蛋白鐵、葉綠素鐵鈉、鐵蛋白鐵、含糖氧化鐵、及硫化甘胺酸鐵中之1種或2種以上之化合物。
- 如請求項1至4中任一項之用途，其中鐵化合物為檸檬酸亞鐵鈉。
- 如請求項5之用途，其中鐵化合物為檸檬酸亞鐵鈉。
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2012
- 2012-09-12 EP EP12839496.2A patent/EP2767278B1/en active Active
- 2012-09-12 CN CN201280050051.4A patent/CN103930103B/zh active Active
- 2012-09-12 JP JP2013538423A patent/JP5907357B2/ja active Active
- 2012-09-12 US US14/350,488 patent/US9314443B2/en active Active
- 2012-09-12 CN CN201610615612.0A patent/CN106110326A/zh active Pending
- 2012-09-12 WO PCT/JP2012/005782 patent/WO2013054470A1/ja active Application Filing
- 2012-09-25 TW TW101135180A patent/TWI543762B/zh active
- 2012-09-25 TW TW105118232A patent/TWI612958B/zh active
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2014
- 2014-08-20 HK HK14108521.5A patent/HK1195008A1/zh unknown
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- 2016-03-09 US US15/064,884 patent/US9937138B2/en active Active
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| HK1195008A1 (zh) | 2014-10-31 |
| TWI612958B (zh) | 2018-02-01 |
| TWI543762B (zh) | 2016-08-01 |
| US9937138B2 (en) | 2018-04-10 |
| JP5907357B2 (ja) | 2016-04-26 |
| WO2013054470A1 (ja) | 2013-04-18 |
| US9901558B2 (en) | 2018-02-27 |
| CN103930103B (zh) | 2016-08-24 |
| EP2767278A1 (en) | 2014-08-20 |
| CN103930103A (zh) | 2014-07-16 |
| EP2767278A4 (en) | 2015-04-08 |
| US9314443B2 (en) | 2016-04-19 |
| JP6172724B2 (ja) | 2017-08-02 |
| JPWO2013054470A1 (ja) | 2015-03-30 |
| US20140249217A1 (en) | 2014-09-04 |
| CN106110326A (zh) | 2016-11-16 |
| TW201325586A (zh) | 2013-07-01 |
| US20160206582A1 (en) | 2016-07-21 |
| JP2016106113A (ja) | 2016-06-16 |
| US20160184250A1 (en) | 2016-06-30 |
| EP2767278B1 (en) | 2019-11-06 |
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