TWI543960B - Erythropoietin production accelerator - Google Patents
Erythropoietin production accelerator Download PDFInfo
- Publication number
- TWI543960B TWI543960B TW101137457A TW101137457A TWI543960B TW I543960 B TWI543960 B TW I543960B TW 101137457 A TW101137457 A TW 101137457A TW 101137457 A TW101137457 A TW 101137457A TW I543960 B TWI543960 B TW I543960B
- Authority
- TW
- Taiwan
- Prior art keywords
- erythropoietin
- group
- anemia
- production
- ala
- Prior art date
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- 229940095064 tartrate Drugs 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
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- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
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Landscapes
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Description
本發明係有關一種紅血球生成素產生促進劑。更詳言之,本發明係有關一種包含ALA類之紅血球生成素產生促進劑。
本發明又有關一種針對紅血球生成素產生能力降低所引起之貧血、典型上為腎性貧血之治療劑及/或預防劑。更詳言之,本發明係有關一種包含ALA類之貧血的治療劑及/或預防劑。
腎臟為產生紅血球生成素的主要器官,而紅血球生成素主要在腎臟的腎小管基質細胞中產生。
紅血球生成素為包含165個胺基酸的激素(荷爾蒙)之一。紅血球生成素係於造血組織中與紅血球前驅細胞上的受體結合,而促進紅血球前驅細胞的增殖與分化。如此一來,紅血球生成素便可調節紅血球的產生。
平時,係藉由血液中的氧氣分壓來調整紅血球生成素的產生,由此亦可調整紅血球的產生。而且,如發生貧血時,腎臟為了進行造血而增加紅血球生成素的產量,結果使血液中的紅血球生成素上升。
然而,因腎臟疾病等導致腎臟中的紅血球生成素的產量下降時,儘管發生貧血,血液中的紅血球生成素亦未上升,仍會引發紅血球的產生受抑制的病狀;此種病狀即為腎性貧血。亦即,腎性貧血係指因腎臟疾病等導致腎臟中的紅血球生成素(EPO)的產量下降,主要由此引起而產生之貧血。在腎臟病當中,尤為慢性腎臟病時,由於腎功能緩慢下降,未必會引起腎性貧血。然而,在腎臟病當中,若為腎衰竭等急性腎疾病時,已知發生腎性貧血的機率甚高。此外,亦可發現多數由與腎臟病的發病完全無關的紅血球生成素產量的下降所引發的貧血。如此,腎疾病,尤為慢性腎臟病與包含腎性貧血之紅血球生成素下降所引起的貧血並非為相同的發病機制。
作為腎性貧血之症狀的特徵,可例舉如氣喘、心悸、暈眩、食慾不振、疲勞感。
此外,對於腎衰竭持續惡化的患者,已知會併發尿毒症。尿毒症係一種因腎功能下降導致尿素等人體廢物殘留於血液中的病狀。尿毒症患者會併發各種症狀,惟腎性貧血的症狀亦為其中之一。
作為治療此種腎性貧血之方法,既已開發有ESA(紅血球造血刺激因子製劑,erythropoiesis stimulating agents),並已實用化。作為ESA之實例,可例舉(1)紅血球生成素、(2)紅血球生成素的衍生物、(3)可刺激其他紅血球生成素受體的化合物等。
再者,日本的腎性貧血之治療方針係基於以下準則(非專利文獻1)來進行:
1)當診斷確定腎性貧血,並滿足投予基準時,應開始進行ESA(紅血球造血刺激因子製劑)療法(積極推薦)。
2)應併用造血所需之鐵劑的投予(積極推薦)。
3)對於維持血液透析(hemodialysis:HD)患者,致力於透析液的淨化,並進行充分的透析(積極推薦)。
4)對於伴有營養失調、炎症的患者,應對此等進行積極治療(積極推薦)。
如上述準則所示,在日本國內,作為腎性貧血治療劑的第一選擇藥係推薦ESA。
然而,已知腎性貧血患者的一部分對ESA療法顯示出抗性。關於對ESA療法產生低反應性的機制,迄今仍有許多有不明瞭處。作為此種對ESA療法呈低反應性的原因之一,茲認為主要原因在於TNF-α、IL-6等發炎性細胞激素的血中濃度增加。發炎性細胞激素係指,引起活體內的各種炎症症狀的病因因子(病原體,causative agent)。又可知發炎性細胞激素會縮短紅血球壽命;還可知發炎性細胞激素會降低紅血球生成素產生細胞所產生之紅血球生成素的產量。因此,茲認為發炎性細胞激素係作為引起貧血的原因物質。
另外,以ESA療法其副作用而言,係有發生血栓症、心肌梗塞等的風險。近來,亦有惡性腫瘤的預後不良之報導。
再者,ESA療法如上述,僅為一種對症療法,並未有使紅血球生成素產生細胞所產生之紅血球生成素的產量下降回復等作用。
更且,ESA通常難以進行經口投予,由用藥意願(compliance)觀點言之亦存有問題。
【非專利文獻1】慢性腎臟病患者的腎性貧血治療之準則
本發明提供一種細胞的紅血球生成素產生促進劑,並提供一種藉由與ESA(紅血球造血刺激因子製劑)等對症療法藥劑不同的新穎途徑,來治療及/或預防貧血,尤為腎性貧血的方法。
本發明人等戮力研究的結果,竟發現ALA類可抑制紅血球生成素產生細胞所產生之紅血球生成素的產量下降。
此表示ALA類對於紅血球生成素產量下降所引起之貧血的根本治療及預防係屬有效。
如上所述,腎性貧血係典型的紅血球生成素的產量下降所引起之貧血,即由腎臟內的紅血球生成素產生細胞所產生之紅血球生成素的產量下降所生成的病狀。因此,以下將紅血球生成素的產量下降所引起之貧血作為所代表之貧血,對「腎性貧血」進行敘述,惟作為本發明對象之貧血並非限於腎性貧血。
本發明可針對腎性貧血的更根本原因進行治療。
更具體而言,本發明人等戮力研究的結果,竟發現ALA類可抑制由發炎性細胞激素或尿毒症毒素引起之紅血球生成素產生細胞所產生之紅血球生成素的產量下降。
關於貧血與ALA的關係,已知ALA對於仔豬的貧血防止係屬有效(參照日本專利第4754731號公報)。業已報導仔豬的貧血係因造血無法趕上急速的生長所引起,且作為造血所需之化合物之一,添加ALA係屬有效。此因ALA為活體內的內在物質,且ALA以其轉化為血紅素,增強血紅蛋白為作用機制。惟,此與所謂「ALA類可抑制紅血球生成素產生細胞所產生之紅血球生成素的產量下降」的本發明之機制完全無關。
又,本發明人等,如既已申請完成但未公開的申請案中所揭示者,獲得以下見解。此外,對於彼等(申請案)中的數個,茲將其作為本申請案之優先權的基礎申請案。
即,本發明人等發現ALA類的癌性貧血的改善效果。惟,此認為係癌特異性溶血反應的抑制所致。又,本發明人等亦發現ALA類的慢性腎臟病的改善、預防效果。惟,其係直接改善腎臟的過濾能力,與所謂「可抑制紅血球生成素產生細胞所產生之紅血球生成素的產量下降」的本發明之機制完全無關。且,本發明人等還發現ALA類的敗血症的治療、預防效果。惟,其係基於抑制發炎性細胞激素的產生自身之效果,與所謂「可抑制紅血球生成素產生細胞所產生之紅血球生成素的產量下降」的本發明之機制完全無關。
如此,所謂「可抑制紅血球生成素產生細胞所產生之紅血球生成素的產量下降」的本發明之特徵,由習知先前技術、作為發明人等之先前申請案的未公開申請案中並無法思及。更者,今後的課題在於瞭解有關「ALA類何以對紅血球生成素產生能力的改善有效」之縝密的機制。
亦即,本發明係有關一種紅血球生成素產生促進劑,含有以下式(I)表示之化合物或其鹽,R1-NHCH2COCH2CH2COOR2 (I)於該式中,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、芳基或芳烷基。
本發明又有關一種促進紅血球生成素的產生之方法,其特徵在於:將治療上有效量之以下式(I)所示之化合物或其鹽針對對象進行投予,R1-NHCH2COCH2CH2COOR2 (I)於該式中,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、芳基或芳烷基。
本發明更有關一種紅血球生成素的產量下降所引起之貧血的治療劑及/或預防劑,含有以下式(I)表示之化合物或其鹽,
R1-NHCH2COCH2CH2COOR2 (I)於該式中,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、芳基或芳烷基。
於此,紅血球生成素的產量下降可能由發炎性細胞激素或尿毒症毒素所引起。
各上式(I)中,R1可選自包含氫原子、碳數1~8之烷醯基、及碳數7~14之芳醯基的群組,且R2可選自包含氫原子、直鏈或分支狀之碳數1~8之烷基、碳數3~8之環烷基、碳數6~14之芳基、及碳數7~15之芳烷基的群組。
本發明之紅血球生成素的產量下降所引起之貧血的治療劑及/或預防劑可進一步含有一種或二種以上之含金屬化合物。該含金屬化合物可為含有選自包含鐵、鎂、及鋅之群組的金屬的化合物。
本發明之紅血球生成素的產量下降所引起之貧血的治療劑及/或預防劑中,該貧血可為腎性貧血。
透過使用本發明之紅血球生成素產生促進劑,可促進紅血球生成素產生細胞所進行之紅血球生成素的產生。由此結果,其對於紅血球生成素的產量下降所引起之貧血,典型上為腎性貧血的根本治療及預防係屬有效。
亦即,本發明係提供一種腎性貧血的治療劑及/或預防劑。
此外,本發明中,「治療」係指「不僅完全治癒腎性貧血,還包含改善腎性貧血的症狀」。對於「預防」,亦同樣意指「不僅完全不產生腎性貧血的症狀,亦包含使未投予本發明之預防劑可能產生的腎性貧血的症狀更加穩定」。
透過使用本發明之紅血球生成素產生促進劑,可抑制紅血球生成素產生細胞所產生之紅血球生成素的產量下降,並可治療及/或預防貧血,尤為腎性貧血。
如此,本發明係提供一種藉由與ESA(紅血球造血刺激因子製劑)
等對症療法藥劑不同的新穎途徑,來治療及/或預防腎性貧血之方法。
更且,本發明之腎性貧血的治療劑及/或預防劑可代替ESA療法、或與ESA療法併用來使用,藉此,可減少單獨使用ESA療法時所產生的副作用。
再者,本發明係提供一種紅血球生成素產生促進劑。
透過使用本發明之紅血球生成素產生促進劑,可促進紅血球生成素產生細胞所進行之紅血球生成素的產生。
本發明中,腎性貧血係指因腎臟疾病等導致腎臟中的紅血球生成素的產量下降,主要由此引起而產生之貧血。於此,腎臟中的紅血球生成素的產量下降,亦包含由發炎性細胞激素、尿毒症毒素所引起者。此處尿毒症毒素係包括吲哚酚硫酸等。
作為本發明之腎性貧血的治療劑及/或預防劑,只要為含有ALA類之腎性貧血的治療劑及/或預防劑則未特別限制。
又作為本發明之紅血球生成素產生促進劑,只要是含有ALA類的紅血球生成素產生促進劑則未特別限制。
本說明書中,ALA類係指ALA或者其衍生物或其等之鹽。
本說明書中,ALA意指5-胺基乙醯丙酸。ALA亦稱之為δ-胺基乙醯丙酸,為胺基酸的1種。
作為ALA衍生物,可例示以下式(I)表示之化合物。式(I)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、芳基或芳烷基。此外,式(I)中,ALA係相當於R1及R2為氫原子的情況。
R1-NHCH2COCH2CH2COOR2 (I)
ALA類只要在活體內,以式(I)之ALA或其衍生物的狀態作為有效成分而發揮作用即可,亦能以由活體內的酵素分解之前驅藥(前驅物,prodrug)的形式進行投予。
作為式(I)之R1之醯基,可例舉甲醯基、乙醯基、丙醯基、丁醯基、異丁醯基、戊醯基、異戊醯基、三甲基乙醯基、己醯基、辛醯基、苯甲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)之R2之烷基,可例舉甲基、乙基、丙基、異丙基、丁基、異丁基、二級丁基、三級丁基、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)之R2之環烷基,可例舉環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環十二基、1-環己烯基等可存在飽和、或一部分不飽和鍵的碳數3~8之環烷基。
作為式(I)之R2之芳基,可例舉苯基、萘基、蒽基、菲基等碳數6~14之芳基。
作為式(I)之R2之芳烷基,芳基部分可例示與上述芳基相同者,烷基部分亦可例示與上述烷基相同者,具體可例舉苯甲基、苯乙基、苯丙基、苯丁基、二苯甲基、三苯甲基、萘甲基、萘乙基等碳數7~15之芳烷基。
作為較佳之ALA衍生物,可例舉R1為甲醯基、乙醯基、丙醯基、丁醯基等的化合物。又作為較佳之ALA衍生物,可例舉上述R2為甲基、乙基、丙基、丁基、戊基等的化合物。此外,作為較佳之ALA衍生物,可例舉上述R1與R2的組合為(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)之各組合的化合物。
ALA類當中,作為ALA或其衍生物之鹽,可例舉藥理學上允許之酸加成鹽、金屬鹽、銨鹽、有機胺加成鹽等。作為酸加成鹽,可例示如鹽酸鹽、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、富馬酸鹽、馬來酸鹽、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,則可例示三乙胺鹽、哌啶鹽、嗎福啉鹽、甲苯胺鹽等各鹽。此外,此等鹽在使用時亦能以溶液形式使用。
以上之ALA類當中,最佳者為ALA、及、ALA甲基酯、ALA乙基酯、ALA丙基酯、ALA丁基酯、ALA戊基酯等各種酯類、以及此等之鹽酸鹽、磷酸鹽、硫酸鹽。特別是,ALA鹽酸鹽、ALA磷酸鹽可例示為特佳者。
上述ALA類可透過例如化學合成、利用微生物生產、利用酵素生產等周知方法來製造。此外,上述ALA類可形成水合物或溶劑合物,亦可單獨或適當組合2種以上來使用ALA類。
本發明之紅血球生成素產生促進劑、本發明之腎性貧血的治療劑及/或預防劑係以在不發生過多症(如用量過多而產生)的範圍,進一步含有含金屬化合物為佳;作為所述含金屬化合物,只要未對本發明之效果造成損害,則可有利地使用金屬化合物。作為本發明之含金屬化合物的金屬部分,可例舉鐵、鎂、鋅、鎳、釩、鈷、銅、鉻、鉬,惟較佳為鐵、鎂、鋅,其中可例示鐵為較佳者。
作為鐵化合物,可例舉檸檬酸亞鐵、檸檬酸亞鐵鈉、檸檬酸鐵鈉、檸檬酸鐵銨、焦磷酸鐵、血質鐵(heme iron)、聚葡萄糖鐵、乳酸鐵、葡萄糖酸亞鐵、二伸乙三胺五乙酸鐵鈉、二伸乙三胺五乙酸鐵銨、乙二胺四乙酸鐵鈉、乙二胺五乙酸鐵銨、三伸乙四胺鐵、二羧甲基麩胺酸鐵鈉、二羧甲基麩胺酸鐵銨、乳鐵蛋白鐵、運鐵蛋白鐵、氯化鐵、三氧化二鐵、鐵葉綠酸鈉、鐵蛋白鐵、富馬酸亞鐵、焦磷酸亞鐵、含糖氧化鐵、乙酸鐵、草酸鐵、琥珀酸亞鐵、琥珀酸檸檬酸鐵鈉、硫酸鐵、硫酸三甘胺酸鐵等,其中較佳為檸檬酸亞鐵、檸檬酸亞鐵鈉。
作為鋅化合物,可例舉氯化鋅、氧化鋅、硝酸鋅、碳酸鋅、硫酸鋅、二伸乙三胺五乙酸鋅二銨、乙二胺四乙酸鋅二鈉、鋅原紫質、鋅酵母。
上述含金屬化合物可分別使用1種或2種以上,作為含金屬化合物的投予量,相對於ALA類的投予量,以莫耳比計可例舉0.01~10倍量,較佳為0.1~5倍量,更佳為0.2~2倍量。
本發明之紅血球生成素產生促進劑、本發明之腎性貧血的治療劑及/或預防劑所含有之ALA類及含金屬化合物,可作成包含ALA類及含金屬化合物的組成物來投予、或各自單獨投予,惟在各自單獨投予時亦以同時投予為佳。然,嚴格說來,即便為非同時,為使ALA類及含金屬化
合物的投予能夠發揮相加效果或相乘效果,亦可於兩者間未隔開相當間隔之下來進行。
作為本發明之紅血球生成素產生促進劑、本發明之腎性貧血的治療劑及/或預防劑的投予路徑,可例舉亦包含舌下投予的經口投予、或者吸入投予、包含點滴的靜脈內投予、使用泥罨劑等的經皮投予、坐劑、或利用鼻胃管、鼻腸管、胃造口管(gastrostomy tube)或是腸造口管之強制性腸道營養法(enteral nutrition)所進行的投予等非經口投予等,惟一般為經口投予。
於此,投予的對象典型上為人類,惟寵物、實驗動物、家畜等非人類動物的情況亦包含在內。
作為本發明之紅血球生成素產生促進劑、本發明之腎性貧血的治療劑及/或預防劑的劑型,可根據上述路徑投予來適當決定,可例舉注射劑、點滴劑、錠劑、膠囊劑、細粒劑、散劑、液劑、溶於糖漿等的水劑、泥罨劑、坐劑等。
為調製本發明之紅血球生成素產生促進劑、本發明之腎性貧血的治療劑及/或預防劑,可視需求添加藥理學上可允許之擔體、賦形劑、稀釋劑、添加劑、崩解佐劑、結合劑、被覆劑、潤滑劑、滑走劑、滑劑、風味劑、甘味劑、溶解化劑、溶劑、凝膠劑、營養劑等,具體可例示水、生理食鹽水、動物性脂肪及油、植物油、乳糖、澱粉、明膠、結晶性纖維素、橡膠、滑石、硬脂酸鎂、羥丙基纖維素、聚烯烴二醇、聚乙烯醇、甘油。此外,以水溶液形式調製本發明之腎性貧血的治療劑及/或預防劑、本發明之紅血球生成素產生促進劑時,為防止ALA類的分解,需留意勿使水溶液呈鹼性,若其呈鹼性時,亦可藉由去除氧氣來防止分解。
作為本發明之紅血球生成素產生促進劑、本發明之腎性貧血的治療劑及/或預防劑的量、頻率、時間,係因腎性貧血患者的年齡、體重、症狀等而異,惟作為較佳投予量之實例,以ALA磷酸鹽換算,可例舉成人每人1mg~3000mg/日,較佳為2mg~1000mg/日,更佳為3mg~700mg/日。使用其他ALA類時,亦可透過進行莫耳換算來計算較佳投予量。再者,上述較佳投予量之範圍僅為例示,並非予以限定。
作為投予頻率,可例示一日一次~多次之投予或點滴等所進行的連續
投予。投予時間亦可基於能診斷出血液中的Hb(血紅蛋白)值、紅血球生成素濃度等的腎性貧血的指標,根據該技術領域之藥理學者、臨床醫師已知的方法來決定。
將本發明之紅血球生成素產生促進劑作為腎性貧血的治療劑及/或預防劑使用時,可與其他既有之腎性貧血的治療劑及/或預防劑組合來使用。作為既有之腎性貧血的治療劑及/或預防劑之實例,可例舉ESA療法中所使用的ESA(紅血球造血刺激因子製劑)等。作為此種ESA(紅血球造血刺激因子製劑)之非限定實例,可舉出Epoetin α(商標)、Epoetin β(商標)、Darbepoetin α(商標)等重組人體紅血球生成素製劑(rHu紅血球生成素)。茲認為此等藥劑與ALA之腎性貧血治療劑及/或預防劑相關之機制於根本上各自相異,因而有相加效果,且依情況,有相乘效果。
本說明書中所使用之用語,除非特別定義,否則係用以說明特定之實施形態,並非用來限定本發明。
又,本說明書中所使用之用語「包含(含有)」,除脈絡上應做明顯相異之理解的情況以外,係意圖指出「記述之事項(構件、步驟、要素、數字等)存在」,且未排除「除此之外之事項(構件、步驟、要素、數字等)存在」(開放式)。
只要沒有不同之定義,此處所使用之所有用語(含技術用語及科學用語)係具有與從事本發明所屬之技術的該行業人士所廣泛理解的意思相同者。此處所使用之用語,只要沒有明示相異定義,否則應作為具有與本說明書及相關技術領域中的意義之整合的意義來解釋,不應就理想化或過度形式化的意義來解釋。
以下將參照實施例對本發明更詳細進行說明。然而,本發明可藉由各種形態而具體化,不應以限定於此處所記載之實施例來解釋。
〈實施例1:針對紅血球生成素產生能力降低之細胞之ALA類投予後之紅血球生成素產生能力的改善效果的測定〉
於低氧下培養紅血球生成素產生細胞,在人為產生紅血球生成素的狀態下添加發炎性細胞激素、或尿毒症之毒素,藉以使紅血球生成素產
生細胞的紅血球生成素產生能力降低。
作為發炎性細胞激素,係採用TNF-α。而作為尿毒症毒素,則採用吲哚酚硫酸。吲哚酚硫酸一般認為係尿毒症毒素的病原體,亦為尿毒症相關標記當中最常使用者。再者,吲哚酚硫酸係一種在體內,來自色胺酸之吲哚在肝臟經硫酸化所合成的物質。如此,藉由添加發炎性細胞激素、或尿毒症毒素,紅血球生成素的產量下降的狀態便為可模擬腎性貧血的狀態。而且,本發明人等發現,藉由在所述狀態下投予ALA類,可抑制紅血球生成素的產量下降。
本實施例中,係使用作為可產生培養條件相異之I~VI群組之紅血球生成素的肝癌細胞的HEP3B細胞(ATCC公司)。首先,作為6群全部所共通的培養步驟,係按12孔板的每1孔(well)培養約30萬個HEP3B細胞。作為培養條件,係使用添加有10%FCS/PC-SM的RPMI1640培養基,於37℃、20%氧氣條件下進行培養。培養24小時後,分作以下I~VI之培養條件,進一步培養24小時。此外,以下作為TNF-α,係使用human recombinant TNF-a(rhTNF-a;Roche)。
於上述I~VI之培養條件下培養24小時後,將培養上清液分離,使用「Human Erythropoietin ELISA kit」(Bender MedSystems公司)來測定培養上清液中所含之紅血球生成素的濃度。
本實施例的結果示於第1圖。此外,本圖中的紅血球生成素濃度的單位係為(mlU/ml)。
添加有TNF-α之區域(III)相較於未投予TNF-α之區域(I),可確認紅血球生成素的濃度減少。又,添加有吲哚酚硫酸之區域(V)相較於未投予吲哚酚硫酸之區域(I),可確認紅血球生成素的濃度減少。
而且,與TNF-α同時添加胺基乙醯丙酸鹽酸鹽之區域(IV)相較於添加有TNF-α之區域(III),顯示出明顯較高的紅血球生成素的濃度值。亦即,可知藉由投予ALA,可明顯抑制紅血球生成素的產量下降。
另外,與吲哚酚硫酸同時添加胺基乙醯丙酸鹽酸鹽之區域(VI)相較於添加有吲哚酚硫酸之區域(V),顯示出明顯較高的紅血球生成素的濃度值。亦即,可知藉由投予ALA,可明顯抑制紅血球生成素的產量下降。
第1圖係表示在培養上清液中所含之紅血球生成素濃度的測定結果的圖表,該培養上清液為以6個相異條件培養可產生紅血球生成素的肝癌細胞(HEP3B細胞)24小時後的培養上清液。
Claims (7)
- 一種式(I)化合物或其鹽用於製備治療及/或預防紅血球生成素的產量下降所引起之貧血的藥物之用途,式(I)為R1-NHCH2COCH2CH2COOR2 (I)於該式中,R1表示氫原子,R2表示氫原子。
- 如申請專利範圍第1項所述之用途,其中,該藥物進一步含有一種或二種以上之含金屬化合物。
- 如申請專利範圍第2項所述之用途,其中,該含金屬化合物為含有選自包含鐵、鎂、及鋅之群組的金屬的化合物。
- 如申請專利範圍第2項所述之用途,其中,該金屬化合物為含有鐵的化合物。
- 如申請專利範圍第1項所述之用途,其中,該紅血球生成素的產量下降係由發炎性細胞激素或尿毒症毒素所引起。
- 如申請專利範圍第1項至第5項中任一項所述之用途,其中,貧血為腎性貧血。
- 如申請專利範圍第6項所述之用途,其中,該化合物或其鹽係藉由促進紅血球生成素的產生來治療及/或預防該腎性貧血。
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