TWI590823B - Cancerous anemia to improve, prevention agent - Google Patents
Cancerous anemia to improve, prevention agent Download PDFInfo
- Publication number
- TWI590823B TWI590823B TW101137452A TW101137452A TWI590823B TW I590823 B TWI590823 B TW I590823B TW 101137452 A TW101137452 A TW 101137452A TW 101137452 A TW101137452 A TW 101137452A TW I590823 B TWI590823 B TW I590823B
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- Prior art keywords
- anemia
- group
- cancerous
- ala
- salt
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Description
本發明係有關一種癌性貧血的改善及/或預防劑，更詳言之，本發明係有關一種包含5-胺基乙醯丙酸(ALA)或者其衍生物或其等之鹽的癌性貧血的改善及/或預防劑。
「癌性貧血」係指癌症患者特有的貧血，周知其為一種迥然相異於一般所知之鐵缺乏性貧血或腎性貧血的貧血。雖程度有別，惟罹患癌症者中高達八成患有癌性貧血，可知隨著癌症的進行，貧血症狀會惡化、或者利用抗癌劑或放射線治療會進一步促進貧血。由於癌性貧血會大幅降低癌症患者的生活品質，以致造成嚴重問題。
被認為會引發癌性貧血者，其中已知有由癌症部位出血引起鐵缺乏性貧血的實例，惟此為極小部分，大部分癌性貧血的原因仍不明。根據大內等人所述，其提出所謂「癌症會分泌促貧血因子並溶解紅血球」之機制並已進行研究，但仍未能斷定促貧血因子為何(例如參照非專利文獻1)。
另一方面，鐵缺乏性貧血大多可由投予鐵劑而緩解，惟鐵劑極少對癌性貧血顯示出效果，且因鐵會促進癌症生長，一般甚少對癌性貧血使用鐵劑。
此外，已知腎性貧血其原因在於可促進分化成紅血球之造血因子，即紅血球生成素的產量降低，紅血球生成素及其衍生物、可刺激紅血球生成素受體的化合物等既經開發且實用化。然而，在一般的癌性貧血患者當中，由於未知有發生紅血球生成素濃度下降之實例，茲認為腎性貧血與癌性貧血係完全不同的原因所致。
儘管如此，仍已進行多數嘗試以對症療法對癌性貧血使用紅血球生成素的試行。然，對於一部分因抗癌劑或放射線治療而惡化的癌性貧血雖可些微看出貧血改善，但因投予群相較於安慰劑群其生存率較低，美國方面的批准被撤銷，在日本亦被核駁。根據試驗結果的解析，已報導投
予群其血栓症或血管系疾病的出現率高，且會促進腫瘤的惡化(例如參照非專利文獻2)。
因此，在癌性貧血的治療方面，作為對症療法係進行輸血，但輸血亦有各種感染症的風險或鐵過剩的問題。更且，由於費用高且血液供給有限，癌性貧血的改善劑及預防劑的開發實屬迫切。
【非專利文獻1】日消外會誌11(11)885-896, 1978
【非專利文獻2】New Current 22(18)7-8, 2011
本發明之課題在於提供一種阻止癌症的進行、可提升癌性貧血患者的生活品質之有用於癌性貧血的改善或預防的貧血改善及/或預防劑。
本發明人等針對貧血整體仔細調查既有的研究或治療劑相關的大量資料，進而對癌性貧血與其他類型的貧血的差異進行探討，達成所謂「造成癌症患者貧血的主要原因並非為造血因子或鐵」之結論。因此，便著手進行除造血因子以外可改善及/或預防癌性貧血的化合物的篩選，而重複進行探討的結果發現，出乎預料的是ALA有癌性貧血改善效果。
在癌症等的診斷、治療領域中，ALA係廣泛使用於光動力學治療(PDT,Photo Dynamic Therapy)、光動力學診斷(PDD,Photo Dynamic Diagnosis)。已知ALA雖為血紅素系化合物的共同前驅物，但在癌細胞中，即使投予ALA亦不會生成血紅素，而是累積作為血紅素系化合物的前驅物的原紫質IX(PPIX)。對累積之PPIX照射光時會產生螢光，由此可進行PDD，而在氧存在下則會產生活性氧，由此可進行PDT。癌性貧血發生與否因患者而異，雖思及ALA與PDT或PDD效果的關係，惟本發明中毋需照光。
如上述，在癌細胞中血紅素並非由ALA生成，惟因血紅素為紅血球的重要構成要素，若為造血細胞癌時，即使添加ALA亦無法進行造血。
然，對於造血細胞癌以外的癌症患者亦可見到癌性貧血，因此難以認為「在癌化造血細胞中，紅血球非由ALA生成而係直接造成癌性貧血的原因」。
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。若為癌性貧血時，因並非生長亢進所致，故難以認為ALA係由相同機制來改善癌性貧血。
如以上所述，從既有資訊並無法推知「ALA對於實癌性貧血確屬有效」。又，考察ALA為何對癌性貧血的改善或預防有效，在無法斷定癌性貧血的原因的此時實屬不易，但大致可認為係與大內先生等人的假說(非專利文獻1參照)中抑制促貧血因子的產量或抑制該因子所致之紅血球的溶血有關，惟對於作用機制的解明仍需進一步研究。更且，亦發現鐵化合物等含金屬化合物若與ALA相輔相成則可增強本發明之效果。在礦物質充足的情況下、或在另外攝取的情況下，單獨投予ALA時毫無任何問題。礦物質當中，以鐵而言對於瘦肉的攝取量少的人有缺乏的傾向(如日本人)。因此，在針對攝取量少的人的實施例中亦同時添加，惟若以貯存鐵充足的人為對象時則無此必要。再者，周知ALA會代謝成紫質，照光時會顯示出PDT(光動力學治療)、PDD(光動力學診斷)活性，惟對於本發明之癌性貧血改善劑，光非為必要者。
本發明人等進一步對於投予方法、與其他成分、其他藥劑的組合、投予量等致力重複進行探討，而確立一種包含ALA之癌性貧血改善劑或預防劑，本發明即臻完成。
即，本發明係有關：(1)一種癌性貧血的改善及/或預防劑，其含有以下式(I)表示之化合物或其鹽：
於式中，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；(2)如上述(1)所述之癌性貧血的改善及/或預防劑，其中，R1及R2為氫原子；(3)更者，如上述(1)或(2)所述之癌性貧血的改善及/或預防劑，其進一步含有一種或二種以上之含金屬化合物；(4)如上述(3)所述之癌性貧血的改善及/或預防劑，其中，含金屬化合物係為含有鐵、鎂、鋅、鎳、釩、銅、鉻、鉬或鈷的化合物；(5)如上述(3)所述之癌性貧血的改善及/或預防劑，其中，含金屬化合物係為含有鐵、鎂或鋅的化合物；(6)如上述(3)所述之癌性貧血的改善及/或預防劑，其中，含金屬化合物係為含有鐵的化合物。
另外，(7)本發明亦有關一種癌性貧血的改善及/或預防方法，其特徵在於投予以式(I)表示之化合物或其鹽、或者以式(I)表示之化合物或其鹽及含金屬化合物。作為其他形態，本發明係有關一種供使用於癌性貧血的改善方法及/或預防方法之以式(I)表示之化合物或其鹽、或者以式(I)表示之化合物或其鹽及含金屬化合物。
根據本發明之癌性貧血的改善及/或預防劑，可獲得優良癌性貧血改善/預防效果，且癌症生長促進等副作用較少或幾無該副作用，能夠大幅改善癌症患者的生活品質。
本發明中「癌性貧血」係指癌症患者所發生的所有的貧血，伴隨消化器官癌等的出血而生之貧血、抗癌劑或放射線治療的副作用所致之貧血亦包含在內，惟其多數為以癌症症狀的一部分的形式發生並隨著進行而惡化的癌症患者特異性貧血，在實際的臨床治療中，亦忌諱投予一般其他貧血症狀所使用的紅血球生成素。癌性貧血與其他貧血不同的是，不僅指紅血球的減少，亦指由多功能性造血幹細胞分化之所有正常血液細胞的降低，白血球、淋巴球、嗜中性白血球、血小板等的降低減少亦包含在內。
可用作本發明之癌性貧血的改善及/或預防劑的有效成分的化合物可例示為以式(I)表示之化合物或其鹽(以下有將此等總稱為「ALA類」)。亦稱為δ-胺基乙醯丙酸的ALA係式(I)之R1及R2皆為氫原子的情況，乃為胺基酸的1種。作為ALA衍生物，可例舉式(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ALA以外的化合物。
作為式(I)中的醯基，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)中的烷基，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)中的環烷基，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)中的芳基，可例舉苯基、萘基、蒽基、菲基等碳數6~14之芳基。
作為式(I)中的芳烷基，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。
作為上述ALA衍生物，較佳為R1為甲醯基、乙醯基、丙醯基、丁醯基等的化合物、或上述R2為甲基、乙基、丙基、丁基、戊基等的化合物，較佳可例舉上述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、丁醯基與乙基之組合的化合物等。
ALA類只要在生物體內以式(I)之ALA或其衍生物之狀態作為有效成分而發揮作用即可，依據投予形態，只要以用於提升溶解性的各種鹽、酯或者可由生物體內的酵素分解的前驅藥(prodrug，前驅物)的形式投予即可。舉例而言，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、鎂鹽、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，較佳為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，ALA鹽酸鹽、ALA磷酸鹽可例示為特佳者。
上述ALA類可透過化學合成、利用微生物生產、利用酵素生產之任一周知方法來製造。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種以上來使用其任一種。
本發明之癌性貧血改善及/或預防劑係以在不發生過多症的範圍，進一步含有含金屬為佳；作為所述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。
以上述鐵化合物而言，可為有機鹽或無機鹽，作為無機鹽可例舉氯化
鐵、三氧化二鐵、硫酸鐵、焦磷酸亞鐵，作為有機鹽則可例舉屬羧酸鹽，例如羥基羧酸鹽的檸檬酸亞鐵、檸檬酸鐵鈉、檸檬酸亞鐵鈉、檸檬酸鐵銨等檸檬酸鹽、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、二羧甲基麩胺酸鐵鈉、二羧甲基麩胺酸鐵銨、富馬酸亞鐵、乙酸鐵、草酸鐵、琥珀酸亞鐵、琥珀酸檸檬酸鐵鈉等有機酸鹽、三伸乙四胺鐵、乳鐵蛋白鐵、運鐵蛋白鐵、鐵葉綠酸鈉、鐵蛋白鐵、含糖氧化鐵、硫酸三甘胺酸鐵。
作為上述鎂化合物，可例舉檸檬酸鎂、苯甲酸鎂、乙酸鎂、氧化鎂、氯化鎂、氫氧化鎂、碳酸鎂、硫酸鎂、矽酸鎂、硝酸鎂、二伸乙三胺五乙酸鎂二胺、乙二胺四乙酸鎂二鈉、鎂原紫質。
作為上述鋅化合物，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的投予量，以莫耳比計只要為0~100倍即可，較佳為0.01倍~10倍，更佳為0.1倍~8倍。
本發明之癌性貧血的改善及/或預防劑所含有的ALA類與含金屬化合物，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；於此，「同時」不僅指「於同時刻進行」，亦指「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，較佳為相乘效果，亦於兩者間未隔開相當間隔之下進行」之意。
作為本發明之癌性貧血的改善及/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。
作為本發明之癌性貧血的改善及/或預防劑的劑型，可根據上述投予路徑來適當決定，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。
為調製本發明之癌性貧血的改善及/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癌性貧血的改善及/或預防劑時，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。
作為本發明之癌性貧血的改善劑的投予量、頻率、時間，係因癌性貧血患者或欲預防癌性貧血者的年齡、體重、症狀等而異，惟作為ALA類的投予量，以ALA莫耳換算計可例舉成人每人0.01mmol~25mmol/日，較佳為0.025mmol~7.5mmol/日，更佳為0.075mmol~5.5mmol/日，再更佳為0.2mmol~2mmol/日，尤其在作為預防劑使用時，係以持續攝取低容量為佳。作為投予頻率，可例示一日一次~多次之投予或使用點滴等的連續投予。就投予期間而言，在作為改善劑使用時，可基於紅血球數、血紅素、白血球數、血小板等表示貧血狀態的指標，利用該技術領域之藥理學者或臨床醫師已知的方法來決定，而在作為預防劑使用時，則可基於紅血球數、血紅素、白血球數、血小板等表示貧血狀態的指標，一面觀察勿使癌性貧血發生惡化，一面利用該技術領域之藥理學者或臨床醫師已知的方法來決定。
本發明之癌性貧血的改善及/或預防劑還可與其他既有的貧血的改善及/或預防劑組合使用。作為既有的貧血改善劑或貧血預防劑，可例舉Ferromia、Ferrum、Fero-Gradumet、Bultal、Slow-Fe、Tetucur等鐵劑；維生素B12、葉酸維生素、維生素B6等維生素劑；人類紅血球生成素(EPO)或EPO的一部分序列經改變且加成有糖鏈的EPO衍生物等造血因子系等的藥劑。茲認為此等藥劑與ALA對癌性貧血的改善及預防效果相關之機制於根本上各自相異，因而可望有相加效果，且視情況而定，有相乘效果。此外，此等既有的貧血藥在單獨使用時，會有無助於癌性貧血的改善或促發癌症的可能性，惟透過與本發明組合，可望有推遲癌症進行
的效果。
以下根據實施例對本發明更具體進行說明，惟本發明之技術範圍並未限定於此等例示。
針對罹患硬性胃癌(scirrhous stomach cancer)的女性，將(1)罹癌前的2008年2月16日(於該時間點為29歲)；(2)2010年7月20日；判斷罹癌的2010年8月19日以後，按每日開始經口攝取100mg胺基乙醯丙酸磷酸鹽與114.7mg檸檬酸亞鐵納後的(3)2010月9月20日；(4)2010年10月12日；(5)2011年1月13日；及(6)2011年7月1日的紅血球數、血紅素值、白血球數示於以下表1。
由上表1可知，罹癌前屬正常值的紅血球數、血紅素值及白血球數之貧血相關的血液指標因罹癌均減少，係發生癌性貧血，而透過投予胺基乙醯丙酸磷酸鹽與檸檬酸亞鐵納，恢復情況極佳。患者在得知罹癌後接受抗癌劑治療(實施TS1+Docetaxel療法；Docetaxel係用點滴，於第1日投予54mg/day，TS1則用內服，以100mg/day投予14日，再停藥7日；1療程係花費21日進行)，在一般情況下茲認為因抗癌劑的副作用會使貧血惡化，而透過攝取ALA與鐵化合物，貧血已消除，此種癌性貧血的治癒效果極為驚人。
對因進行期的大腸癌引起腸阻塞的女性，於2009年8月19日(於該時間點為61歲)進行緊急手術。根據手術時所見，係存有拳頭大的大腸癌，即使摘出腫瘤、消除腸阻塞，但仍可見多數腹膜腔轉移，經診斷為剩餘壽命3個月。手術後，作為抗癌劑治療，除FOLFOX(5-FU、
Isovorin、Elplat此3劑併用)及FOLFIRI(5-FU、Isovorin、Campto此3劑併用)外亦併用Avastin等分子標靶藥物。其後，與此抗癌劑治療同時進行，按每日經口攝取50mg胺基乙醯丙酸磷酸鹽與57.4mg檸檬酸亞鐵鈉。其結果，手術後1年可以持續進行抗癌劑治療。1年後，雖因副作用而已放棄抗癌劑的投予，但仍持續經口攝取50mg胺基乙醯丙酸磷酸鹽與57.4mg檸檬酸亞鐵鈉，而大幅超過所宣告的剩餘壽命3個月，在1年半期間，能夠以副作用經改善的狀態生存。
(i)即將手術前的2009年8月19日、及(ii)開始攝取胺基乙醯丙酸磷酸鹽與檸檬酸亞鐵鈉經過約1年5個月後的2011年1月28日的紅血球數、血紅素值、白血球數示於以下表2。
由上表2可理解，於即將手術前雖可看出因癌性貧血導致紅血球與血紅素減少、及炎症導致白血球增加，但在(ii)之攝取開始起約1年5個月後的時間點，透過投予胺基乙醯丙酸磷酸鹽與檸檬酸亞鐵鈉，紅血球數與血紅素增加，貧血獲改善；另一方面，白血球數平穩地回復至正常值。如考量到抗癌劑所產生的強烈副作用出現，則認為亦會對造血系統造成強烈的損傷，但所謂「貧血獲改善」的結果極為驚人，縱然罹患腹膜腔轉移，在大幅超過醫師所宣告的剩餘壽命3個月的1年半後仍可過著生活品質經改善的生活。
某83歲女性既罹患慢性淋巴性白血病，而接受使用抗癌劑Rituxan的治療。治療後，按每日經口攝取150mg胺基乙醯丙酸磷酸鹽與172mg檸檬酸亞鐵納。治療前後的白血球數、紅血球數、血紅素、血小板數示於以下表3。
由上表3可知，白血球數由2010年1月13日的檢查值起呈現上升而已患有白血病，同時可知紅血球數、血紅素、血小板下降，已發生癌性貧血。自2010年11月15日起開始進行Rituxan®的抗癌劑治療，於抗癌劑治療的1循環結束後的2010年11月22日早就觀察到白血球數下降，同時紅血球數、血紅素、血小板數亦減少，茲認為作為副作用的貧血持續惡化。
於2011年3月16日結束抗癌劑治療，雖無結束時間點的檢查值，但可料知貧血進一步惡化。在由該時間點起按每日開始經口攝取胺基乙醯丙酸磷酸鹽與檸檬酸亞鐵納經過約2個月後的5月20日的檢查之後，可看出紅血球、血紅素、血小板均大幅回升，血小板數亦回升至正常值。
特別值得一提的是，就白血球數而言，在白血病的治療中以Rituxan®抑制白血球數時，白血球數通常會下降，但仍經常保持原狀未回升而造成免疫方面的障礙；另一方面，若減少抗癌劑投予量則再復發的可能性增高。由表3可明瞭，其歷經所謂「使白血球數充分下降且隨後使其回升」的極佳過程，惟此種實例在臨床上幾乎不存在，所述結果可謂投予ALA與鐵化合物所致之效果。一般而言，「貧血」係指缺乏紅血球或血紅素之意，而白血球及紅血球均不外乎是由造血幹細胞分化而成的細胞，如此教示「ALA的癌性貧血改善效果乃前所未聞之效果」。
本發明之癌性貧血的改善及/或預防劑可於醫療領域中有利地利用。
Claims (1)
- 一種式(1)化合物、其鹽或酯類以及含有一種或二種以上之含金屬化合物用於製備改善及/或預防癌性貧血的藥物之用途，
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| EP2767280B1 (en) | 2024-05-22 |
| EP2767280A1 (en) | 2014-08-20 |
| WO2013054770A1 (ja) | 2013-04-18 |
| US20140288173A1 (en) | 2014-09-25 |
| US9539225B2 (en) | 2017-01-10 |
| JPWO2013054770A1 (ja) | 2015-03-30 |
| JP5881722B2 (ja) | 2016-03-09 |
| JP2016033160A (ja) | 2016-03-10 |
| CN103974702A (zh) | 2014-08-06 |
| TW201320995A (zh) | 2013-06-01 |
| HK1200323A1 (zh) | 2015-08-07 |
| EP2767280A4 (en) | 2015-04-08 |
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