TWI605815B - 用於製備包含阿米福丁與胺基酸之腎保護劑的組成物及方法 - Google Patents
用於製備包含阿米福丁與胺基酸之腎保護劑的組成物及方法 Download PDFInfo
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- TWI605815B TWI605815B TW103120850A TW103120850A TWI605815B TW I605815 B TWI605815 B TW I605815B TW 103120850 A TW103120850 A TW 103120850A TW 103120850 A TW103120850 A TW 103120850A TW I605815 B TWI605815 B TW I605815B
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Description
本發明係相關於包含阿米福丁(Amifostine)與至少一胺基酸,具有或不具有一或多種醫藥活性化合物之組成物。本發明之組成物稱之為AminoMedixTM,並可用於降低經放射線標記與非放射線標記之治療與診斷化合物之腎毒性作用。本發明之另一觀點為相關於一種製備AminoMedixTM組成物之方法,該組成物包含阿米福丁(Amifostine)與至少一胺基酸,具有或不具有一或多種醫藥活性化合物。該組成物可與用於靜脈內注射之醫藥上可接受鹽類一同製備。
由於其腎小管再吸收與高遲滯作用,腎臟為胜肽受器放射核種療法(PRRT)之劑量限制器官。腎毒性為使用經放射標記之胜肽、蛋白質、抗體與非放射線標記之化合物、化療、胺基苷類、抗體與顯影劑之副作用(Pool E,2010;Melis M,2005)。
胺基苷類抗體與經放射線標記之生長素抑制因子類似物會堆積在腎臟中,經由巨蛋白(megalin)與肘臀蛋白(cubulin)受器-媒介之胞吞作用。與巨蛋白(megalin)-標靶配位體如帶正電胺基酸之共投藥,可降低這些腎毒性化合物於腎近端小管細胞中之堆積(Nagai,2010;Moestrup SK,1996;Hammond PJ,1993;Baron R,2004;MelisM.,2012.;Vegt E.2010)。
阿米福丁(Amifostine)(亦已知為WR-2721)已顯示出可於進行體外放射治療之病患體內,作為腎放射線保護試劑。阿米福丁(Amifostine)為一種前藥,可藉由鹼性去磷酸酶進行酵素性去磷酸化,形成活性代謝物,WR-1065。與癌細胞相較,此過程在正常細胞中會以較高速率進行,由於健康組織中會表現出較高之鹼性去磷酸酶(Copp RR,2013;Andreasssen CN,2003;Santini V,2001;Culy CR,2001)。
例如,歐洲專利申請案號EP1368038(以WO2002062350A1為基礎)描述投予阿米福丁(Amifostine)及/或相關之硫代磷酸酯衍生物作為細胞保護化合物,在傳統體外放射治療中。
阿米福丁(Amifostine)以靜脈注射投藥,單一劑量為200mg/m2,已證實可於頭頸部癌症之放射治療時,作為放射線保護劑(Lindegaard,2003)。阿米福丁(Amifostine)為唯一證實在急性放射線誘發食道炎病患中,具有放射線保護效果(Giraud P.,2012)。
帶正電胺基酸已顯示可降低經放射線標記之生長抑制素類似物之腎堆積,並保護腎臟不受放射線傷害。在大鼠中,L-離胺酸(400mg/kg)與111In-DTPA-阿曲肽(octretide)之靜脈內共注射已顯示出可產生40%之腎保護作用(DeJong,1996)。
D-離胺酸與L-離胺酸之靜脈內注射,已顯示出可產生大於50%之腎保護作用,對抗111In-DTPA-阿曲肽(octretide)腎堆積(Betrand,1997)。相對於L-離胺酸,D-離胺酸對於此追蹤劑在生長抑制素受器(SSTR)-陽性器官如胰臟與腎上腺之滯留現象並無作用。因此,D-離胺酸較佳可用於SSTR-陽性神經內分泌腫瘤之PRRT。
在歐洲,已於使用177Lu與Y90-l標記生長抑制素類似物之NET病患之PRRT期間,使用140g離胺酸與29g精胺酸(Aminosyn II 7%,Abbott Lab.)共輸液。Lys/Arg之組合可降低這些放射性胜肽之腎吸收,並降低腎放射性暴露達35%(Breeman,1996;Valkema,2005)。胺基酸溶液(2L)以靜脈內輸液投藥至經Y90-OctreoTher(Bushnell,2004)處理超過4小時之病患,可產生腎保護作用達32%。
Aminsteril N-hepa 8%(10.32g離胺酸與16.08g精胺酸)可降低病患中111In-DTPA-阿曲肽(octretide)之腎堆積達21%±14%。在同一研究中,投以25g離胺酸可保護腎臟17%±9%,而輸液75g離胺酸顯示出在腎保護上具有較高之效果,達44%±11%(Rolleman 2002)。
25g離胺酸與25g精胺酸之組合,在使用111In-噴
曲肽(pentetreotide)治療期間,可降低此放射性胜肽之腎濃度,產生腎保護作用達至多33±23%(Rolleman,2002)。
美國專利申請案號2009/0318330 A1(依據PCT/EP00/06917),描述離胺酸(聚-離胺酸)與佳樂施(Gelofusine)組合之放射性保護作用。當投以177Lu-DOTAo-Tyr3]-阿曲肽(octretide)於雄性Lewis大鼠中時,佳樂施(Gelofusine)(20mg)與離胺酸(100mg)之組合可提供腎保護達65±11%。佳樂施(Gelofusine)與離胺酸之組合對於腎臟明顯具有較高之放射性保護作用,與單獨使用佳樂施(Gelofusine)(20mg)或離胺酸(100mg)相較。
投以離胺酸(25g)、精胺酸(25g)與佳樂施(Gelofusine)至經高劑量177Lu-DOTAo-Tyr3]-阿曲肽(octretide)治療之病患,可額外產生25%之保護作用,與使用Lys與Arg但無佳樂施(Gelofusine)(W02007137871A1)之組成物相較。
這些先前技藝方法係提供可降低PRRT之腎傷害之組成物與方法,但目前仍需要更有效之組成物與方法。
本發明之一觀點係相關於一種新穎之組成物,包含阿米福丁(Amifostine)與至少一胺基酸或其寡合物。本發明之組成物可更包含一或多種醫藥活性化合物。該醫藥活性化合物可包括,但不侷限於維生素B12、肉鹼、L-組胺酸、D-組胺酸、丙磺舒(Probenecid)、白蛋白或其蛋白質分解產
物、球蛋白或其蛋白質分解產物、細胞色素c之胜肽片段,或肌動蛋白-調節蛋白之胜肽片段。這些化合物可在胜肽受器放射核種治療(PRRT)期間,使用作為腎放射線保護試劑。
依據本發明之某些實施例,該組成物包含阿米福丁(Amifostine),其量為約2mg至約180mg每公斤體重,以及至少一胺基酸或其寡合物,其量為約150mg至約1,000mg每公斤體重。
本發明之另一觀點係相關於在進行放射線標記及/或非放射線標記化合物進行造影及/或治療時,使用本發明組成物,其包含阿米福丁(Amifostine)與至少一胺基酸,具有或不具一或多種醫藥活性化合物。經放射線標記之試劑包含放射性核種,選自於177Lu、111In、90Y、117mSn、45Ti、59Fe、60Cu、61Cu、62Cu、64Cu、67Ga、68Ga、89Sr、99mTc、149Pm、153Gd、153Sm、186Re、188Re、211At、212Bi、225Ac、125I、123I、32P,或223Ra。經放射線標記之試劑可為胜肽、蛋白質、抗體、碳水化合物、醣胜肽、尿素衍生物、核苷酸、核苷、雜環化合物、植物萃取物、奈米顆粒、聚合物、奈米材料,或包含植物衍生化合物之組成物。
依據本發明之某些實施例,該治療為胜肽受器標靶治療(PRRT),使用經放射線標記之促效劑或拮抗劑。促效劑或拮抗劑之標靶為生長抑制素-受器,其中該促效劑或拮抗劑為DOTA-、DTPA-或NOTA-基礎衍生物。DOTA-、
DTPA-或NOTA-基礎衍生物可選自DOTATATE、DOTATOC、DOTANOC、DOTA-BASS或DOTA-BIM。
本發明之其他觀點將依下列圖示與詳細說明而更臻清楚。
圖1顯示投予小鼠阿米福丁(Amifostine)與至少一胺基酸之組成物之流程圖。組成物之第一次靜脈內注射可安排在68Ga-DOTATATE投藥前30分鐘,而第二次注射則分別於放射性胜肽投藥後15與60分鐘進行。
圖2顯示於經市售Clinisol®及佳樂施(Gelofusine)與68Ga-DOTATATE(40uCi)共投藥治療之小鼠中,離胺酸-精胺酸(分別為12.4mg/ml與12.5mg/ml)之腎保護特性。
圖3顯示68Ga-DOTATATE之腎吸收,以及離胺酸-精胺酸(分別為12.5mg/ml與12.5mg/ml)與市售Clinisol®與佳樂施(Gelofusine)之腎保護特性結果。投予離胺酸-精胺酸組成物(分別為12.5mg/ml與12.5mg/ml)可保護腎臟達36.45%。Clinisol®與佳樂施(Gelofusine)可降低經放射線標記之胜肽堆積,並保護腎臟分別達32.12%與57.7%。
圖4顯示阿米福丁(Amifostine)與胺基酸(離胺酸與精胺酸)與68Ga-DOTATATE共投藥之腎保護特性。
圖5顯示68Ga-DOTATATE在腎臟中之滯留時間,以及阿米福丁(Amifostine)與胺基酸(離胺酸與精胺酸)之腎保護特性。在離胺酸-精胺酸組成物存在下(25mg/ml與25mg/ml),腎保護作用達57.83%,而在離胺酸-精胺酸(25
mg/ml與25mg/ml)與阿米福丁(Amifostine)(0.63mg/ml)存在下達67.62%。
圖6顯示阿米福丁(Amifostine)與至少一胺基酸(離胺酸及/或精胺酸),具有或不具其他醫藥活性化合物,與68Ga-DOTATATE共投藥之腎臟放射線保護特性。
圖7顯示68Ga-DOTATATE在腎臟中之滯留時間,以及阿米福丁(Amifostine)與至少一胺基酸(離胺酸及/或精胺酸),具有或不具醫藥活性化合物之放射線保護特性。阿米福丁(Amifostine)(0.63mg/ml)、離胺酸(25mg/ml)與L-組胺酸(25mg/ml)之共投藥,可產生腎臟放射線保護作用達56.3%。
圖8顯示在阿米福丁(Amifostine)與至少一胺基酸與維生素B12存在下,與68Ga-DOTATATE共投藥之腎保護百分比。
圖9顯示68Ga-DOTATATE在腎臟中之滯留時間,以及阿米福丁(Amifostine)與至少一胺基酸與維生素B12之腎保護特性。阿米福丁(Amifostine)(0.63mg/ml)、離胺酸(25mg/ml)、L-精胺酸(25mg/ml)與維生素B12之投藥,可產生腎保護作用達42.64%,而僅使用阿米福丁(Amifostine)則只有12.24%。
圖10顯示當與68Ga-DOTATATE共投藥時,阿米福丁(Amifostine)與至少一胺基酸之腎放射線保護特性。
圖11顯示68Ga-DOTATATE在腎臟之滯留時間,以及阿米福丁(Amifostine)與至少一胺基酸之腎放射線保護特
性。
本發明實施例係相關於用於降低PRRT之腎放射線傷害之組成物與方法。這些組成物可稱之為AminoMedixTM,並包含阿米福丁(Amifostine)與至少一胺基酸及/或其寡合物。此外,這些組成物可更包含一或多種醫藥上可接受之賦形劑、載體、鹽類、稀釋劑或其組合。本發明組成物可製備為乾燥套組製劑,用於藥局或cGMP設施。
如上所述,阿米福丁(Amifostine)已顯示在傳統體外放射治療中,具有細胞保護作用。然而,阿米福丁(Amifostine)並未顯示出可有效保護組織或器官,對抗投至病患之治療或診斷試劑(即非體外放射線)之傷害。
AminoMedixTM組成物中之胺基酸可為天然性或非天然性胺基酸,可選自於帶正電胺基酸,如組胺酸、離胺酸、精胺酸、鳥胺酸,或其組合。這些胺基酸可包括L-胺基酸、D-胺基,或L-與D-胺基酸之混合物AminoMedixTM組成物中之寡合物可包含這些帶正電之胺基酸。該寡合物可為同元寡合物(即包含同一種形式之胺基酸,如聚-組胺酸、聚-離胺酸,或聚-精胺酸)。此外,該寡合物可為雜寡合物(即包含二或多種不同形式之胺基酸),其可包含所有帶正電之胺基酸(如包含組胺酸、離胺酸與精胺酸之混合物),或可包含帶正電胺基酸與非帶正電胺基酸之混合物。
該AminoMedixTM組成物可使用作為腎保護試劑,尤其是使用經放射線標記之化合物如經放射線標記之胜肽,及/或非-經放射線標記之化合物,進行造影及/或治療時。這些組成物可與或不與一或多種其他活性化合物(如其他保護性化合物)一同使用。
該AminoMedixTM組成物可包含醫藥活性化合物,如維生素B12、肉鹼、L-組胺酸、D-組胺酸、丙磺舒(Probenecid)、白蛋白或其蛋白質分解產物、球蛋白或其蛋白質分解產物、細胞色素c之胜肽片段,或肌動蛋白-調節蛋白之胜肽片段。使用於此之醫藥活性化合物係指一化合物,其可進一步增進阿米福丁(Amifostine)與至少一胺基酸之腎放射線保護作用。該AminoMedixTM組成物可在使用經放射性同位素標記之化合物造影及/或治療時,保護腎臟。下列為用於此目的之不同放射核種之非限制性範例,如177Lu、111In、90Y、117mSn、45Ti、59Fe、60Cu、61Cu、62Cu、64Cu、67Ga、68Ga、89Sr、99mTc、149Pm、153Gd、153Sm、186Re、188Re、211At、212Bi、225Ac、125I、123I、32P、223Ra。
依據本發明實施例,該治療可使用抗生素(如但不侷限於胺基苷類或雙性黴素B),以及其他非-經放射線標記之腎毒性藥物。該治療可為使用化療試劑之化學療法,如但不侷限於,順鉑與其衍生物。
依據本發明之實施例,該造影係涉及使用放射性顯影劑,或釓-系顯影劑。該造影亦可涉及使用多模態化合
物,如但不侷限於經放射線標記/光學探針。
該AminoMedixTM組成物可於使用化合物如,但不侷限於,胜肽、蛋白質、抗體、碳水化合物、醣胜肽、尿素衍生物、核苷酸、核苷、雜環化合物、植物萃取物、奈米顆粒、聚合物、奈米材料,或包含植物衍生化合物之組成物,進行造影及/或治療時保護腎臟。
該AminoMedixTM組成物可在使用經放射線標記之促效劑或拮抗劑,進行胜肽受器放射線核種治療(PRRT)時,保護腎臟。下列為標靶為生長抑制素-受器之不同促效劑與拮抗劑之非限制性範例,包括其DOTA-與DTPA-、NOTA-系衍生物如DOTATATE、DOTATOC、DOTANOC、DOTA-BASS、DOTA-BIM。
該AminoMedixTM組成物可用於在使用抗生素(如但不侷限於胺基苷類、雙性黴素B)與其他非-經放射線標記之腎毒性藥物治療時,保護腎臟。該AminoMedixTM組成物可用於在進行化學療法如,但不侷限於,順鉑或其衍生物時,保護腎臟。
該AminoMedixTM組成物可在使用放射性顯影劑,或釓系顯影劑造影時,保護腎臟。該AminoMedixTM組成物可在使用多模態化合物如,但不侷限於,經放射線標記/光學探針進行造影時,保護腎臟。
該AminoMedixTM組成物中之各成分可以任一適當之量或濃度使用。熟習此技術領域者應瞭解到適當量係取決於病患以及所使用之治療或診斷試劑。適當量之最佳
化涉及常規技術,且此技術領域者應可直接找出適當量,不需經由實驗。例如,AminoMedixTM組成物中之阿米福丁(Amifostine)濃度為約10mg至約500mg每公斤體重,較佳為約18mg至約180mg每公斤體重。AminoMedixTM組成物中之至少一胺基酸之使用範圍為約50mg至約1g每公斤體重,較佳為約150mg至約700mg每公斤體重。該AminoMedixTM組成物可與或不與一或多種活性化合物一同使用,其濃度為約18mg至約180mg每公斤體重。例如,該AminoMedixTM組成物可包含阿米福丁(Amifostine),使用濃度為18mg至約500mg每公斤體重,而精胺酸之使用量範圍為150mg至約800mg每公斤體重,而離胺酸之使用量為150mg至約800mg,具有或不具活性化合物,其濃度為18mg至約180mg每公斤體重。
該AminoMedixTM組成物可在投以此類治療或診斷化合物之前,使用作為保護試劑,或可與一或多種其他治療或診斷化合物共投藥之前,作為保護試劑。
本發明實施例可以下列範例進行解說。這些範例僅用於說明,不應用於限制本發明範疇。
係提供下列範例說明包含阿米福丁(Amifostine)與至少一胺基酸,具有或不具有一或多種治療或診斷化合物之AminoMedixTM組成物之效果。這些組成物可使用作為腎保護試劑。
離胺酸-精胺酸(分別為12.4mg/ml以及12.5mg/ml)與市售Clinisol®及佳樂施(Gelofusine),與68Ga-DOTATATE(40uCi)之共注射之腎保護作用,係依據小鼠之生物分佈試驗決定。離胺酸-精胺酸、Clinisol®與佳樂施(Gelofusine)溶液係使用作為陽性控制組,以決定本發明實施例之組成物的效果。
小鼠(n=5/組,雄性6-8週大)在投以68Ga-DOTATATE前30分鐘,係以各溶液(200ul)進行尾巴靜脈內注射,之後於注射後15分鐘與1小時再次注射。施加程序範例係示於圖1。
之後小鼠以CO2窒息法犧牲,收集腎臟,以測定放射線吸收量,其之後與總注射放射活性劑量相較。
如圖2與3所示,投以離胺酸-精胺酸組成物(分別為12.5mg/ml與12.5mg/ml),係提供腎放射線保護作用達36.45%。Clinisol®與佳樂施(Gelofusine)注射,可保護腎臟分別達32.12%與57.7%。
係測量AminoMedixTM組成物對於68Ga-DOTATATE腎吸收之降低量。該AminoMedixTM組成物包含阿米福丁(Amifostine)與至少一胺基酸。這些組成物可與或不與一或多種治療或診斷化合物一同使用。
係測試下列AminoMedixTM組成物:˙離胺酸:精胺酸:阿米福丁(Amifostine)(7.5mg/ml:17mg/ml:0.63mg/ml);
˙離胺酸:精胺酸:阿米福丁(Amifostine)(7.5mg/ml:12.5mg/ml:0.63mg/ml);˙離胺酸:精胺酸:阿米福丁(Amifostine)(12.5mg/ml:12.5mg/ml:0.63mg/ml);˙離胺酸:精胺酸:阿米福丁(Amifostine)(25mg/ml:25mg/ml:0.63mg/ml);包含阿米福丁(Amifostine)與至少一胺基酸,具有或不具有一或多種治療或診斷化合物之AminoMedixTM組成物,可製備於醫藥上可接受之稀釋劑中,如但不侷限於,水、生理食鹽水與林格氏液,以及PBS,而溶液之最終pH值可調整至範圍約5.6-7.8。
小鼠(n=5/組,雄性6-8週大)在投以68Ga-DOTATATE前30分鐘,係以各溶液進行尾巴靜脈內注射(200ul),之後於注射後15分鐘與1小時再次注射。如範例1所述。
如圖4與5所示,以包含離胺酸:精胺酸:阿米福丁(Amifostine)(25mg/ml:25mg/ml:0.63mg/ml)之AminoMedixTM組成物進行共注射,具有最高之腎放射線保護作用,高達67.62%,而僅使用離胺酸:精胺酸(25mg/ml:25mg/ml)則具有保護作用57.83%。添加濃度為0.63mg/ml之阿米福丁(Amifostine)至離胺酸與精胺酸之組成物中,可具有明顯之助益。亦即,阿米福丁(Amifostine)可進一步增強離胺酸與精胺酸之保護作用。
與其他物質相較,離胺酸:精胺酸:阿米福丁
(Amifostine)(12.5mg/ml:12.5mg/ml:0.63mg/ml)之AminoMedixTM組成物可提供更有效之腎保護作用,對抗放射性胜肽。使用此組成物之腎保護作用為50.13%,而僅使用離胺酸:精胺酸(12.5mg/ml:12.5mg/ml)(亦即不使用阿米福丁(Amifostine))則只有36.45%。
因此,添加阿米福丁(Amifostine)至精胺酸與離胺酸之組成物中,可具有降低放射性胜肽腎吸收之協同作用,因而增進各成分之放射線保護特性。
此範例測試阿米福丁(Amifostine)與至少一胺基酸,具有或不具一或多種治療或診斷化合物,之腎保護作用。該組成物與68Ga-DOTATATE共投藥。
下列阿米福丁(Amifostine)與至少一胺基酸,具有或不具一或多種治療或診斷化合物,之組成物係經測試:˙阿米福丁(Amifostine)(15mg/ml);˙阿米福丁(Amifostine)(0.63mg/ml):離胺酸(25mg/ml):L-組胺酸(25mg/ml);˙丙磺舒(Probenecid)(10mg/ml);以及˙阿米福丁(Amifostine)(25mg/ml):離胺酸(25mg/ml):丙磺舒(Probenecid)(10mg/ml)。
小鼠(n=5/組,雄性6-8週大)在投以68Ga-DOTATATE前30分鐘,係以各溶液進行尾巴靜脈內注射(200ul),之後於注射後15分鐘與1小時再次注射。如範例
1所述。
如圖6與7所示,僅使用劑量為0.63mg/ml之阿米福丁(Amifostine)作為腎放射線保護試劑,僅可提供腎保護作用12.2%。阿米福丁(Amifostine)在腎臟之放射線保護作用上,若於至少一胺基酸(離胺酸、組胺酸、精胺酸)存在下,以及醫藥活性化合物(丙磺舒(Probenecid))存在下會更顯著。例如,由阿米福丁(Amifostine)(0.63mg/ml):離胺酸(25mg/ml)與L-組胺酸(25mg/ml)組成之AminoMedixTM組成物共投藥,可保護腎臟達56.3%。
此範例測試阿米福丁(Amifostine)與至少一胺基酸及維生素B12之腎保護作用。該組成物係與68Ga-DOTATATE共投藥。
係測試下列阿米福丁(Amifostine)與至少一胺基酸,具有或不具活性化合物(維生素B12)之組成物:
˙阿米福丁(Amifostine)(0.63mg/ml);
˙阿米福丁(Amifostine)(0.63mg/ml):離胺酸(25mg/ml):L-精胺酸(25mg/ml):維生素B12(1mg/ml)
˙阿米福丁(Amifostine)(0.63mg/ml):離胺酸(12.5mg/ml):L-精胺酸(12.5mg/ml):維生素B12(1mg/ml)
小鼠(n=5/組,雄性6-8週大)在投以68Ga-DOTATATE前30分鐘,係以各溶液進行尾巴靜脈內注射(200ul),之後於注射後15分鐘與1小時再次注射。如範例
1所述。
如圖8與9所示,僅使用劑量為0.63mg/ml之阿米福丁(Amifostine)作為腎放射線保護試劑,僅可提供腎保護作用12.24%。阿米福丁(Amifostine)在腎臟之放射線保護作用上,若於至少一胺基酸(離胺酸、精胺酸)存在下,以及醫藥活性化合物(維生素B12)存在下會更顯著。例如,由阿米福丁(Amifostine)(0.63mg/ml):離胺酸(25mg/ml)與L-組胺酸(25mg/ml):維生素B12(1mg/ml)組成之AminoMedixTM組成物共投藥,可保護腎臟達42.49%。
本範例測試Clinisol®或阿米福丁(Amifostine)與至少一胺基酸之腎保護作用。該組成物係與68Ga-DOTATATE共投藥。
係測試下列Clinisol®或阿米福丁(Amifostine)與至少一胺基酸之組成物:
˙阿米福丁(Amifostine)(0.6mg/ml)
˙Lys(0.21mg/ml):Arg(2.5mg/ml):Amif(0.63mg/ml)
˙Lys(0.21mg/ml):Arg(2.5mg/ml):Amif(1mg/ml)
˙Clinisol®
˙Lys(12.5mg/ml):Arg(12.5mg/ml)
˙Lys(2.5mg/ml):Arg(2.5mg/ml):Ami(0.63)
˙Lys(1.05mg/ml):Arg(12.5mg/ml):Amif(0.63mg/ml)
˙Lys(2.1mg/ml):Arg(25mg/ml):Ami(0.63mg/ml)
小鼠(n=5/組,雄性6-8週大)在投以
68Ga-DOTATATE前30分鐘,係以各溶液進行尾巴靜脈內注射(200ul),之後於注射後15分鐘與1小時再次注射。如範例1所述。
如圖10與11所示,Clinisol僅提供腎保護作用31.12%。由阿米福丁(Amifostine)(0.63mg/ml):L-離胺酸(2.1mg/ml)與L-精胺酸(25mg/ml)組成之AminoMedixTM組成物共投藥,可保護腎臟達52.22%。
儘管本發明已以有限之範例進行詳細描述,此技術領域者應瞭解到,亦可進行其他修飾或變化,而不脫離本發明範疇。因此,該保護範疇應只受到後附申請專利範圍與其等效物限制。
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Claims (16)
- 一種組成物,其用於在使用經放射線標記及/或非放射線標記化合物進行造影或治療時之腎保護,其包含:阿米福丁(Amifostine),其濃度為18mg至約180mg每公斤體重;精胺酸,其濃度為150mg至約800mg每公斤體重;以及離胺酸,其濃度為150mg至約800mg每公斤體重。
- 如請求項1之組成物,更包含醫藥上可接受之賦形劑、稀釋劑、載體,或其組合。
- 如請求項1之組成物,更包含醫藥上可接受之活性化合物,其選自於維生素B12、肉鹼、L-組胺酸、D-組胺酸、丙磺舒(Probenecid)、白蛋白或其蛋白質分解產物、球蛋白或其蛋白質分解產物、細胞色素c之胜肽片段,或肌動蛋白-調節蛋白之胜肽片段。
- 一種如請求項1之組成物於製造一藥劑之用途,該藥劑係用於治療起因於使用經放射性同位素標記之試劑進行造影及/或治療的腎毒性作用。
- 如請求項4之該組成物之用途,其中該經放射性同位素標記之試劑包含一放射性核種,選自於177Lu、111In、90Y、117mSn、45Ti、59Fe、60Cu、61Cu、62Cu、64Cu、67Ga、68Ga、89Sr、99mTc、149Pm、153Gd、153Sm、186Re、188Re、211At、212Bi、225Ac、125I、 123I、32P,或223Ra。
- 如請求項4之該組成物之用途,其中該經放射性同位素標記之試劑為胜肽、蛋白質、抗體、碳水化合物、醣胜肽、尿素衍生物、核苷酸、核苷、雜環化合物、植物萃取物、奈米顆粒、聚合物、奈米材料,或包含植物衍生化合物之組成物。
- 如請求項6之該組成物之用途,其中該治療為使用經放射線標記之促效劑或拮抗劑的胜肽受器標靶治療(PRRT)。
- 如請求項7之該組成物之用途,其中該促效劑或拮抗劑之標靶為生長抑制素-受器。
- 如請求項8之該組成物之用途,其中該促效劑或拮抗劑為DOTA-、DTPA-或NOTA-系衍生物。
- 如請求項9之該組成物之用途,其中該DOTA-、DTPA-或NOTA-系衍生物係選自於DOTATATE、DOTATOC、DOTANOC、DOTA-BASS、JR-11或DOTA-BIM。
- 如請求項4之該組成物之用途,其中該治療係使用抗生素或非放射線標記之腎毒性藥物。
- 如請求項4之該組成物之用途,其中該治療為化學療法。
- 如請求項4之該組成物之用途,其中該造影係使用放射性顯影劑,或釓系顯影劑。
- 如請求項4之該組成物之用途,其中該造影係使用多模態化合物,其具有經放射線標記之探針與光學性探針。
- 如請求項4之該組成物之用途,其中該組成物更包含一活性化合物,選自於維生素B12、肉鹼、L-組胺酸、D-組胺酸、丙磺舒(Probenecid)、白蛋白或其蛋白質分解產物、球蛋白或其蛋白質分解產物、細胞色素c之胜肽片段,或肌動蛋白-調節蛋白之胜肽片段。
- 一種組成物,其用於在使用經放射線標記及/或非放射線標記化合物進行造影或治療時之腎保護,其包含:阿米福丁(Amifostine),其濃度為18mg至約180mg每公斤體重;精胺酸,其濃度為150mg至約800mg每公斤體重;離胺酸,其濃度為150mg至約800mg每公斤體重;以及維生素B12,其濃度為18mg至約180mg每公斤體重。
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WO2020224780A1 (en) | 2019-05-08 | 2020-11-12 | ITM Isotopen Technologien München AG | Para-aminohippuric acid (pah) as a renal protective substance |
CN116133655A (zh) * | 2020-07-22 | 2023-05-16 | 国立大学法人新潟大学 | 维生素b12在抑制肾损伤中的应用 |
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US6573253B2 (en) | 1997-02-12 | 2003-06-03 | Medimmune Oncology Inc. | Methods for the administration of amifostine and related compounds |
US5994409A (en) * | 1997-12-09 | 1999-11-30 | U.S. Bioscience, Inc. | Methods for treatment of neuro--and nephro--disorders and therapeutic toxicities using aminothiol compounds |
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US8815833B2 (en) * | 2006-11-09 | 2014-08-26 | Seidose, LLC | Stable amifostine liquid concentrate |
US8865646B2 (en) * | 2007-03-28 | 2014-10-21 | University Of South California | Dietary compositions and methods for protection against chemotherapy, radiotherapy, oxidative stress, and aging |
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