CN112469404A - 肾损伤的预防或治疗用的药物组合物 - Google Patents
肾损伤的预防或治疗用的药物组合物 Download PDFInfo
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- CN112469404A CN112469404A CN201980037585.5A CN201980037585A CN112469404A CN 112469404 A CN112469404 A CN 112469404A CN 201980037585 A CN201980037585 A CN 201980037585A CN 112469404 A CN112469404 A CN 112469404A
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Abstract
本发明涉及包含D‑丙氨酸、或其衍生物的肾脏病的预防或治疗用的药物组合物、肾脏中的炎症抑制剂、肾脏中的炎症性细胞死亡抑制剂、或者肾脏病的预防用或改善用食品。另外，本发明涉及D‑丙氨酸或其衍生物用于制造肾脏病的预防或治疗用的药物组合物的用途。
Description
技术领域
本发明涉及肾损伤的预防或治疗用的药物组合物、以及肾脏中的炎症抑制剂、炎症性细胞死亡抑制剂、肾损伤的预防用或改善用食品、和肾脏的保护剂。
背景技术
肾脏是以通过过滤血液中的废旧物、多余的水分作为尿排出，从而维持体液的恒定性，此外通过内分泌功能而调节血压、造血、骨代谢等作为任务的脏器。肾脏由于免疫***异常、药剂、高血压、糖尿病、出血和/或急剧血压下降、感染症、伴随烧伤产生的脱水等因素而受到损伤，功能降低。将该状态称为肾脏病，特别是以糖尿病为原因的肾脏病称为糖尿病性肾脏病。
急性肾损伤(Acute Kidney Injury:AKI)是指直到发病的时间为数小时至数周的肾损伤。急性肾损伤是由于缺血、药剂、内毒素休克等原因而肾功能急剧下降的状态，可发现作为体内代谢产物的尿素氮、肌酸酐的血中浓度上升、电解质代谢异常和酸中毒等症状，一般根据血清肌酸酐值的急剧上升而诊断。
慢性肾脏病(Chronic Kidney Disease:CKD)是指由于各种肾损伤而用肾小球滤过率表示的肾功能有所下降，或者提示肾脏损伤的表征慢性(3个月以上)地持续的状态。慢性肾脏病是相当于日本成人人口的约13％的1330万人罹患的疾病，发展成晚期肾衰竭(ESKD)的风险高，威胁国民的健康。没有对慢性肾脏病有效的治疗方法，如果病情进行而肾功能降低，则呈现***，最终需要人工透析、肾移植等肾代替疗法，因此在医疗经济上也成为大的负担(非专利文献1)。慢性肾脏病如果肾功能没有显著降低则不表现自觉症状，因此期望开发对早期发现、进行抑制有用的生物标志物。
作为肾脏病的生物标志物，使用作为排出到尿中的废旧物的肌酸酐和尿素氮(BUN)、由炎症细胞表达的NGAL、由受到损伤的近曲小管上皮细胞表达的KIM-1，但这些标志物并不是作为早期的生物标志物能够满足的。近年来，能够测定到血中或尿中的D-氨基酸了，由此显示了D-氨基酸作为肾脏病生物标志物的潜质(专利文献1)。
报告了肾脏病中的、血中或尿中的D-氨基酸的变化受到肠内细菌的代谢的影响。另外，近年的代谢组学研究中渐渐搞清楚了，肠内细菌来源的短链脂肪酸的抑制性T细胞增殖作用等，代谢产物在恒定性维持、脏器保护中承担重要的作用。然而，关于肠内细菌群来源的D-氨基酸影响脏器的损伤、保护并没有任何记载或启示。
现有技术文献
专利文献
专利文献1：国际公开第2013/140785号
非专利文献
非专利文献1：KDIGO 2012Clinical Practice Guideline for the Evaluationand Management of Chronic Kidney Disease,Kidney International Supplements 1(2013)
发明内容
发明要解决的课题
期望开发具有肾脏病的治疗或预防、或肾脏的保护作用的药剂。
用于解决课题的手段
本发明者们对于在肾脏病的患者的体内显示与病情相关的变化的D-丙氨酸，深入研究了其生理作用，结果发现，D-丙氨酸具有肾脏的保护作用、对肾脏病的治疗/预防作用，从而完成了本发明。
因此具体地，本发明涉及下述发明：
[1]肾脏病的预防或治疗用的药物组合物，包含D-丙氨酸、或其衍生物。
[2]根据项目1所述的药物组合物，所述预防或治疗用的药物组合物用于肾脏的保护或肾功能的恢复。
[3]根据项目1或2所述的药物组合物，所述肾脏病包含急性肾损伤、和慢性肾脏病。
[4]根据项目1或2所述的药物组合物，所述肾脏病是由缺血引起的肾损伤。
[5]根据项目1～4的任一项所述的药物组合物，用于局部施与、经肠道施与或非经口施与。
[6]根据项目1～5的任一项所述的药物组合物，所述衍生物是在施与之后转变为D-丙氨酸的化合物。
[7]肾脏中的炎症抑制剂，包含D-丙氨酸、或其衍生物。
[8]肾脏中的炎症性细胞死亡抑制剂，包含D-丙氨酸、或其衍生物。
[9]肾脏病的预防用或改善用食品，包含D-丙氨酸、或其衍生物。
[10]根据项目9所述的肾脏病的预防用或改善用食品，所述衍生物是在施与之后转变为D-丙氨酸的化合物。
[11]肾脏病的预防或治疗方法，包括施与D-丙氨酸、或其衍生物的步骤。
[12]用于在肾脏病的预防或治疗中使用的D-丙氨酸、或其衍生物。
[13]D-丙氨酸或其衍生物用于制造肾脏病的预防或治疗用的药物组合物的用途。
[14]根据项目11～13的任一项所述的方法、D-丙氨酸或其衍生物、或用途，用于肾脏的保护或肾功能的恢复。
[15]根据项目11～14的任一项所述的方法、D-丙氨酸或其衍生物、或用途，所述肾脏病包含急性肾损伤、和慢性肾脏病。
[16]根据项目11～15的任一项所述的方法、D-丙氨酸或其衍生物、或用途，所述肾脏病是缺血诱导性或炎症诱导性的肾损伤。
[17]根据项目11～16的任一项所述的方法、D-丙氨酸或其衍生物、或用途，用于局部施与、经肠道施与或非经口施与。
[18]根据项目11～17的任一项所述的方法、D-丙氨酸或其衍生物、或用途，所述衍生物是在施与之后转变为D-丙氨酸的化合物。
发明的效果
D-丙氨酸在血中发挥肾脏的保护作用/炎症抑制作用、和由炎症性细胞死亡抑制作用带来的肾脏病的治疗效果、肾功能的恢复效果中的至少1种作用/效果。
附图说明
图1：图1显示缺血再灌注之后第10天的肾脏组织切片的PAS染色图像(倍率100倍和400倍)。水摄取组中染色强度上升，可见中性粒细胞、嗜酸性粒细胞等炎症性细胞的积累，另一方面D-丙氨酸摄取组(20mM、和80mM)中这样的染色强度用量依赖性地降低。
图2：图2分别显示缺血再灌注之后第10天的肾脏组织切片中的(A)坏死(Necrosis)、(B)腔内碎片(Intraluminal debris)、(C)刷状缘区域(Brush borderregion)的等级。与水摄取组相比，D-丙氨酸摄取组中数值用量依赖性地改善。
图3：图3(A)显示缺血再灌注之后第10天的肾脏组织切片的F4/80染色图像(倍率100倍和400倍)。水摄取组中染色强度上升，可见巨噬细胞、单核细胞等炎症性细胞的积累，另一方面D-丙氨酸摄取组中这样的染色强度用量依赖性地降低。图3(B)是将F4/80的染色区域数值化而显示的图。
图4：图4(A)显示缺血再灌注之后第10天的肾脏组织切片的AZAN染色图像(倍率100倍和400倍)。水摄取组中染色强度上升，可见纤维化的进行，另一方面D-丙氨酸摄取组中这样的染色强度用量依赖性地降低。图4(B)是将AZAN染色的染色区域数值化而显示的图。
图5：图5(A)显示对肾小管上皮细胞(TEC)施加低氧胁迫而培养时的D-丙氨酸添加的时间表。图5(B)显示根据D-丙氨酸的用量的KIM-1表达的变化。
具体实施方式
本发明的1个状态涉及包含D-丙氨酸、或其衍生物的肾损伤的预防或治疗用的药物组合物。
D-丙氨酸是作为构成蛋白质的氨基酸的一种的L-丙氨酸的光学异构体。本发明中，D-丙氨酸可以是其酸性盐、碱性盐、两性盐的任一形态，例如盐酸盐、硫酸盐、硝酸盐、钠盐、钾盐、钙盐、铵盐等，只要是生理上可容许的盐，就可以使用任意的盐。
D-丙氨酸的衍生物是指改变了疏水性、静电特性而得的物质、或在施与之后能够使血中、组织中的D-丙氨酸浓度上升的物质。只要是能够将血中、组织中的D-丙氨酸浓度调整为最适的量的物质，就可以使用任意的D-丙氨酸衍生物。作为D-丙氨酸衍生物的一例，可列举D-丙氨酸的羧基或氨基被保护/取代了的化合物。羧基例如可以被酯化、酰胺化等。氨基可以被酰胺化。作为衍生物的一例，可列举D-丙氨酸甲酯、D-丙氨酸乙酯、包含D-丙氨酸的肽例如二肽、三肽、寡肽、多肽等。
在使用肽的情况下，可以仅由丙氨酸构成，也可以由丙氨酸以及其他氨基酸、例如丝氨酸、甘氨酸、缬氨酸、亮氨酸、异亮氨酸、苏氨酸、半胱氨酸、甲硫氨酸、天冬氨酸、谷氨酸、天冬酰胺、谷氨酰胺、赖氨酸、精氨酸、苯丙氨酸、酪氨酸、色氨酸、组氨酸等构成。除了这些D-丙氨酸以外的氨基酸可以是L型异构体也可以是D型异构体。D-丙氨酸残基、分解而生成的D-丙氨酸还可以带来生理活性、例如肾脏保护效果。
肾脏病通过蛋白尿、肾小球滤过率(GFR)的降低来确定。慢性肾脏病通过以下：
(1)通过尿检查、图像诊断、血液检查、病理等而肾损伤的存在明确，特别是有0.15g/gCr以上的蛋白尿(30mg/gCr以上的白蛋白尿)
(2)肾小球滤过率小于60mL/min/1.73m2
中任一方或两方持续3个月以上，从而诊断为慢性肾脏病。肾小球滤过率也可以通过由血清肌酸酐值、年龄、性别计算出推算肾小球滤过率，从而确定。
慢性肾脏病可以由各种原因引起。作为具有肾脏病的风险的对象，可列举患有糖尿病、高血压、肾炎、多囊肾、肾移植、脂质异常症、肥胖的对象。因此，本发明中，D-丙氨酸或其衍生物可以对这样的具有肾脏病的风险的对象施与。作为这样的对象，可列举通过健康诊断而判定为肾功能降低的对象。健康诊断中，作为一例，基于尿蛋白、尿鲜血、BUN、肌酸酐、eGFR等，进行肾功能的检查，可以将在这些中的至少1种检查中发现轻度异常的对象、需要随访等的对象作为具有肾脏病的风险的对象。另外，对于患有肾脏病的患者，也可以期待肾功能的恢复、恶化的防止而施与D-丙氨酸或其衍生物。
也可以作为肾脏病生物标志物使用的KIM-1(Kidney injury molecule-1，肾损伤分子-1)是在受到损伤而修复再生中的近曲小管上皮细胞中被表达诱导的全长104kDa的1次跨膜型蛋白质。认为KIM-1作为针对在发生凋亡的细胞的表面表现出的eat-me信号的受体发挥作用，介由KIM-1而有助于除去死细胞。
急性肾损伤是在数小时～数天之间肾功能急剧降低的疾病，主要可以分为由缺血造成的损伤和由肾毒性物质造成的损伤。如果因为由出血等造成的休克而不能给肾脏提供充分的血液，则肾脏的肾小管、肾单位等发生炎症，功能丧失。肾毒性物质可列举农药或药物、造影剂、抗生剂等，通过这些物质而肾单位被伤害，从而肾功能丧失。另外，根据被伤害的部位可以分类为肾前性、肾性、肾后性的肾脏病。肾前性的肾脏病是指由于全身疾病而向肾脏的血流降低等而产生的肾脏病，例如脱水症、休克、烧伤、大量出血、充血性心力衰竭、肝硬化、肾动脉狭窄症等成为其原因。肾性的肾脏病是指在肾脏自身存在原因的情况下的肾脏病，可列举例如，肾脏中的血流障碍、肾小球损伤、和肾小管/间质损伤等作为其原因。肾后性的肾脏病是指肾脏的下游的尿路有问题的情况下的肾脏病。急性肾损伤通过早期的应对能够预计肾功能的恢复，但如果没有进行适当的处置，则有时直接向慢性肾脏病转变。因此，本发明中D-丙氨酸或其衍生物可以对患有急性肾损伤的对象、或具有其风险的对象施与。
肾功能可以通过测定血中的肌酸酐量、血中总蛋白量、血尿素氮(BUN)、和肾小球滤过率来判定。肌酸酐量、血中总蛋白量、血尿素氮(BUN)、和推定肾小球滤过量在健康诊断中也普遍采用，可以对其数值低于基准、或显示恶化倾向的对象施与本发明的D-丙氨酸或其衍生物。
肾脏病有时伴随肾脏的炎症，通过抑制这样的损伤，可以恢复肾功能或治疗肾脏病。肾脏病中也包含肾小球、间质等发生炎症的肾小球肾炎、间质性肾炎等。进而肾小球肾炎有急性肾小球肾炎(急性肾炎)、慢性肾小球肾炎(慢性肾炎)等。
肾损伤的预防用或改善用食品是指，标示了给患有肾损伤的对象或具有患肾损伤的风险的对象摄取的食品。作为这样的食品，可列举功能性食品、保健用食品、营养补充剂等。D-丙氨酸或其衍生物、和含有它们的原料可以对任意食品配合。D-丙氨酸到目前为止作为食品在10g数量级的摄取经验中也没有报告有害迹象，可以从发挥肾脏保护作用或抗炎症作用的观点考虑而设定任意的用量。
治疗是指恢复肾功能或缓和肾损伤。一般对于慢性肾脏病虽然不能期待肾损伤的完全恢复，但可以为了抑制恶化的目的而施与本发明的治疗用的组合物。对于急性肾损伤，可以以肾功能的恢复为目的施与本发明的治疗用的组合物。本发明中，预防是指对患有肾脏病、或有患的风险的对象，抑制肾损伤的发生和进行，或使其恢复。
D-丙氨酸的施与用量可以根据施与途径任意选择。用量可以通过动物试验、临床试验任意选择。对于D-丙氨酸没有由经口施与产生毒性的报告，其用量的上限和下限可以从发挥肾脏的保护作用/炎症抑制作用、和由炎症性细胞死亡抑制作用产生的肾脏病损伤的治疗效果、保护效果、肾功能的恢复效果、肾脏中的炎症抑制效果、和炎症性细胞死亡抑制效果中的至少1种作用/效果的观点考虑任意选择。
本发明的药物组合物除了D-丙氨酸或其衍生物之外，还可以含有药理学上可容许的担载体、稀释剂或赋形剂。本发明的药物组合物除了D-丙氨酸或其衍生物之外，还可以含有进一步的抗炎症性药剂、肾功能改善剂等。这样的药物组合物可以制成适合局部施与(皮肤上、吸入、灌肠、滴眼、滴耳、经鼻、***内等)、经肠道施与(经口、经食道、经灌注等)、非经口施与(经静脉、经动脉、经皮、肌肉注射等)的剂型提供，但施与途径不限于这些。
本发明的治疗剂或药物组合物可以选择适合其施与途径的剂型而进行制剂化。在用于经口施与的情况下，可以设计片剂、胶囊剂、液剂、粉末剂、颗粒剂、咀嚼剂等剂型，在非经口施与的情况下，可以设计注射剂、粉末剂、输液制剂等剂型。另外，这些制剂可以含有用于医药用的各种辅助剂、即担载体、其他助剂，例如，稳定剂、防腐剂、镇痛剂、增味剂、矫味剂、香料、乳化剂、填充剂、pH调节剂等，可以在不损害本发明的组合物的效果的范围内配合。
本说明书中提到的所有文献其整体通过引用而纳入本说明书中。以下说明的本发明的实施例仅以例示为目的，并不限定本发明的技术的范围。本发明的技术的范围仅受权利要求书的记载限定。以不偏离本发明的宗旨为条件，可以进行本发明的变更，例如，本发明的构成要素的添加、删除和替换。
实施例
实施例1：利用缺血再灌注诱导肾损伤
1.材料和方法
(1)研究伦理
所有的实验按照设施的准则，并获得该设施的动物实验委员会的认可而实施。
(2)材料
氨基酸的对映异构体和HPLC级的乙腈从ナカライテスク(京都)购买。HPLC级的甲醇、三氟乙酸、硼酸等从和光纯药(大阪)购买。水使用Milli-Q梯度A10***进行了纯化。
(3)动物
动物是在SPF环境、每12小时明暗交替的条件下，以能够自由摄取水和饲料的方式饲养的。C57BL/6J小鼠从日本クレア(大阪)购买。
(4)肾缺血再灌注处理
将12-16周龄的雄性小鼠进行肾缺血再灌注(以下也称为“IRI”)处理。在戊巴比妥麻醉下使用Non-traumatic clip(无创钳，Natsume Seisakusho.Tokyo)夹住肾蒂，诱发缺血。40分钟后打开钳。处置中将对应保持37℃。
从IR处理14天前开始，以小鼠能够自由摄取水(对照)和含20mMD-丙氨酸的水的方式进行饲养。在IR处理后第10天采集肾脏组织。
染色
将在缺血再灌注之后第10天采集的肾脏用10％中性缓冲***固定，进行石蜡包埋，用periodic acid-Schiff(PAS染色)(过碘酸雪夫染色)染色。将染色后的切片用亮视野显微镜拍摄(图1)。被PAS染色的碎片(皮髓质交界区)或刷状缘(皮髓质交界区和皮质区域)通过最少10处不同的部位来定量评价。将碎片、肾小管扩张、刷状缘损伤、肾小管坏死用ATN得分评价(0,无；1,温和；2,适中；3,严重)。样品的评价通过盲测进行。结果示于图2(A)～(C)。
将缺血再灌注后第10天采集的肾脏组织用10％中性缓冲***固定，使用F4/80抗体(invitrogen,catalog#:MF48000)供于免疫染色。F4/80是在巨噬细胞中特异地表达的蛋白质，可以将肾脏组织内的巨噬细胞可视化。在水施与的对照组中，可见肾组织中被F4/80染色的细胞的积累(第5天)，另一方面，D-丙氨酸施与组(20mM和80mM)中，这样的细胞的积累较少(图3(A))。测定各组中的染色区域的比例(图3(B))。
将缺血再灌注后第10天采集的肾脏组织用10％中性缓冲***固定，供于AZAN染色。AZAN染色中，纤维化的组织被苯胺蓝染色。在水施与的对照组中，广泛观察到纤维化的组织，另一方面在D-丙氨酸施与群(20mM和80mM)中，被苯胺蓝染色的区域用量依赖性地减少(图4(A))。测定各组中的染色区域的比例(图4(B))。
实施例2：对肾小管上皮细胞(TEC)施加低氧胁迫
作为小鼠肾小管上皮细胞的mProx24细胞由Sugaya(St.Marianna UniversitySchool of Medicine,Tokyo)提供。将该细胞用添加了5％胎牛血清(FBS)和1％青霉素和链霉素的DMEM培养基培养。将培养而得的细胞使用添加了1％FBS的DMEM培养基以1.0×106细胞/孔接种，在37℃、5％CO2和20％O2加湿气氛下培养24小时。低氧胁迫施加组中，在培养24小时之后，在添加了5％FBS的DMEM培养基中在5％CO2和5％O2加湿气氛下进一步培养20小时，在低氧胁迫未施加组中，在添加了5％FBS的DMEM培养基中在5％CO2和20％O2加湿气氛下进一步培养20小时(图5(A))。在这些DMEM培养基中作为试验药剂添加1μM、10μM、和100μM的D-丙氨酸，在对照中不包含D-丙氨酸。
KIM-1的基因表达的测定
回收培养后细胞，使用the High Pure RNA Isolation Kit(Roche Diagnostics,Tokyo)提取总RNA。使用了SYBR Green fluorescence(Bio-Rad,Tokyo)的实时定量PCR在Villa 7Real-Time PCR System(Thermo Fisher Scientific,Tokyo)中进行，使用下述的引物。数据通过delta-delta Ct法进行分析(图5(B))。
KIM-1正向:5’-aggaagacccacggctattt-3’(序列号1)
KIM-1反向:5’-tgtcacagtgccattccagt-3’(序列号2)
Claims (16)
1.肾脏病的预防或治疗用的药物组合物，包含D-丙氨酸、或其衍生物。
2.根据权利要求1所述的药物组合物，所述预防或治疗用的药物组合物用于肾脏的保护或肾功能的恢复。
3.根据权利要求1或2所述的药物组合物，所述肾脏病包含急性肾损伤或慢性肾脏病。
4.根据权利要求1或2所述的药物组合物，所述肾脏病是由缺血引起的肾损伤。
5.根据权利要求1～4的任一项所述的药物组合物，用于局部施与、经肠道施与或非经口施与。
6.根据权利要求1～5的任一项所述的药物组合物，所述衍生物是在施与之后转变为D-丙氨酸的化合物。
7.肾脏中的炎症抑制剂，包含D-丙氨酸、或其衍生物。
8.肾脏中的炎症性细胞死亡抑制剂，包含D-丙氨酸、或其衍生物。
9.肾脏病的预防用或改善用食品，包含D-丙氨酸、或其衍生物。
10.根据权利要求9所述的肾脏病的预防用或改善用食品，所述衍生物是在施与之后转变为D-丙氨酸的化合物。
11.D-丙氨酸或其衍生物用于制造肾脏病的预防或治疗用的药物组合物的用途。
12.根据权利要求11所述的使用，所述药物组合物用于肾脏的保护或肾功能的恢复。
13.根据权利要求11或12所述的使用，所述肾脏病包含急性肾损伤、和慢性肾脏病。
14.根据权利要求11～13的任一项所述的使用，所述肾脏病是缺血诱导性或炎症诱导性的肾损伤。
15.根据权利要求11～14的任一项所述的使用，所述药物组合物用于局部施与、经肠道施与或非经口施与。
16.根据权利要求11～15的任一项所述的使用，所述衍生物是在施与之后转变为D-丙氨酸的化合物。
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| US20150079623A1 (en) * | 2012-03-18 | 2015-03-19 | Kyushu University, National University Corporation | Apparatus, system and method for analyzing disease sample |
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