CN112839678A - 抗癌剂的效果增强剂 - Google Patents
抗癌剂的效果增强剂 Download PDFInfo
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- CN112839678A CN112839678A CN202080004021.4A CN202080004021A CN112839678A CN 112839678 A CN112839678 A CN 112839678A CN 202080004021 A CN202080004021 A CN 202080004021A CN 112839678 A CN112839678 A CN 112839678A
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Abstract
本发明涉及一种医药组合物，其包含柠檬酸盐类，其用于抗癌剂的效果增强。
Description
技术领域
本发明涉及一种抗癌剂的效果增强剂、该效果增强的判定方法、以及关联医疗用具。
背景技术
在着重强调癌的缩小的现有的抗癌剂的治疗中，伴随对癌患者的健康造成严重影响的副作用的情况不少见。与癌分子靶向药、癌免疫疗法相关的抗体医药大多数药价昂贵，在近年来逐渐增加的老年的癌患者、社会的弱者中成为严重的社会问题。
近年来进行了预测癌免疫疗法剂、癌分子靶向药、癌化学疗法剂的效果的诊断药的开发，进行了临床应用，但其是昂贵的，与药剂费用一起医疗费被担心在今后持续增加。
因此，迫切期望开发预测癌免疫疗法剂、癌分子靶向药、癌化学疗法剂的治疗效果的廉价且简便的诊断方法和关联医疗用具。
通常，正常细胞的细胞内pH(以下记载为“pHi”)为6.9～7.2，其细胞外pH(以下记载为“pHe”)为7.3～7.4，正常细胞的pHe与pHi相比更碱性。另一方面，癌细胞的pHi为7.1～7.6，而pHe为6.2～6.9，癌细胞的pHe与pHi相比更酸性。即，癌细胞的pHi和pHe的pH梯度与正常细胞的梯度相比反转。癌细胞与正常细胞相比，糖酵解亢进，乳酸与质子(氢离子)的产生增大，产生的乳酸通过单羧酸转运蛋白(MCT)，质子通过Na+/H+交换输送体1(NHE-1)、Na+依赖性HCO3 -/Cl-交换器、H+/乳酸共输送器，积极地向细胞外排出。其结果是，癌细胞的pHe与pHi相比酸性化。研究报告了在pHi高、NHE-1的活性增大的细胞中，细胞的恶性化、细胞增殖、癌基因的表达、生长因子的激活、糖酵解的亢进、DNA合成促进、细胞周期亢进、细胞凋亡诱导的降低、细胞迁移、血管新生、癌转移、药剂耐性提高(非专利文献1)。
此外，研究报告了在癌细胞中，NHE-1被激活，促进了伪足的形成和在伪足前端的包含蛋白质分解酶的溶酶体的集合。通过NHE-1的进一步激活，癌细胞变形为阿米巴样，促进了从局限的溶酶体分泌蛋白质分解酶，使癌细胞向组织外的浸润变得容易，助长了癌细胞的增殖(非专利文献2)。
迄今，在试管水平下研究报告了通过提高血清中的碳酸氢钠浓度，使癌细胞的pHe从酸性变化为碱性，能够抑制癌细胞的增殖、浸润(非专利文献3)。
研究报告了在使移植了B16黑色素瘤细胞的C57B/6小鼠饮用碳酸氢钠的水溶液(200mmol/L(17g/L))的同时，静脉内给予抗PD-1抗体等癌免疫检查点抑制剂，与仅饮用水的组相比，抗肿瘤效果显著提高(非专利文献4)。
研究报告了在移植了HT29人非小细胞肺癌的细胞系的C57B/6小鼠中移植，在饮用碳酸氢钠水溶液(200mmol/L(17g/L))的同时，给予雷帕霉素等mTORC1抑制剂，与仅饮用水的组相比，抗肿瘤效果显著提高(非专利文献5)。
以确认到EGFR(上皮生长因子受体)的基因突变的非小细胞肺癌的患者作为对象的通过给予吉非替尼、厄洛替尼、阿法替尼等上皮生长因子受体的酪氨酸激酶抑制剂而进行的肺癌患者的寿命延长效果的验证中，碱性饮食(减少在生物体内容易产生尿酸的肉食，以在生物体内容易生成碳酸氢根的包含柠檬酸盐、丁二酸盐、苹果酸盐等的水果、蔬菜为中心的饮食)的癌患者的尿碱化，暗示有助于寿命延长效果(非专利文献6)。
柠檬酸钾·柠檬酸钠水合物片(商品名Uralyt片(日本ケミファ株式会社制))在口腔内容易溶解于饮用水中而容易饮用，在老年的吞咽困难的患者中也容易服用。此外，酸中毒的改善剂、高尿酸血症的酸性尿的改善剂、痛风的酸性尿的改善剂的适应症中被广泛临床应用(非专利文献7、8)。
尚不知道立刻测定癌细胞的周围的微小环境的pH变动的方法。血液的pH保持为7.4(中性)，因此也难以在药物动力学上根据血液的pH变动来预测癌细胞周围的微小环境的pH变动。已知通过尿的pH变动来推测癌细胞的周边的微小环境的pH变动(非专利文献6和专利文献1)，但难以成为癌细胞的周边的微小环境的pH变动的直接证据。
癌患者的患病率据称二人中就有一人，但在老年人种患病率更高。迫切期望出现对患者温和的抗癌剂、诊断药和医疗用具。
现有技术文献
专利文献
专利文献1：日本专利第6359198号公报
非专利文献
非专利文献1：S.Harguindey et al.,Biochimica et Biophysica Acta 1756(2005)：1-24
非专利文献2：Rosa A.Cardone et al.,Nature Reviews,Cancer 5(2005)：786-795
非专利文献3：Ariosto S.Silva et al.,Cancer Research 69(2009)：2677-2684
非专利文献4：Shari Pilon-Thomas,et al.,Cancer Research Science 76(2016)：1381-1390
非专利文献5：Serina Faes et al.,Molecular Cancer(2016)15：78
非专利文献6：Reo Hamaguch et al.,Anticancer Research 37(2017)：5141-5145
非专利文献7：Uralyt配合片的随附文章(2014年3月修订(第8版))
非专利文献8：上田泰他：临床评价9,421,1981
发明内容
发明要解决的课题
随着老年化社会和医疗的高度化，医疗费的增大是必然的结果，但患者的负担大，对国家、地方地方政府的医疗保险财政也造成巨大影响。因此，本发明的目的在于，提供使抗癌剂的效果增强成为可能的新手段。
用于解决课题的手段
本发明人等为了解决以上的课题而深入研究的结果发现，通过组合使用给予柠檬酸盐类和抗癌剂，该抗癌剂的效果得到增强。本发明基于这些见解。
即，本发明包括以下的发明。
[1]一种医药组合物，其包含柠檬酸盐类，其用于抗癌剂的效果增强。
[2]根据[1]所述的医药组合物，其中，柠檬酸盐类包含选自柠檬酸的钠盐、钾盐、钙盐、镁盐、和它们的溶剂化物中的一种或两种以上。
[3]根据[1]或[2]所述的医药组合物，其用于经口给予。
[4]根据[1]～[3]中任一项所述的医药组合物，其包含柠檬酸钾和柠檬酸钠水合物的组合。
[5]一种判定使用柠檬酸盐类的抗癌剂的效果增强的可能性的方法，其包括：
测定给予了柠檬酸盐类的癌患者的血液或尿中的碳酸氢根浓度，在该碳酸氢根浓度增大的情况下，判定为对该患者而言该柠檬酸盐类有效，和/或
测定该患者的尿pH，在该尿pH碱化的情况下，判定为对该患者而言该柠檬酸盐类有效。
[6]一种筛选使用柠檬酸盐类的抗癌剂的效果增强有效的癌患者的方法，其包括：
测定给予了柠檬酸盐类的癌患者的血液或尿中的碳酸氢根浓度，在该碳酸氢根浓度增大的情况下，判定为对该患者而言该柠檬酸盐类有效，和/或
测定该患者的尿pH，在该尿pH碱化的情况下，判定为对该患者而言该柠檬酸盐类有效。
[7]一种一次性尿布，其具有尿的pH试验构件。
[8]根据[5]或[6]所述的方法，其进一步包括：对前述判定为有效的患者给予柠檬酸盐类和抗癌剂，进行癌的治疗。
[9]根据[5]、[6]或[8]中任一项所述的方法，其中，柠檬酸盐类包含选自柠檬酸的钠盐、钾盐、钙盐、镁盐、和它们的溶剂化物中的一种或两种以上。
[10]根据[5]、[6]、[8]或[9]中任一项所述的方法，其中，给予为经口给予。
[11]根据[5]、[6]、[8]～[10]中任一项所述的方法，其中，柠檬酸盐类为柠檬酸钾和柠檬酸钠水合物的组合。
[12]一种用于治疗癌的方法，其包括对癌患者给予柠檬酸盐类和抗癌剂。
[13]根据[12]所述的方法，其中，柠檬酸盐类包含选自柠檬酸的钠盐、钾盐、钙盐、镁盐、和它们的溶剂化物中的一种或两种以上。
[14]根据[12]或[13]所述的方法，其中，将柠檬酸盐类经口给予。
[15]根据[12]～[15]中任一项所述的方法，其中，柠檬酸盐类为柠檬酸钾和柠檬酸钠水合物的组合。
[16]柠檬酸盐类在制造药物中的用途，所述药物用于抗癌剂的效果增强的方法。
[17]根据[16]所述的用途，其中，柠檬酸盐类包含选自柠檬酸的钠盐、钾盐、钙盐、镁盐、和它们的溶剂化物中的一种或两种以上。
[18]根据[16]或[17]所述的用途，其中，柠檬酸盐类为柠檬酸钾和柠檬酸钠水合物的组合。
[19]柠檬酸盐类，其用于抗癌剂的效果增强的方法。
[20]根据[19]所述的柠檬酸盐类，其选自柠檬酸的钠盐、钾盐、钙盐、镁盐、和它们的溶剂化物中的一种或两种以上的化合物。
[21]根据[19]或[20]所述的柠檬酸盐类，其为柠檬酸钾和柠檬酸钠水合物的组合。
[22]配制剂，其包含抗癌剂和柠檬酸盐类。
[23]根据[22]所述的配制剂，其中，柠檬酸盐类包含选自柠檬酸的钠盐、钾盐、钙盐、镁盐、和它们的溶剂化物中的一种或两种以上。
[24]根据[22]或[23]所述的配制剂，其中，柠檬酸盐类为柠檬酸钾和柠檬酸钠水合物的组合。
[25]组合医药，其包含抗癌剂和柠檬酸盐类。
[26]根据[25]所述的组合医药，其中，柠檬酸盐类包含选自柠檬酸的钠盐、钾盐、钙盐、镁盐、和它们的溶剂化物中的一种或两种以上。
[27]根据[25]或[26]所述的组合医药，其中，柠檬酸盐类为柠檬酸钾和柠檬酸钠水合物的组合。
本说明书包括作为本申请的优先权的基础的日本专利申请2019-132679号的说明书和/或附图中记载的内容。
本说明书中引用的全部出版物、专利和专利申请直接以参考方式并入本说明书中。
发明效果
根据本发明，能够提供使抗癌剂的效果增强成为可能的新手段。此外，根据本发明，能够提供判定使用柠檬酸盐类的抗癌剂的效果增强的可能性的方法、和能够用于该判定等的医疗器具。
附图说明
图1是示出酸性尿的老年的男性(70岁)各自服用柠檬酸钾·柠檬酸钠水合物的配合片(表示为“Uralyt”)3g、或柠檬酸钾·柠檬酸钠水合物的活性代谢物的碳酸氢根的钠盐3g后，采集的尿的pH的随时间变化的图示。
图2是示出对荷瘤小鼠经口给予柠檬酸钾·柠檬酸钠水合物的配合散剂(表示为“Uralyt”)时的柠檬酸钾·柠檬酸钠水合物的活性代谢物、即碳酸氢根的(A)血中的浓度变化、和(B)尿中的浓度变化、以及(C)尿的pH变动的图示。
图3是示出对荷瘤小鼠(皮下移植B16小鼠黑色素瘤细胞系的模型)给予(1)小鼠的抗PD-1抗体(5mg/kg)、(2)柠檬酸钾·柠檬酸钠水合物的配合散剂(表示为“Uralyt”)(10mg/天或30mg/天/小鼠(经口))、或者(3)小鼠的抗PD-1抗体(5mg/kg)和柠檬酸钾·柠檬酸钠水合物的配合散剂(10mg/天或30mg/天/小鼠(经口))后的肿瘤的增殖抑制效果和体重变化的图示。示出(A)Uralyt 10mg/天/小鼠的结果、(B)Uralyt 30mg/天/小鼠的结果。
图4是示出因副作用而途中放弃了作为胰腺癌的标准疗法的吉西他滨(商品名Gemzar(Eli Lily))和nab-紫杉醇(商品名アブラキサン(大鹏药品工业))的组合使用疗法的伴随肝转移的胰腺癌的患者(女性、83岁)在2018年4月拍摄的(A)PET像(正电子放射断层摄影))和(B)CT像(计算机断层摄影)的照片图。
图5是示出自2016年6月接受他莫昔芬的柠檬酸盐(商品名タスオミン(バイエル药品))的连日经口给予(20mg/天)和柠檬酸钾·柠檬酸钠水合物的活性代谢物的碳酸氢根的钠盐的连日经口给予(15g/天)的乳腺癌患者(54岁的女性)的血中肿瘤标记物(CEA、CA15-3和BCA225)的测定值的图示。
图6是示出对伴随多发肺转移和癌性腹膜炎的IV期的S状结肠癌的患者(40岁的女性)每日给予(10g/天))结肠·直肠癌的标准化学疗法(FOLFOX+Bev)和柠檬酸钾·柠檬酸钠水合物的活性代谢物、即碳酸氢根的钠盐时的尿的pH的变动与肿瘤标记物(CEA和CA19-9)水平的推移的图示。
图7是示出对伴随肺门的纵膈淋巴结转移、多发骨转移的IVB期的非小细胞肺癌(腺癌)的患者(87岁的男性)连日给予柠檬酸钾·柠檬酸钠水合物的活性代谢物、即碳酸氢根的钠盐(10g/天))，同时以隔周约1个月经口给予100mg的UFT的1胶囊(通常量的5分之1以下的给予量)治疗前后的(A)PET图像、和(B)肺部的CT图像的照片图。
图8是示出IVB期的末期的卵巢癌患者(57岁的女性)在2018年7月23日拍摄的(A)PET图像和(B)CT图像的照片图。(C)是示出自2018年8月开始的以隔周服用柠檬酸钾·柠檬酸钠水合物的活性代谢产物的碳酸氢根的钠盐的连日给予(15g/天)和环磷酰胺50mg片/天(相当于通常量的数分之1的量)的治疗前后的尿的pH和血中肿瘤标记物(CA125)水平的测定值的图示。
图9是示出对荷瘤小鼠(将PANC-1人胰腺癌细胞系对小鼠皮下移植的模型)各自给予溶媒(对照)、柠檬酸钾·柠檬酸钠水合物的配合散剂(表示为“Uralyt”)(500mg/kg/天(经口))、替加氟·吉美嘧啶·奥替拉西钾配制剂(表示为“S-1”)(18mg/kg/天(经口))、S-1(18mg/kg/天(经口给予))和Uralyt(500mg/kg/天(经口))的组合使用后的(A)肿瘤的大小的变化(肿瘤的增殖抑制)和(B)体重的变化的图示。
具体实施方式
本发明涉及用于抗癌剂的效果增强的包含柠檬酸盐类的医药组合物。
本发明中，“抗癌剂的效果增强”是指抗癌剂具有的抗癌活性与单独使用抗癌剂的情况相比，提高20％以上、30％以上、40％以上、50％以上、60％以上、70％以上、80％以上、或90％以上。“抗癌活性”不仅是指使癌完全消失，还是指暂时性或者永久性地使癌缩小或消失、使癌不恶化、稳定。作为通过抗癌活性而受到的效果，例如包括癌的大小的降低、肿瘤标记物水平的降低、与癌相伴的症状改善、全生存期、无恶化生存期、生存期中位数等尺度的延长等中的一种以上。通过“抗癌剂的效果增强”，抗癌剂与单独使用该抗癌剂的情况相比，能够以减少至90％、80％、70％、60％、50％、40％或其以下的量的剂量、和/或以具有减少的给予期间和/或扩大的停药期的用法进行给予。由此，能够抑制或延迟因给予抗癌剂而可能引起的副作用(例如骨髄抑制、溶血性贫血、播散性血管内凝固综合征、重症肝炎、脱水症状、肠炎、间质性肺炎、口腔炎、消化道溃疡、消化道出血、消化道穿孔、急性肾衰竭、皮肤粘膜眼综合征、中毒性表皮坏死症、精神神经障碍、急性胰腺炎、横纹肌溶解症、嗅觉丧失等，不限于此)的发症，此外，能够大幅减少癌患者的经济的负担、国家、地方政府的医疗保险财政的负担。
本发明中，“癌”是指可以举出血液癌(急性骨髄性白血病、慢性骨髄性白血病、恶性淋巴瘤、多发性骨髄瘤等)和固体癌(脑肿瘤·神经胶质瘤、下垂体腺瘤、听神经鞘瘤、葡萄膜恶性黒色素瘤、髄膜瘤、咽癌、喉癌、舌癌、甲状腺癌、乳腺癌、肺癌、胸腺瘤、胸腺癌、间皮瘤、食道癌、胃癌、大肠癌、肝细胞癌、胆管癌、胰腺癌、肾细胞癌、膀胱癌、前列腺癌、肾盂·输尿管癌、阴茎癌、睾丸(睾丸)肿瘤、子宫癌、卵巢癌、外阴癌、皮肤癌、恶性黒色素瘤(皮肤)、基底细胞癌、皮肤癌的前驱症、表皮内癌、鳞状细胞癌、蕈样真菌病、恶性骨肿瘤(骨肉瘤)、软瘤、软骨肉瘤、恶性纤维性组织细胞瘤等)和它们的转移癌，但不限于此。
本发明中，“抗癌剂”是指制药用于癌的治疗即可，没有特别限定，可以举出癌免疫疗法剂、癌分子靶向药、癌化学疗法剂。更详细而言，可以举出例如替加氟、替加氟·尿嘧啶配制剂(商品名：ユーエフティ)、替加氟·吉美嘧啶·奥替拉西钾配制剂(商品名：ティーエスワン(注册商标))、氟尿嘧啶、吉西他滨(商品名：Gemzar(注册商标))、依诺他滨、卡莫氟、去氧氟尿苷、阿糖胞苷、阿糖胞苷十八烷基磷酸盐、巯嘌呤、氟达拉滨、卡培他滨、甲氨蝶呤、克拉屈滨、培美曲塞(商品名：アリムタ(注册商标))、羟基脲、环磷酰胺、噻替派、异环磷酰胺、白消安、达卡巴嗪、米尔法兰、雷莫司汀、尼莫司汀、替莫唑胺、卡铂、顺铂、奥沙利铂、奈达铂、阿霉素、阿克拉霉素、伊达比星、放线菌素D、道诺霉素、净司他丁苯马聚合物、博来霉素、丝裂霉素C、吡柔比星、表阿霉素、培洛霉素、氨柔比星、长春花生物碱、拓扑异构酶抑制药、索拉非尼、厄洛替尼、阿西替尼、依维莫司、舒尼替尼、伊马替尼、拉帕替尼、利妥昔单抗、达沙替尼、硼替佐米、他米巴罗汀、吉非替尼、替伊莫单抗、尼洛替尼、替西罗莫司、曲妥珠单抗、帕尼单抗、维甲酸、吉妥珠单抗奥佐米星、克唑替尼、阿法替尼、贝伐珠单抗(商品名：アバスチン(注册商标))、紫杉醇(商品名：アブラキサン(注册商标))、多西他赛(商品名：タキソテール(注册商标))、纳武单抗(商品名：Opdivo(注册商标))、派姆单抗(商品名：キイトルーダ(注册商标))、伊匹单抗(商品名：ヤーボイ(注册商标))、阿替利珠单抗(商品名：テセントリク(注册商标))、[2S]-2-[(2S,3R)-3-氨基-2-羟基-4-苯基丁酰基氨基]-4-甲基戊酸(通用名：乌苯美司)(商品名：ベスタチン)、香菇多糖，但不限于此。优选抗癌剂为癌免疫疗法剂，特别优选为纳武单抗(商品名：Opdivo(注册商标))、派姆单抗(商品名：キイトルーダ(注册商标))、伊匹单抗(商品名：ヤーボイ(注册商标))、阿替利珠单抗(商品名：テセントリク(注册商标))。
本发明中“柠檬酸盐类”是指可以举出选自柠檬酸的钠盐、钾盐、钙盐、和镁盐、以及它们的溶剂化物中的任一种或两种以上的组合。优选本发明中“柠檬酸盐类”是指柠檬酸钾和柠檬酸钠水合物的组合。
本发明的医药组合物除了上述柠檬酸盐类之外，可以进一步包含医药的制造中通常使用的赋形剂、结合剂、崩解剂、润滑剂等，可以制成适合于期望的给予通路的剂型。
作为赋形剂，可以举出例如糖(单糖、二糖类、环糊精和藻酸等多糖类)、金属盐、高岭土、硅酸、聚乙二醇和它们的混合物等。
作为结合剂，可以举出例如单糖浆、葡萄糖液、淀粉液、明胶溶液、聚乙烯醇、聚乙烯基醚、聚乙烯基吡咯烷酮、羧基甲基纤维素、虫胶、甲基纤维素、乙基纤维素、和它们的混合物等。
作为崩解剂，可以举出例如干燥淀粉、藻酸钠、琼脂粉末、昆布多糖粉末、碳酸氢钠、碳酸钙、聚氧乙烯脱水山梨糖醇脂肪酸酯类、月桂基硫酸钠、硬脂酸甘油单酯、淀粉、乳糖和它们的混合物等。
作为润滑剂，可以举出例如精制滑石、硬脂酸盐、硼砂、聚乙二醇和它们的混合物等。
根据需要，还可以进一步适当包括医药的制造中通常使用的稀释剂、稳定剂、等渗剂、pH调节剂、缓冲剂、溶解助剂、混悬剂、着色剂、矫味剂、矫臭剂、包衣剂、保存剂、防腐剂、抗氧化剂等。
在柠檬酸盐类为两种以上的成分的组合(例如柠檬酸钾和柠檬酸钠水合物的组合)的情况下，各自可以以各自的医药组合物的形态提供，或者可以以组合医药的形态提供。
在作为各自的医药组合物而提供的情况下，这些医药组合物意图通过组合使用给予而使用，可以在其附属文件的示出“效能·效果”的栏、或示出“用法·剂量”的栏中，记载该内容。本发明中“组合使用给予”是指不仅同时给予各成分的情况，还包括跨治疗期间将各成分各自以规定的间隔依次给予的情况(组合使用疗法)。组合使用给予的各成分的给予通路、给予手段可以相同，也可以不同。如果以上述柠檬酸钾和柠檬酸钠水合物的组合为例，针对包含柠檬酸钾的医药组合物，在其附属文件中可以记载用于抗癌剂的效果增强、或用于使用抗癌剂的癌的治疗的“与柠檬酸钠水合物组合使用给予”的内容，针对包含柠檬酸钠水合物的医药组合物，在其附属文件中，可以记载用于抗癌剂的效果增强、或用于使用抗癌剂的癌的治疗的“与柠檬酸钾组合使用给予”的内容。
在以组合医药的形态提供的情况下，可以为在相同的组合物中包含各成分的配制剂的形态，或者可以将各成分各自单独准备、制成作为适合于组合使用给予的单一包装而制造·包装·流通的形态(即，套件制剂)。如果以上述柠檬酸钾和柠檬酸钠水合物的组合为例，则组合医药可以制成包含它们的配制剂的形态。本发明中，可以使用市售的配制剂，也可以适合使用例如Uralyt(注册商标)(日本ケミファ株式会社制)。
柠檬酸盐类的给予量和给予通路可以根据癌的种类、危重度、患者的年龄、体重、状态而变化，所给予的患者中的尿的pH值与给予前的尿的pH值相比偏向于碱侧，可以优选使用任意的给予通路(经口给予、或非经口给予)给予对将所给予的患者中的尿的pH值维持为中性～碱性而言充分的量。和/或，使用任意的给予通路(经口给予、或非经口给予)给予对所给予的患者中的血液或尿中的柠檬酸盐类的活性代谢物(如果以上述柠檬酸钾和柠檬酸钠水合物的组合为例，则为碳酸氢根)的浓度与给予前的浓度相比增大而言充分的量。
例如，可以将选自100mg～10g、优选为150mg～5g、更优选为200mg～2g中的量1天分为1次～5次(例如2次或3次)，每日、隔日或隔多天经口给予柠檬酸盐类(在包含多个成分的情况下，针对各自的成分)。例如，如果以上述柠檬酸钾和柠檬酸钠水合物的组合为例，则可以将选自1～20g、优选为1～10g、更优选为1～5g中的量1天分为1次～5次(例如2次或3次)，每日、隔日或隔多天经口给予其配制剂(例如Uralyt(注册商标)(日本ケミファ株式会社制))。
本发明中柠檬酸盐类可以用于组合使用给予的抗癌剂的效果增强。对癌患者给予的柠檬酸盐类可以认为在癌细胞周围的微小环境中造成变化，由此提高了癌细胞对抗癌剂的敏感性，造成其效果增强。虽然不容易直接测定癌细胞周围的微小环境的变化，但可以以给予了柠檬酸盐类的癌患者的血液或尿中的柠檬酸盐类的活性代谢物的浓度变化(如果以上述柠檬酸钾和柠檬酸钠水合物的组合为例，则为碳酸氢根的浓度变化)为指标，确认该微小环境的变化。在此基础上或替代其，可以以给予了柠檬酸盐类的癌患者的尿pH值的变化为指标，确认该微小环境的变化。在样品为血液的情况下，在柠檬酸盐类的给予后大约36小时以内、优选为大约24小时以内、更优选为12小时以内、进一步优选为6小时以内进行测定。在样品为尿的情况下，在柠檬酸盐类的给予后大约12小时以内、更优选为6小时以内、进一步优选为3小时以内进行测定。
因此，在向对象的癌患者给予柠檬酸盐类后，测定该患者的血液或尿中的柠檬酸盐类的活性代谢物(如果以上述柠檬酸钾和柠檬酸钠水合物的组合为例，则为碳酸氢根)的浓度，在该浓度与给予柠檬酸盐类前相比增大的情况下，表示癌细胞周围的微小环境可能变化，即通过在该患者中组合使用给予柠檬酸盐类，能够期待抗癌剂的效果增强。此外，在给予柠檬酸盐类后，测定该患者的尿pH值，与给予柠檬酸盐类前相比该尿pH值偏向碱侧，优选在所给予的患者中的尿的pH值达到中性～碱性的情况下，表示癌细胞周围的微小环境可能变化，即通过在该患者中组合使用给予柠檬酸盐类，抗能够期待癌剂的效果增强。
由此，通过组合使用给予柠檬酸盐类，可以容易地筛选能够期待抗癌剂的效果增强的癌患者，在筛选该患者后，能够对该患者实施给予柠檬酸盐类和抗癌剂的组合使用给予的癌治疗。在与柠檬酸盐类的组合使用给予中，抗癌剂如上所述，与单独使用该抗癌剂的情况相比，能够以减少至90％、80％、70％、60％、50％、40％或其以下的量的剂量、和/或以具有减少的给予期间和/或扩大的停药期的用法给予。例如，抗癌剂能够以维持或不显著(例如，以40％以上、50％以上、60％以上、70％以上、或者其以上的比例)降低所给予的癌患者的免疫功能的用法剂量使用。癌患者的免疫能的变动可以基于外周血中的中性粒细胞数、粒细胞数、单核细胞数、淋巴细胞数、血小板数等中的一个或多个值的变动、优选为淋巴细胞数的变动而判定。
根据本发明，通过抗癌剂(例如抗PD-1抗体、抗PDL-1抗体等癌免疫疗法剂、癌分子靶向药、癌化学疗法剂)与柠檬酸盐类(例如柠檬酸钾和柠檬酸钠水合物的组合)的组合使用，能够阻碍或抑制癌患者中的细胞的恶性化、细胞的增殖、癌基因的表达、生长因子的激活、糖酵解的亢进、DNA合成的促进、细胞周期的亢进、细胞凋亡诱导的降低、细胞的遊走、血管新生、癌的转移、药剂耐性等与癌的恶性化、增殖、转移相关的一个或多个机制，由此能够将癌镇静化、治疗或缓解、或者预防复发或转移。特别地，在难治性(进行性和/或末期)的癌中显著确认到其效果，能够大幅提高其生存率。
本发明的柠檬酸盐类其本身对癌的治疗或缓解、或者癌的复发、转移的预防是有效的，但通过与抗癌剂的组合使用，能够大幅减少癌患者的经济的负担、国家、地方政府的医疗保险财政的负担。
本发明此外还涉及一种用于测定尿的pH值的医疗用具。本发明的医疗用具具有一次性尿布(例如纸尿布)的形态，其具有尿的pH试验构件。“尿的pH试验构件”是指具有用于测定尿的pH值的手段的构件，可以在尿布中配置于接受尿的部位(例如尿垫、吸水材料等)。“用于测定尿的pH值的手段”制药能够测定尿的pH值即可，没有特别限定，例如可以使用根据pH值而显示特有的颜色的物质(pH指示剂)。作为pH指示剂，可以举出甲基橙、酚酞、BTB等(不限于此)，可以组合使用它们中的一种或多种。或者，作为“用于测定尿的pH值的手段”，还可以利用pH试纸。
根据本发明的医疗用具，通过在穿戴者排尿后确认“尿的pH试验构件”，可以测定尿的pH值，可以判定酸性尿的诊断、上述的柠檬酸盐类的给予后的尿的pH值的碱化的有无。
实施例
以下，通过实施例具体说明本发明，但本发明不限于此。
[实施例1]因服用柠檬酸盐类而导致的尿的pH的变动
在使酸性尿的男性(70岁)以以下的用法剂量服用柠檬酸盐类后，随时间测定尿的pH值的变动。
(用法·剂量)
(1)在餐后以1次/天服用柠檬酸钾·柠檬酸钠水合物500mg片(Uralyt(日本ケミファ株式会社))的6片(3g)
(2)在餐后以1次/天服用柠檬酸钾·柠檬酸钠水合物的主要活性代谢物的碳酸氢根的钠盐(500mg碳酸氢钠片“マイライン”(マイライン制药))6片(3g)
(结果)
服用柠檬酸盐类后的尿的pH的测定结果示于图1。通过在餐后以1次/天经口摄取柠檬酸钾·柠檬酸钠水合物的500mg片(Uralyt配合片(日本ケミファ株式会社))的6片(3g)，尿的pH被碱化，得到维持。
另一方面，在餐后以1次/天服用与柠檬酸钾·柠檬酸钠水合物的主要活性代谢物、即碳酸氢根的钠盐相当的碳酸氢钠的500mg片(マイライン制药))的6片(3g)的情况下，与摄取柠檬酸钾·柠檬酸钠水合物的情况相比，碱化的速度快，但恢复至酸性的速度也快，尿的碱化时间短，在尿的碱化的持久性方面差。此外，在摄取碳酸氢根的钠盐的情况下，伴随打嗝的情况多。
[实施例2]因服用柠檬酸盐类而导致的血中和尿中的碳酸氢根浓度的变动
随时间测定对癌细胞的移植用的小鼠经口给予50mg的柠檬酸钾·柠檬酸钠水合物的散剂(Uralyt-U配合散(日本ケミファ株式会社))时的血液的柠檬酸钾·柠檬酸钠水合物的活性代谢物(碳酸氢根)的浓度，其结果示于图2(A)。
此外，随时间测定该小鼠的给予后的尿的柠檬酸钾·柠檬酸钠水合物的活性代谢物(碳酸氢根)的浓度、和尿的pH，其结果各自示于图2(B)、和图2(C)。
以上的结果显示，尿的柠檬酸钾·柠檬酸钠水合物的活性代谢物(碳酸氢根)的浓度变化与尿的pH变化首尾良好联动，血液的柠檬酸钾·柠檬酸钠水合物的活性代谢物(碳酸氢根)的浓度低于尿的柠檬酸钾·柠檬酸钠水合物的活性代谢物(碳酸氢根)的浓度(约40％)，但血液的碳酸氢根浓度的持久时间与尿的碳酸氢根浓度的持久时间相比长数倍以上。
应予说明，血中与尿中的碳酸氢根浓度用东洋纺的ダイヤカラー(碳酸氢根浓度测定用套件)测定。尿的pH用东洋滤纸制的pH试纸测定。
[实施例3]因服用柠檬酸盐类而导致的抗癌剂的增强效果
对荷瘤小鼠(皮下移植B16小鼠黑色素瘤细胞的模型)，进行(1)小鼠的抗PD-1抗体(Bio X Cell、BE0146)(5mg/kg)的给予、(2)柠檬酸钾·柠檬酸钠水合物的配合散剂(Uralyt-U配合散(日本ケミファ株式会社))(10mg/天或30mg/天/小鼠(经口))的给予、或者(3)小鼠的抗PD-1抗体(5mg/kg)和柠檬酸钾·柠檬酸钠水合物的配合散剂(Uralyt-U配合散(日本ケミファ株式会社))(10mg/天或30mg/天/小鼠(经口))的组合使用给予，随时间测定肿瘤体积和小鼠的体重。柠檬酸钾·柠檬酸钠水合物每日给予，抗PD-1抗体在细胞移植之日的第二天(第1天)以5mg/kg/天的剂量仅腹腔内给予一次而进行。
示出相对肿瘤体积(％)(肿瘤增殖抑制效果)和体重变化(％)的是图3(A),(B)。在柠檬酸钾·柠檬酸钠水合物30mg/天和柠檬酸钾·柠檬酸钠水合物10mg/天中任一者中，均在连日给予下，示出皮下移植B16小鼠黑色素瘤细胞的小鼠中的抗PD-1抗体(5mg/kg)的抗癌效果得到增强。其结果示出，柠檬酸钾·柠檬酸钠水合物能够成为药价昂贵、此外效果不充分而因此在癌患者的治疗中存在极限的Opdivo(抗PD-1抗体)、Keytruda(抗PDL-1抗体)的效果增强剂。
以下的实施例4～8中，针对在实际的癌患者中确认的通过组合使用柠檬酸钾·柠檬酸钠水合物(以下，使用其活性代谢物、即碳酸氢根的钠盐)的抗癌剂的增强效果而示出。
[实施例4]胰腺癌患者中的抗癌剂的增强效果
伴随肝转移的胰腺癌的患者(女性、83岁)接受胰腺癌的标准疗法的吉西他滨(商品名Gemzar(Eli Lily))和nab-紫杉醇(商品名アブラキサン(大鹏药品工业))的组合使用疗法，但因副作用而在治疗途中放弃。如2018年4月拍摄的PET像(正电子放射断层摄影))和CT像(计算机断层摄影)所示那样，是在肝脏中确认到肿瘤的严峻状态(图4(A),(B))。
其后，切换为通常量的3分之1量的Gemzar和柠檬酸钾·柠檬酸钠水合物的活性代谢物的碳酸氢根的钠盐(10g/天))的组合使用给予。自组合使用给予的开始起，仅3个月，胰腺癌的肿瘤标记物的CA19-9降低(150→50)，其后也持续降低。尿的pH为7.5～8.5，保持碱性。该患者完全没有接受高剂量的维生素C点滴疗法或糖尿病药的二甲双胍的经口给予。
[实施例5]乳腺癌患者中的抗癌剂的增强效果
在2001年7月进行左乳房的部分切除后，在2011年8月乳腺癌复发，诱发癌性胸膜炎的乳腺癌患者(54岁的女性)自2016年6月进行他莫昔芬的柠檬酸盐(商品名タスオミン(バイエル药品))的连日给予(20mg/天)和柠檬酸钾·柠檬酸钠水合物的柠檬酸盐代谢物的碳酸氢根的钠盐的连日给予(15g/天)。
其结果是，尿的pH落入7.5～8.5的范围，保持碱性，血中肿瘤标记物的CEA、CA15-3、BCA225经过1年半以上持续降低(图5)。该患者完全没有接受进行复发乳腺癌中通常应用的化学疗法、高剂量的维生素C的点滴疗法或糖尿病药的二甲双胍的经口给予。
[实施例6]结肠癌患者中的抗癌剂的增强效果
对术后复发、伴随多发肺转移和癌性腹膜炎的IV期的S状结肠癌的患者(40岁的女性)，自2017年12月，每日给予(10g/天))大肠癌的标准化学疗法(FOLFOX+Bev)和柠檬酸钾·柠檬酸钠水合物的活性代谢物、即碳酸氢根的钠盐。在该治疗期间，该患者中的尿的pH的变动与肿瘤标记物(CEA和CA19-9)水平的推移示于图6。尿的pH碱化，肿瘤标记物的CEA和CA19-9的水平均降低。此外，根据肺部的CT图像，也可以确认多发肺转移癌缓解。该患者完全没有接受高剂量的维生素C的点滴疗法或糖尿病药的二甲双胍的经口给予。
[实施例7]非小细胞肺腺癌患者中的抗癌剂的增强效果
对伴随肺门的纵膈淋巴结转移和多发骨转移的IVB期的非小细胞肺腺癌患者(87岁的男性)，自2018年10月25日至2019年4月18日，连日给予柠檬酸钾·柠檬酸钠水合物的代谢物、即碳酸氢根的钠盐(10g/天)，同时以隔周大致1个月经口给予100mg的UFT(大鹏药品工业)的1胶囊(通常量的5分之1以下的给予量)。图7中各自示出半年服用柠檬酸钾·柠檬酸钠水合物的代谢物的碳酸氢根的钠盐前后的(A)PET图像、和(B)肺部的CT图像。根据其结果，确认肺门的纵膈淋巴结转移、多发骨转移完全消失。该非小细胞肺腺癌的患者完全没有接受通常的癌化学疗法、高剂量的维生素C点滴疗法或作为糖尿病药的二甲双胍的经口给予。
[实施例8]卵巢癌患者中的抗癌剂的增强效果
IVB期的卵巢癌患者(57岁的女性)自2017年1月经3次接受卵巢癌的标准化学疗法(紫杉醇与卡铂的组合使用)，同时接受以15g/天的剂量连日给予柠檬酸钾·柠檬酸钠水合物的代谢产物的碳酸氢根的钠盐。其结果是，卵巢癌开始缩小，血中肿瘤标记物的CA125降低。效果持久1年左右，但自2018年7月起卵巢癌依次开始变大(图8示出于2018年7月拍摄的(A)PET图像和(B)CT图像)，CA125的值也增大至199。因此，在继续给予柠檬酸钾·柠檬酸钠水合物的代谢产物下，自2018年8月30日，以隔周开始服用环磷酰胺50mg片/天(通常量的数分之1的量)。其结果是，CA125的值依次开始降低，于半年后的2019年2月降低至53，尿的pH为8.5(图8(C))。该患者完全没有接受高剂量的维生素C点滴疗法或糖尿病药的二甲双胍的经口给予。
[实施例9]利用柠檬酸盐类的抗癌剂的效果增强
对荷瘤小鼠(将PANC-1人胰腺癌细胞系对小鼠皮下移植的模型)，进行2周每日经口给予溶媒(对照)，2周每日经口给予替加氟·吉美嘧啶·奥替拉西钾配制剂(ティーエスワン(大鹏药品工业)(以下记载为“S-1”)(18mg/kg/天)，2周每日经口给予柠檬酸钾·柠檬酸钠水合物的配合散剂(Uralyt-U配合散(日本ケミファ株式会社)、以下记载为“Uralyt”)(500mg/kg/天))，2周每日经口给予S-1(18mg/kg/天)和Uralyt(500mg/kg/天)，随时间测定肿瘤体积和小鼠的体重。
测定的肿瘤体积(肿瘤增殖抑制效果)和小鼠的体重各自示于图9的(A)和(B)。
根据图9的(A)，与S-1(18mg/kg/天)单独给予组、Uralyt(500mg/kg/天))单独给予组相比，在S-1(18mg/kg/天)与Uralyt(500mg/kg/天)的组合使用组中，确认到显著的肿瘤增殖抑制效果。即，在荷瘤小鼠(将PANC-1人胰腺癌细胞系对小鼠皮下移植的模型)中，确认到利用Uralyt(500mg/kg/天))(碱剂)的S-1(18mg/kg/天)(抗癌剂)的抗肿瘤效果的增强。
根据图9的(B)，任意给予组中均未确认到显著的体重变化。根据其结果，在荷瘤小鼠(将PANC-1人胰腺癌细胞系对小鼠皮下移植的模型)中，确认到在利用Uralyt(500mg/kg/天))的S-1(18mg/kg/天)(抗癌剂)的组合使用中显著的抗肿瘤效果的增强，但确认到利用Uralyt(500mg/kg/天))的对S-1(18mg/kg/天)(抗癌剂)的毒性未叠加。
S-1是具有胰腺癌等适应症的5-FU系的经口抗癌剂，以日本为中心是通用的。S-1的通常的用法剂量中，通过反复经口给予，容易出现血小板减少等毒性，成为利用S-1的治疗上的问题。然而可知，在将S-1的剂量降低至一半量左右而能够确保高安全性的条件下，通过与本发明所涉及的柠檬酸盐类组合使用给予，不需要任何担心利用S-1的副作用，抑制了癌的增殖。
[实施例10]测定尿的pH的医疗用具
在大人用的纸尿布(花王制的リリーフパンツタイプ)的吸水材料部位中并入pH试纸(东洋滤纸制的BTB(pH6.2-7.8))，制作能够测定尿的pH值的纸尿布。使酸性尿的人(70岁的男性)穿戴制作的纸尿布，在柠檬酸钾·柠檬酸钠水合物500mg片(日本ケミファ制)的服用(4～6片)的前后，观察排尿后的该纸尿布的吸水材料部位的pH试纸的颜色的变化。服用前的吸水材料部位呈现表示酸性(pH6.2)的黄色，但服用后(数小时后)的纸尿布的吸水材料部位呈现碱化的淡蓝色(7.4)。使用该纸尿布，能够确认对酸性尿的患者而言因服用柠檬酸钾·柠檬酸钠水合物片而导致的中和效果。
该能够测定尿的pH值的纸尿布能够成为用于判定或确认与服用本发明所涉及的包含柠檬酸盐类的医药组合物相伴的酸性尿的改善作用(例如老年者的高尿酸血症中的酸性尿的改善作用)、酸中毒的改善作用、抗PD-1抗体、抗PDL-1抗体等癌免疫疗法剂、癌分子靶向药和癌化学疗法剂的效果增强作用。
Claims (7)
1.一种医药组合物，其包含柠檬酸盐类，其用于抗癌剂的效果增强。
2.根据权利要求1所述的医药组合物，其中，柠檬酸盐类包含选自柠檬酸的钠盐、钾盐、钙盐、镁盐、和它们的溶剂化物中的一种或两种以上。
3.根据权利要求1或2所述的医药组合物，其用于经口给予。
4.根据权利要求1～3中任一项所述的医药组合物，其包含柠檬酸钾和柠檬酸钠水合物的组合。
5.一种判定使用柠檬酸盐类的抗癌剂的效果增强的可能性的方法，其包括：
测定给予了柠檬酸盐类的癌患者的血液或尿中的碳酸氢根浓度，在该碳酸氢根浓度增大的情况下，判定为对该患者而言该柠檬酸盐类有效，和/或
测定该患者的尿pH，在该尿pH碱化的情况下，判定为对该患者而言该柠檬酸盐类有效。
6.一种筛选使用柠檬酸盐类的抗癌剂的效果增强有效的癌患者的方法，其包括：
测定给予了柠檬酸盐类的癌患者的血液或尿中的碳酸氢根浓度，在该碳酸氢根浓度增大的情况下，判定为对该患者而言该柠檬酸盐类有效，和/或
测定该患者的尿pH，在该尿pH碱化的情况下，判定为对该患者而言该柠檬酸盐类有效。
7.一种一次性尿布，其具有尿的pH试验构件。
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| Publication number | Publication date |
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| TW202114715A (zh) | 2021-04-16 |
| KR20210013760A (ko) | 2021-02-05 |
| TWI814983B (zh) | 2023-09-11 |
| WO2021009950A1 (ja) | 2021-01-21 |
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