CN107635547A - 用于治疗和预防肿瘤的甲苯哒唑多形体 - Google Patents
用于治疗和预防肿瘤的甲苯哒唑多形体 Download PDFInfo
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- CN107635547A CN107635547A CN201680014427.4A CN201680014427A CN107635547A CN 107635547 A CN107635547 A CN 107635547A CN 201680014427 A CN201680014427 A CN 201680014427A CN 107635547 A CN107635547 A CN 107635547A
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Abstract
甲苯哒唑为一种抗寄生虫药物，具有超过40年的安全使用史。最近甲苯哒唑被重新利用，用于成胶质细胞瘤治疗。甲苯哒唑存在三种多形体(polymorph)，但现有药物的多形体相对含量不同，并且不同多形体的抗癌治疗相关性是未知的。作为口服药物，甲苯哒唑多形体C为优异的形式，并以有效浓度到达脑和脑肿瘤。通过将甲苯哒唑与P‑糖蛋白抑制剂组合进一步提高功效。甲苯哒唑也可以用于其他癌症的治疗，以及作为化疗防护剂。
Description
本发明根据由国立神经障碍与中风研究所(National Institute ofNeurological Disorders and Stroke)授予的R25NS065729以及来自美国国立卫生研究院(National Institutes of Health)的P30-CA006973、UL1-RR025005和1S10RR026824-01在政府支持下进行。政府在本发明中具有一定权利。
发明技术领域
本发明涉及药物学领域。特别地，本发明涉及癌症治疗剂。
发明背景
中枢神经系统(CNS)癌症难以治疗，因为大多数全身施用的治疗剂不能在颅内肿瘤中达到有效浓度(1)。这由血脑屏障(BBB)部分地解释。在CNS中，BBB沿着包括紧密连接(tight junctions)的所有毛细管存在，从而阻断大的和亲水性的分子传递至CNS组织。据估计，仅约2％的小分子药物能够有效地跨越BBB(2)。
甲苯哒唑(MBZ)已经安全地用作人类抗寄生虫药物超过四十多年，并且显示出针对颅内蠕虫感染的功效。我们最近在原位神经胶质瘤和成神经管细胞瘤啮齿动物模型中证明了MBZ的临床前功效(3，4)。MBZ显著降低肿瘤生长并改进携带脑肿瘤小鼠的存活率。基于这些结果，开始了用于新诊断的高级神经胶质瘤患者的具有MBZ剂量递增的I期临床试验(NCT01729260)。已经产生了支持MBZ的几种抗癌机制，包括微管蛋白结合、激酶抑制、抗血管生成和促凋亡的证据(3-8)。然而，MBZ的脑渗透和药代动力学的重要特征仍有待确定。这种理解对潜在地改进MBZ的临床使用是重要的。
MBZ为高度疏水性的，并且可以基于结晶条件形成三种不同的多形体(polymorph)(9)。多形体A、B和C(MBZ-A、MBZ-B和MBZ-C)在驱虫药(anthelmintic)应用中显示了在溶解度、毒性和治功效果方面的独特特征(10-12)。虽然三种多形体的抗肿瘤功效的差异尚未被研究，然而，该信息可能对未来的MBZ癌症治疗至关重要，因为药物制剂可能包含不同量或组合的各种多形体。进一步研究的另一个关键原因是，多形体C(在驱虫药使用中最有效的多形体)可以随时间转化成不太有效的多形体A，特别是在较高的温度和湿度下(13)。由于多形体仅以固体形式存在，并且MBZ仅为口服药物，研究不同多形体的相关抗肿瘤特性最好通过经由口服施用MBZ多形体确定动物模型中的生物可利用度和功效来完成。本领域对鉴定用于治疗癌症，特别是脑癌的更有效、更一致且更安全的治疗剂存在持续需求。
发明概述
根据本发明的一个方面，提供了甲苯哒唑的药物制剂。制剂中甲苯哒唑的至少90％为多形体C，并且制剂为粒状的。
根据本发明的另一个方面，提供了一种甲苯哒唑的药物制剂，所述药物制剂包含多形体C和P-糖蛋白的抑制剂。
根据本发明的另一个方面，提供了一种药物制剂，所述药物制剂包含甲苯哒唑和非甾族抗炎药物(NSAID)。
本发明的另一个方面为施用甲苯哒唑药物制剂的方法。甲苯哒唑药物制剂可以是其中制剂中甲苯哒唑的至少90％为多形体C的粒状的制剂，或它可以是多形体C和P-糖蛋白的抑制剂的组合制剂，或它可以是包含多形体C和NSAID的甲苯哒唑制剂。根据该方法，在摄入食物之前将制剂应用于食物。
根据本发明的仍然另一个方面，提供了监测甲苯哒唑药物制剂的抗癌效力的方法。测定包含甲苯哒唑的药物制剂，并且确定多形体C的量和多形体A的量。
本发明的另一个方面为一种治疗肿瘤或降低人类发展肿瘤的风险的方法。甲苯哒唑的药物制剂，无论是其中甲苯哒唑的至少90％为多形体C的粒状的制剂、还是多形体C和P-糖蛋白的抑制剂的组合制剂、还是多形体C和NSAID的组合制剂，被施用或分配至人类以便口服摄入。所述人类患有肿瘤或处于提高的发展肿瘤的风险。
本发明的另外的方面为用于治疗肿瘤或降低发展肿瘤的风险的试剂盒。试剂盒包含(a)甲苯哒唑(任选地包含多形体C)和(b)P-糖蛋白的抑制剂或NSAID。
本发明的又另一个方面为治疗人类的肿瘤或降低发展肿瘤的风险的方法。将甲苯哒唑(任选地包含多形体C)和P-糖蛋白的抑制剂或NSAID施用或分配至人类以便口服摄入。
本领域技术人员在阅读说明书后将是明显的这些和其他实施方案为本领域提供了用于对抗高度难治性癌症的工具。
附图简述
图1A-1E.MBZ-C为具有有限毒性的最有效的多形体。
图1A和图1B.来自以下不同供应商的MBZ多形体和MBZ片剂的红外光谱：S2015和S2017(Aurochem)、Teva(在RT储存2年之后)、Medley和Janssen。两个峰代表分子中的-NH和–C＝O基团。黑色箭头指示MBZ-C对照的峰。
图1C.卡普兰-迈耶存活率曲线(Kaplan-Meier survival curve)和萤光素酶计数。植入有GL261-luc神经胶质瘤并用不同MBZ多形体(A、B和C)治疗的小鼠的卡普兰-迈耶存活率曲线。通过冠状切面(coronal cut)示出了携带GL261-luc神经胶质瘤的小鼠脑的H&E染色。在肿瘤植入之后5天，将小鼠用MBZ管饲，且对照动物用媒介物喂养。MBZ-B组中的一只小鼠推测死于药物毒性，因为在脑中未发现明显的肿瘤。指示了对照对MBZ-B以及对照对MBZ-C的p-值。MBZ-B对MBZ-C的p-值为0.72。m：以天计的生存中值(median survival)。对照：n＝6；MBZ-A:n＝5；MBZ-B:n＝6；MBZ-C:n＝6。
图1D.通过Xenogen测量的萤光素酶计数反映了用MBZ多形体治疗20天的小鼠中GL261-luc脑肿瘤的尺寸。
图1E.用来自不同供应商的MBZ片剂治疗的携带GL261-luc的小鼠的存活率曲线。对照：n＝6；S2015:n＝5；S2017:n＝6；Medley:n＝5；Janssen:n＝5。
图2A-2F.MBZ多形体的血浆和脑分布。
图2A.在以50mg/kg口服管饲MBZ-A、MBZ-B或MBZ-C之后的C57BL6小鼠中的MBZ血浆水平的时间过程。
图2B.在以50mg/kg口服管饲之后的时间过程中的MBZ-C的脑和血浆水平。对于所有脑分布研究,对动物充分灌注PBS。
图2C.MBZ-C的脑/血浆(B/P)比。收集三只小鼠在每一个时间点的数据。
图2D.在口服管饲(50mg/kg)之后6h时的MBZ多形体的脑和血浆水平。在口服管饲之后的6h时的MBZ多形体的B/P比。
图2E.MBZ-A的平均B/P比为0.32，MBZ-B的平均B/P比为0.64，且MBZ-C的平均B/P比为0.80。
图2F.MBZ-C同等地分布于脑和脑肿瘤中。将植入于小鼠额叶右侧的GL261肿瘤切除，并与对侧正常脑组织进行比较。
图3A-3D.MBZ代谢物的分布。
图3A-图3D.在口服管饲50mg/kg MBZ-C之后，分析了MBZ及其代谢物MBZ-OH(外消旋二氢甲苯哒唑(rac dihydro mebendazole)，CAS60254-95-7)和MBZ-NH2(2-氨基-5-苯甲酰基-苯并咪唑，CAS 52329-60-9)的血浆(图3A和图3C)和脑(图3B和图3C)水平。图3D示出了MBZ及其代谢物对GL261的抑制(IC50曲线)。
图4A-4C.MBZ与依克立达(elacridar)的组合。
图4A.用依克立达(ELD)治疗的GL261神经胶质瘤细胞的IC50曲线。IC50＝5.8μM。
图4B.MBZ(0.25μM)、ELD(1μM或5μM)或组合对GL261细胞的抑制。将细胞与所指示的药物孵育72h，并通过比色测定测量活细胞。
图4C.ELD提高了小鼠中MBZ的平均B/P比。
图5A-5D.MBZ与依克立达的组合提高了功效。
图5A和图5B.将用萤光素酶转染的GL261细胞植入C57BL6小鼠中，并且在植入之后5天开始治疗。将依克立达(ELD)以50mg/kg口服管饲，2小时后施用MBZ(50mg/kg)，持续第一个7天或14天治疗。此后，对于治疗的剩余部分，以相同的剂量每周5天给予MBZ。单独的ELD组用ELD管饲，持续14个日剂量。从肿瘤植入之后25天开始，通过Xenogen监测由MBZ和ELD治疗的动物的肿瘤萤光素酶信号(图5A)。
图5C和图5D.将D425成神经管细胞瘤细胞植入小鼠小脑并形成小脑肿瘤(图5C，H&E染色)。在肿瘤植入之后5天，将小鼠用以下处理：媒介物(对照)、7天的50mg/kg依克立达(ELD)、7天的ELD与一周5天的50mg/kg MBZ-C(MBZ-ELD)或单独的MBZ-C(MBZ)。
图6A-6B.(表1).表1.MBZ多形体在小鼠中的药代动力学。
图6A.使用LS-MS测量用指定的MBZ多形体口服管饲的小鼠的血浆样品中的MBZ及代谢物MBZ-NH2和MBZ-OH。在血浆AUC24h方面，其为B>C>A，其中p<0.05。
图6B.用MBZ或MBZ与依克立达(ELD)的组合管饲的小鼠中的MBZ-C及代谢物的药代动力学。
图7.GL261神经胶质瘤小鼠模型中的苯并咪唑的测试。从在肿瘤植入之后第5天开始，经由口服管饲法，对携带GL261-luc神经胶质瘤的小鼠用100mg/kg噻苯哒唑(thiabendazole)(TBZ)、氟苯哒唑(flubendazole)(FLZ)、奥芬哒唑(oxfendazole)(OXZ)、芬苯哒唑(fenbendazole)(FBZ)治疗。在Mantel-Cox检验中所有存活率的差异都不显著。n：小鼠的数目；m：以天计的生存中值。
图8.用于制备甲苯哒唑的合成方案。
图9A-9E.口服甲苯哒唑抑制两种不同结肠癌细胞系侧腹异种移植物(twodifferent colon cancer flank cell line xenografts)的生长和增殖。将两种人类结肠直肠癌细胞系HT29和SW480皮下植入到裸鼠的侧腹中，并通过口服管饲用50mg/kg MBZ处理4周。在实验过程中每周两次测量肿瘤体积、取平均值、并作图。HT29异种移植物(图9A)和SW480异种移植物(B)生长抑制曲线。在实验结束时将来自每一组的切除的侧腹肿瘤称重，并与未治疗的对照进行比较(图9C、图9D)。将石蜡包埋的侧腹肿瘤组织的Ki67增殖标志物染色。在两种模型中，MBZ治疗的组织显示出显著较少的阳性(棕色核)染色(图9E)。来自每一个载玻片的5个随机选择的视野以Ki67-阳性细胞百分比×100/总细胞数目定量，并代表5只动物的平均值±SEM。*，P<0.05。
图10A-10D.甲苯哒唑降低APC min/+小鼠肠内息肉的形成。在化疗防护研究结束时，对APC min/+小鼠的小肠和结肠进行分析，并且对息肉的总数目/小鼠取平均值并跨多个治疗组进行比较(图10A)；来自对照对MBZ+舒林酸组合治疗的APC min/+中部小肠和远端小肠的代表性图(图10B)；来自对照(图10C，左侧)和MBZ+舒林酸组合治疗(图10C，右侧)的代表性H&E染色的瑞士卷样小肠(swiss rolled intestine)。每一个治疗组中息肉的数目和位置的结果被列成表(图10D)。
图11A-11C.甲苯哒唑和舒林酸的组合协同降低APC min/+小鼠肠的所有区段中的肿瘤发生和肿瘤尺寸。针对近端、中部和远端小肠和结肠，对每一个治疗组的平均息肉数目制图(图11A)。测量各个息肉并基于尺寸进行分类。分别针对肠的每一个部分分析舒林酸与MBZ+舒林酸组合的平均息肉数目(图11B)。统计学分析示于图11C中。
图12A-12C.甲苯哒唑在治疗的Min小鼠息肉和侧腹异种移植物中显示出抗炎和抗血管生成作用。使用c-myc、COX-2和CD31抗体通过免疫组织化学分析侧腹肿瘤组织和APCmin息肉的石蜡包埋切片。示出每一个的代表性图片(图12A)。分析来自单独HT29(对照n＝5，MBZ n＝5)和SW480(对照n＝5，MBZ n＝4)侧腹异种移植物组织的裂解物的c-myc和Bcl-2蛋白表达(图12B)，显示在用MBZ治疗的大多数情况下，这些蛋白减少。类似地，在息肉方面，特别是在组合治疗的情况下，min小鼠存在c-myc和Bcl-2的减少。探测代表每一个治疗组的APC min/+小鼠肠组织的c-myc和Bcl-2(图12C)。C1＝对照，M1、M2＝MBZ治疗的，S1、S2＝舒林酸治疗的，M/S1、M/S2＝MBZ+舒林酸组合治疗。将GAPDH用作荷载对照(loadingcontrol)。
图13.甲苯哒唑加舒林酸的组合对APC min/+肠中的炎性细胞因子和血管生成因子的减少比任一单独的药物多。将对TNFa、IL-6、VEGF、MCP-1、IL-1B、G-CSF、GM-CSF、和FGFβ反应性的小鼠ELISA比色条用于测量每一个治疗组中促炎性标志物的降低。将相对吸光度值取平均值，并将值的百分比差异与未治疗的对照小鼠的结果进行比较(对于每一个治疗组平均n＝3只小鼠)。
发明详述
本发明人已经开发了用于治疗肿瘤，特别是脑肿瘤、乳腺肿瘤和肺肿瘤的有效且安全的制剂。也可以治疗其他肿瘤，包括但不限于结肠直肠肿瘤、卵巢肿瘤、肉瘤肿瘤、胃肿瘤、食管肿瘤、前列腺肿瘤、胰腺肿瘤、肝肿瘤、和甲状腺肿瘤。
已经发现甲苯哒唑的多形体C是治疗肿瘤最有效的多形体。然而，通常，由于多形体C的损失或向其他多形体的转化，制剂的效力似乎随时间而减弱。优选地，本发明中使用的甲苯哒唑的制剂为至少90％的多形体C。在一些情况下，其可以是至少91％、92％、93％、94％、95％、96％、97％、98％或99％的多形体C。甲苯哒唑可以任选地为粒状的。这提供了用于添加至食物(comestibles)和提供可口的药物的合适制剂。其还可以增加胃吸收。任选地，粒状的形式可以为包衣的。这可以增加药物的适口性。用于肠溶包衣的典型材料包括脂肪酸、蜡、虫胶、塑料和植物纤维。可以使用本领域中使用的任何此类肠溶包衣。
P-糖蛋白(P-gp)、通透性糖蛋白或血浆糖蛋白为一种主动的、外排性的(efflux)、膜结合的转运蛋白泵。它为ATP结合盒(ABC)超家族的成员。它有许多名字，包括ABCB1、MDR1、PGY1、和CD243。它参与肿瘤中的多重耐药性。在这种情况下，它可以被称为多重耐药泵。任何P-gp的抑制剂都可以用于具有甲苯哒唑的制剂中，任何P-gp的抑制剂包括但不限于依克立达、孕酮、gomasin A、胡椒碱、apocyanin、安普那韦(amprenavir)、奎尼丁(quinidine)和伐司朴达(valspodar)。P-gp抑制剂可以与甲苯哒唑一起共包被，或者P-gp抑制剂可以是未包被的或单独包被的。两种剂可以被同时、组合或单独施用。两种剂可以作为组合方案的一部分彼此在数天或数周内递送。
在一些制剂中和对于一些用途诸如预防用途，多形体C可以与非甾族抗炎药物一起配制。这些包括，但不限于，阿司匹林、胆碱和水杨酸镁、水杨酸胆碱、塞来昔布(celecoxib)、双氯芬酸钾、双氯芬酸钠、双氯芬酸钠与米索前列醇(Diclofenac sodiumwith misoprostol)、二氟尼柳(Diflunisal)、依托度酸(Etodolac)、非诺洛芬钙(Fenoprofen calcium)、氟比洛芬(Flurbiprofen)、布洛芬(Ibuprofen)、吲哚美辛(Indomethacin)、酮洛芬(Ketoprofen)、水杨酸镁、甲氯芬那酸钠(Meclofenamatesodium)、甲芬那酸、美洛昔康(Meloxicam)、萘丁美酮(Nabumetone)、萘普生(Naproxen)、萘普生钠、噁丙嗪(Oxaprozin)、吡罗昔康(Piroxicam)、罗非考昔(Rofecoxib)、双水杨酯(Salsalate)、水杨酸钠、舒林酸、托美丁钠(Tolmetin sodium)和伐地考昔(valdecoxib)。该组合在预防作用上是有效的。
具有较高的发展结肠直肠癌风险的个体为具有各种环境、行为和遗传因素中的任一个因素的那些个体。这些包括，但不限于，超重或肥胖、身体活动不足、高红肉(诸如牛肉、猪肉、羊肉或肝脏)和加工肉类的饮食、吸烟、酗酒(heavy alcohol use)、结肠直肠息肉或结肠直肠癌的个人病史、炎性肠病的个人病史、结肠直肠癌或腺瘤性息肉的家族史、家族性癌症综合征、家族性腺瘤性息肉病(FAP)、Lynch综合征、轻表型FAP(attenuated FAP)、Turcot综合征、Peutz-Jeghers综合征、MUTYH相关性息肉病和2型糖尿病。这些个体可以得益于用甲苯哒唑，特别地用多形体C的预防，且更特别地得益于用甲苯哒唑和非甾族抗炎药物的组合治疗的预防。两种剂可以被同时、组合或单独施用。两种剂可以作为组合预防方案的一部分彼此在数天或数周内递送。甲苯哒唑的外消旋混合物或甚至包含的多形体A或B比C多的组合物可以用于预防性和/或治疗性抗癌治疗。
制剂对食品的应用可以包括本领域已知的任何手段。例如，喷洒、震荡、喷涂、浸泡(dowsing)或混合可以用于将制剂应用于食物。用于口服摄入的制剂的施用或分配可以包括，例如，在杯子中、在盘子上或直接递送到受试者的口中。
可以被治疗的脑肿瘤包括星形细胞瘤；非典型畸胎样横纹肌样瘤(ATRT)；软骨肉瘤；脉络丛肿瘤；颅咽管瘤；囊肿；室管膜瘤；生殖细胞肿瘤；成胶质细胞瘤；神经胶质瘤；血管瘤；脂肪瘤；淋巴瘤；成神经管细胞瘤；脑膜瘤；转移性脑肿瘤；神经纤维瘤；神经元&混合神经元胶质肿瘤；少突星形细胞瘤；少突神经胶质瘤；松果体肿瘤；垂体肿瘤；PNET；和神经鞘瘤(Schwannoma)。
可以用所述制剂治疗的人类肿瘤包括急性成淋巴细胞性白血病(ALL)；急性骨髓性白血病(AML)；青少年中的癌症；儿童肾上腺皮质癌；AIDS相关的癌症；卡波西肉瘤；淋巴瘤；肛门癌；阑尾癌；儿童星形细胞瘤；儿童中枢神经系统的非典型畸胎样瘤/横纹肌样瘤；儿童基底细胞癌–参见皮肤癌(非黑色素瘤)；肝外胆管癌；儿童膀胱癌；骨癌；尤文肉瘤家族肿瘤(Ewing Sarcoma Family of Tumors)；骨肉瘤和恶性纤维组织细胞瘤；儿童脑干神经胶质瘤；脑肿瘤；儿童星形细胞瘤；儿童脑和脊髓肿瘤治疗概览；儿童脑干神经胶质瘤；儿童中枢神经系统非典型畸胎样瘤/横纹肌样瘤；儿童中枢神经系统胚胎肿瘤；儿童中枢神经系统生殖细胞肿瘤；儿童颅咽管瘤；儿童室管膜瘤；男性儿童乳腺癌；妊娠乳腺癌；和儿童支气管肿瘤；伯基特淋巴瘤–参见非霍奇金淋巴瘤；儿童类癌肿瘤；儿童不明原发性胃肠道癌；儿童心脏(Cardiac)(心(Heart))肿瘤；儿童中枢神经系统非典型畸胎样瘤/横纹肌样瘤；儿童胚胎性肿瘤；儿童生殖细胞肿瘤；原发性淋巴瘤；儿童子宫颈癌；儿童癌症；儿童脊索瘤；慢性淋巴细胞白血病(CLL)；慢性髓细胞性白血病(CML)；慢性骨髓增生性赘生物；结肠癌；儿童结肠直肠癌；儿童颅咽管瘤；皮肤T细胞淋巴瘤–参见蕈样肉芽肿瘤和Sézary综合征；肝外胆汁管道肿瘤；原位导管癌(DCIS)；儿童中枢神经系统胚胎肿瘤；子宫内膜癌；儿童室管膜瘤；儿童食管癌；儿童嗅神经母细胞瘤；尤文肉瘤；儿童颅外生殖细胞肿瘤；性腺外生殖细胞肿瘤；肝外胆管癌；眼癌；眼内黑素瘤；视网膜母细胞瘤；输卵管癌–参见卵巢上皮癌、输卵管癌和原发性腹膜癌；恶性骨纤维组织细胞瘤和骨肉瘤；胆囊癌；儿童胃(Gastric)(胃(Stomach))癌；胃肠道类肿瘤；儿童胃肠道间质瘤(GIST)；儿童中枢神经系统生殖细胞肿瘤；儿童颅外疾病；性腺外疾病；卵巢疾病；睾丸疾病；妊娠滋养细胞疾病；神经胶质瘤–参见儿童脑干脑肿瘤；毛细胞白血病；儿童头颈癌；儿童心脏癌；肝细胞(肝)癌；朗格汉斯细胞组织细胞增生症；霍奇金淋巴瘤；下咽癌；眼内黑素瘤；胰岛细胞肿瘤，胰腺神经内分泌肿瘤；卡波西肉瘤；肾肿瘤；肾细胞肿瘤；肾母肿瘤(Wilms Tumor)和其他儿童肾肿瘤；朗格汉斯细胞组织细胞增生症；儿童喉癌；白血病；急性成淋巴细胞性白血病(ALL)；急性骨髓性白血病(AML)；慢性淋巴细胞白血病(CLL)；慢性髓细胞性白血病(CML)；毛细胞癌；唇和口腔癌；儿童肝癌(原发性)；儿童肺癌；非小细胞肺癌；小细胞肺癌；淋巴瘤；AIDS相关的淋巴瘤；伯基特淋巴瘤–参见非霍奇金淋巴瘤；皮肤T细胞淋巴瘤–参见蕈样肉芽肿和Sézary综合征；霍奇金淋巴瘤；非霍奇金淋巴瘤；原发性中枢神经系统(CNS)癌症；巨球蛋白血症；男性乳腺癌；恶性骨纤维组织细胞瘤和骨肉瘤；儿童黑素瘤；眼内(眼)癌；默克尔细胞癌；儿童恶性间皮瘤；隐匿性原发性的转移性鳞状颈癌；牵涉NUT基因的中线呼吸道癌；口腔癌；儿童多发性内分泌肿瘤综合征；多发性骨髓瘤/浆细胞瘤；蕈样肉芽肿；骨髓增生异常综合征；骨髓增生异常赘生物/骨髓增生性赘生物；慢性髓细胞性白血病(CML)；急性骨髓性白血病(AML)；多发性骨髓瘤；慢性骨髓增生性赘生物；鼻腔和鼻旁窦癌；儿童鼻咽癌；成神经细胞瘤；非霍奇金淋巴瘤；非小细胞肺癌；儿童口腔癌(Oral Cancer)；口腔癌；唇和口咽癌；骨肉瘤和恶性骨纤维组织细胞瘤；儿童卵巢癌；上皮细胞肿瘤；生殖细胞肿瘤；低度恶性潜在肿瘤(Low Malignant Potential Tumor)；儿童胰腺癌；胰腺神经内分泌肿瘤(胰岛细胞肿瘤)；儿童乳头状瘤病；儿童副神经节瘤；鼻旁窦和鼻腔癌；甲状旁腺癌；阴茎癌；咽癌；儿童嗜铬细胞瘤；垂体肿瘤；浆细胞赘生物/多发性骨髓瘤；儿童胸膜肺母细胞瘤；妊娠和乳腺癌；原发性中枢神经系统(CNS)淋巴瘤；前列腺癌；直肠癌；肾细胞(肾)癌；肾盂和输尿管移行细胞癌；视网膜母细胞瘤；儿童横纹肌肉瘤；儿童唾液腺癌；肉瘤；尤文肉瘤；卡波西肉瘤；骨肉瘤(骨癌)；横纹肌肉瘤；软组织；子宫；Sézary综合征；儿童皮肤癌；黑素瘤；默克尔细胞癌；非黑素瘤；小细胞肺癌；小肠癌；软组织肉瘤；儿童鳞状细胞癌–参见皮肤癌(非黑素瘤)；隐匿性原发性的转移性鳞状颈癌；儿童胃(胃)癌；皮肤T细胞淋巴瘤–参见蕈样肉芽肿和Sézary综合征；儿童睾丸癌；喉癌；儿童胸腺瘤和胸腺癌；儿童甲状腺癌；儿童不明原发性肾盂和输尿管移行细胞癌；儿童不罕见癌症；输尿管和肾盂移行细胞癌；输尿管癌；子宫癌，子宫内膜癌；子宫肉瘤；儿童阴道癌；外阴癌；巨球蛋白血症；和肾母细胞瘤。
试剂盒为在单个容器中包装两个或更多个物品的工具(means)。试剂盒可以包含多个内部容器以保持组分分离。试剂盒可以包含说明或其他印刷品(诸如标准曲线)以便于使用。也可以在电子存储介质诸如盘或驱动器上提供信息。可以通过参考网站来提供信息。还可以提供可用于治疗癌症的其他组分。可以包括用于施用的工具。可以在试剂盒中提供用于混合组分的容器。
甲苯哒唑可以通过本领域已知的任何方法被制备。在一种方法中，对氯甲苯被用作起始材料。参见图8。通常对于纯化，在室温使用甲醇使多形体C结晶。甲苯哒唑商购可得。
在本研究中，我们证明MBZ可以以显著的浓度和高的脑与血浆比到达脑组织。在口服施用之后1小时与8小时之间，MBZ-C维持高于0.767μg/g(相当于2.7μM)的脑水平，其中C最大为2,016μg/g(相当于7.1μM)。这些值超过MBZ对VEGFR2激酶的体外IC50(4.3μM)和组织培养中的一系列神经胶质瘤和成神经管细胞瘤细胞系中的IC50(0.11-1μM)(3,4)。此外，MBZ-C成为最有效的多形体，达到0.82的AUC0-24h B/P比。这是令人鼓舞的，因为替莫唑胺(temozolomide)，对于高级神经胶质瘤的标准治疗，被测量为在小鼠中具有0.408的B/P比，而在人类中具有0.2的脑脊液(CSF)/血浆比(21,22)。在我们的研究中，MBZ在GL261脑肿瘤和正常脑组织中的分布差异不显著。值得提及的是，与其他神经胶质瘤模型相似，GL261神经胶质瘤的后期生长(advanced growth)在肿瘤中产生大量的血液，并且充分的灌注对于消除血液中MBZ的污染是必需的。
在三种多形体中，仅为用MBZ-C测量的AUC0-24h的19％的非常低的血浆存在解释了MBZ-A在GL261神经胶质瘤模型中未显示出功效。MBZ-A的低生物可利用度和较差的抗肿瘤功效与先前对其在抗寄生虫应用方面表现不理想的报道一致(10,12)。相比之下，MBZ-B能够在血浆中达到MBZ-C的AUC0-24h的165％，同时通过在6h测量证明的，显示相似脑浓度。这可以解释MBZ-B在携带GL261神经胶质瘤的小鼠中的升高的毒性，因为与MBZ-C相比，抗脑肿瘤功效基本相同。因此，我们建议MBZ-C为脑肿瘤疗法中的更好选择。实际上，尽管我们不知道在我们先前研究中曾经是有效的Teva品牌的MBZ中多形体C的原始浓度(3)，但是这些片剂可能由于在3年内在标准RT条件下转化为多形体A而可能已经损失其功效，因此由MBZ-C制成的片剂应该储存在较低的温度下(13)。
MBZ的小尺寸(295道尔顿)和亲脂性有利于脑渗透(2)。值得注意的是，迄今所测试的共有相似的物理性质的其他苯并咪唑，诸如阿苯哒唑(albendazole)、噻苯哒唑、氟苯哒唑、奥芬哒唑和芬苯哒唑，甚至在比MBZ更高的剂量也未能提高或仅略微提高携带GL261神经胶质瘤的小鼠的存活率(补充图1)(3)。正如我们先前所观察到的，饲料中的芬苯哒唑使无胸腺裸鼠对成神经管细胞瘤细胞系的植入物的摄取受损(3)，通过在植入之后5天管饲，其仅在GL261神经胶质瘤模型中产生非常少量且统计学上不显著的存活率的提高。存在可能促成多种苯并咪唑的脑肿瘤治疗的鲜明差异的几个因素。对于MBZ多形体A显示的一种因素，可能由于不良吸收而导致的低生物可利用度，可能对这类药物的治疗性能是不利的。其次，这些苯并咪唑的脑渗透尚未被充分研究，并且对于任何显著的治疗效果可能是不足的。此外，虽然在最近的报道中，MBZ已经牵涉抑制多种酪氨酸激酶，而阿苯哒唑显示缺乏此类能力，表明苯并咪唑间的抗肿瘤机制的差异(4,7,8)。
P-糖蛋白(P-gp，ABCB1)为ATP结合盒(ABC)转运蛋白，并且在限制药物摄取到脑中起重要作用(23)。依克立达为P-gp外排转运蛋白的第三代抑制剂，并且还抑制乳腺癌耐药蛋白(BCRP，ABCG2)，即，BBB中的另一种关键外排转运蛋白(24)。先前的研究证明，啮齿动物中依克立达的共施用已经显著地多倍增加了许多癌症药物，诸如舒尼替尼(sunitinib)、帕唑帕尼(pazopanib)、埃罗替尼(erlotinib)和克唑替尼(crizotinib)的脑分布，这些药物在体外和动物研究中被确定为P-gp和ABCG2的底物(25-28)。此外，在I期临床试验中已经发现依克立达为安全的(19)。在本研究中，我们研究了依克立达与可能增强其功效的MBZ的组合。我们发现该组合大大改进了两种原位脑肿瘤模型的存活率。然而，在这项有限的研究中，MBZ的B/P比例和脑AUC0-8h未伴随依克立达的共施用而显示统计学上显著的差异，尽管其有能力显著增加携带脑癌的小鼠的存活率。当分析代谢物时，啮齿动物和人类中的两种主要代谢物之一，MBZ-NH2(20)，由于共施用依克立达在B/P比(2.5倍)和AUC0-8h(2.4倍)方面显著提高。还值得注意的是，我们发现与正常脑组织相比MBZ-NH2优先地在GL261脑肿瘤中积累。尽管这些数据可能表明，MBZ-NH2是P-gp和/或ABCG2的可能底物，但这一发现的意义在这时尚不清楚。MBZ-NH2可能具有直接的细胞毒性作用似乎不太可能，因为进一步的测试仅显示对培养的GL261细胞的极小的细胞毒性。然而，MBZ-NH2通过在酸性肿瘤环境中优先积累而增加毒性不能被排除，并且需要进一步的研究。进一步的研究包括研究MBZ和依克立达的相互作用，特别是外排转运蛋白的潜在底物谱与MBZ的相互作用，以便更好地理解与MBZ的组合并从而对其进行改进。
MBZ-C为脑肿瘤治疗中最有效的多形体。MBZ-C与依克立达(一种P-糖蛋白抑制剂)的组合可以大大改进功效。该组合可以用于治疗，尤其是，高级神经胶质瘤和/或成神经管细胞瘤。该组合可以作为治疗方案的一部分共施用或单独施用。
以上公开内容大体地描述了本发明。本文公开的所有参考文献通过引用明确并入。通过参考以下具体实施例可以获得更完整的理解，这些具体实施例仅出于说明的目的而提供，并不意图限制本发明的范围。
实施例1
材料和方法
化学物质和药物
来自Janssen Pharmaceuticals和Medley Pharmaceuticals的MBZ片剂(500mg)于2013年从在巴西(Brazil)的当地药店购买，并储存于-20℃冰箱。来自TevaPharmaceuticals USA的MBZ片剂(100mg)于2011年从在翰霍普金斯医院的门诊药房(Outpatient Pharmacy at Johns HopkinsHospital)购买，并储存于室温(RT)。Teva已经自2011年10月起在美国市场停产MBZ。Aurochem Laboratories LTD.(Mumbai,India)制造包含通常具有混合的多形体的通用活性药物成分(API)的MBZ片剂(500mg)S2015及具有已揭示的(revealed)特定API的S2017(多形体C)。Aurochem还友好地向我们供应了MBZ多形体A、B和C。依克立达(ELD；GF120918；N-(4-(2-(1,2,3,4-四氢-6,7-二甲氧基-2-异喹啉基)乙基)苯基)-9,10-二氢-5-甲氧基-9-氧代-4-吖啶甲酰胺))从Sigma(St.Louis,MO,USA)购买。噻苯哒唑(TBZ)、氟苯哒唑(FLZ)、奥芬哒唑(OXZ)和芬苯哒唑(FBZ)购自Sigma(St.Louis,MO,USA)。
细胞系和组织培养物
用于本研究的细胞系：小鼠神经胶质瘤细胞系GL261和人类成神经管细胞瘤异种移植物D425Med(D425)如先前描述获得(3,14)。将GL261和D425细胞在包含5％CO2的加湿空气中在37℃维持在补充有10％胎牛血清和抗生素的DMEM培养基中。之前描述了表达萤火虫萤光素酶的GL261-luc细胞(3)。
MBZ多形体的红外光谱
使用Direct DetectTM红外(IR)光谱仪(Millipore,Billerica,MA,USA)。先将MBZ粉末或研磨为粉末的MBZ片剂与水混合，遵循制造商的说明应用于卡片并空气干燥。如之前描述得分析并比较–C＝O和–NH的光谱(9)。
颅内小鼠模型
所有动物研究都被约翰霍普金斯大学(Johns Hopkins University)动物保护和使用委员会(Animal Care and Use Committee)(ACUC)批准。GL261-luc在小鼠脑的额叶和D425细胞在小鼠脑的小脑的颅内植入遵循之前描述的程序(3,4)。在肿瘤植入之后5天，对小鼠每周5天管饲以50mg/kg的MBZ或其他苯并咪唑。通过将粉末与PBS和芝麻油(1:1,v:v)(Sigma)混合或通过将片剂研磨为粉末并重悬于以上提及的PBS/芝麻油混合物中来准备MBZ和其他苯并咪唑。类似于之前描述的，将依克立达准备为10mg/ml在0.5％羟丙基甲基纤维素和0.5％Tween 80的PBS中的悬浮液(15)。
MBZ药代动力学研究
5-6周龄的雌性C57BL6小鼠从NCI购买。动物实验根据批准的IACUC方案执行，并符合当地和国家指导方针。将所有MBZ多形体和片剂都以50mg/kg的剂量通过口服管饲施用。将依克立达在施用MBZ-C之前2小时以50mg/kg通过口服管饲施用。先将小鼠(3只动物/时间点)经由腹膜内注射60μl储备溶液进行麻醉，所述储备溶液在无菌0.9％NaCl溶液中包含盐酸氯胺酮(75mg/kg)(100mg/ml；盐酸氯胺酮(ketamine HCl；Abbot Laboratories,Chicago,IL,USA)和赛拉嗪(7.5mg/kg)(100mg/ml；Phoenix Pharmaceutical,St.Joseph,MO,USA)。然后通过从左心室穿刺和吸液(aspiring)取得血液样品。将血液样品与5mM EDTA混合，并以10000g离心5分钟，以获得用于进一步分析的血浆。
对于脑分布研究，在麻醉下通过使用20号针(20gauge needle)缓慢注射到左心室对小鼠灌注补充有20μl 0.02％肝素的20ml冰冷盐水。将右心房切开，然后允许血液流出。黄色的肾指示好的灌注质量，好的灌注质量对消除脑组织中的血液是必需的。在携带GL261肿瘤的小鼠中，通过容易识别的颜色和色度(shade)差异，将GL261肿瘤与正常脑区分开。将GL261肿瘤用解剖刀分离，并且将正常脑组织从对侧半球切下。将所有脑样品都称重并在处理前储存于-80℃。
MBZ施用之后随时间的变化(as a function of time)获取血液、脑和脑肿瘤组织。为了比较MBZ多形体的药代动力学，对三个列队的小鼠各自通过口服管饲施用50mg/kg的单一剂量。对于初步比较研究，在MBZ施用之后在1小时、2.5小时、4小时、6小时、8小时、15小时和24小时时获得血浆样品，而仅在6小时时收集脑组织。对于伴随或不伴随ELD的多形体C的比较研究，在MBZ施用之后2.5小时、4小时和8小时时获取血浆和脑组织样品。还获取对于单独的多形体C的脑肿瘤组织样品。
MBZ和代谢物的测量
定量血浆、脑和脑肿瘤组织中的MBZ及两种代谢物2-氨基-5-苯甲酰基-苯并咪唑(MBZ-NH2,CAS 52329-60-9)和外消旋二氢甲苯哒唑(MBZ-OH,CAS 60254-95-7)。以200mg/ml的浓度在血浆中制备组织匀浆，然后提取。用0.1ml包含0.5μg/ml内标A620223.69的甲醇从50μl血浆或组织匀浆提取甲苯哒唑及代谢物。在离心之后，将上清液(60μl)与水(40μl)混合，并然后转移到自动进样小瓶中。在室温用Atlantis dC18(2.1×100mm,3μm)柱用包含0.1％甲酸的甲醇/水流动相(60:40，v:v)使用0.25ml/min的等度流速持续5分钟实现分离。使用AB Sciextriple quadrapoleTM 5500质谱检测器(Applied Biosystems,Foster City,CA,USA)使用以正离子模式(positive mode)运行的电喷雾电离来监测分析物。将光谱仪编程为允许MBZ、MBZ-NH2、MBZ-OH、和A620223.69的[MH+]离子分别以m/z 296.0、238.0、298.0、和287.2穿过第一个四极杆(Q1)并进入碰撞池(Q2)。监测通过第三个四极杆(Q3)的MBZ(m/z 263.9)、MBZ-NH2(m/z 105.1)、MBZ-OH(m/z266.0)和A620223.69(m/z 124.1)的子代离子。通过使用二次方程式以1/x加权函数对稀释度多达1:100(v:v)的5ng/ml至500ng/ml(MBZ)和1ng/ml至500ng/ml(代谢物)的范围使用相对于内标的面积比峰值的分析来计算MBZ的校准曲线。如果一个或更多个浓度低于定量限值，则将药物动力学计算值指定为定量限值的1/2的值。如果连续两个时间点低于定量限值，则将后一个从分析中排除。
对于MBZ及其代谢物两者计算在每一个时间点的平均血浆和脑浓度。1.045g/ml用作啮齿动物脑组织的平均湿密度(16)。如在 第6.3版(PharsightCorp.,Mountain View,CA)中分析的，使用非房室模型法(noncompartmental method)从平均MBZ及其代谢物浓度-时间数据计算药代动力学参数。C最大和T最大为来自平均浓度数据的观察值。使用对数线性梯形方法(log-linear trapezoidal method)计算AUC最后。由浓度-时间曲线的终末阶段的斜率确定λz。终末半衰期(T1/2)通过将0.693除以λz来确定。如果λz的r2为<0.9，则不报告T1/2。使用AUC最后：代谢物AUC最后/MBZ AUC最后计算MBZ的相对系统暴露。使用AUC最后：脑或脑肿瘤AUC最后/血浆AUC最后计算与血浆相比在脑或脑肿瘤中的相对系统暴露。
统计分析
通过GraphPad Prism 5.0分析动物存活率数据。通过Mantel-Cox检验确定p-值。低于0.05的p-值被接受为统计学显著的。
对于将多形体或与ELD一起的施用进行比较的药代动力学研究，在给出在每一个时间点的平均浓度的计算方差的情况下，使用Bailer方法估计AUC最后的方差(17)。这然后是使用Z检验的成对比较，以确定由AUC最后表示的MBZ暴露之间是否存在显著差异(18)。使用非参数Wilcoxon符号秩检验进行个体数据的比较，使用All Pairs Tukey-Kramer检验进行事后分析。显著水平为P<0.05。
实施例2
多形体C对治疗小鼠中的脑肿瘤最有效
通过将几种商购可得的片剂(Janssen、Medley和Teva)以及两种定制的片剂(Aurochem S2015，其使用通常具有混合多形体的通用API；和S2017，其被指定为纯MBZ-C)的IR光谱与单独的MBZ进行比较，我们检验了这些片剂的多形体含量(图1A和B)。基于–C＝O和-NH键的IR峰值，我们确定了Janssen和Medley片剂以及Aurochem S2017主要由MBZ-C制成。已经在RT储存了2年的Aurochem S2015和Teva片剂大体上显示MBZ-A的光谱。作为对照，将多形体A、B和C溶解于DMSO中，并单独地与GL261神经胶质瘤细胞孵育，其显示等同的细胞毒性(数据未示出)。
MBZ-A似乎对治疗携带颅内GL261神经胶质瘤的小鼠无效，而MBZ-C显示出最佳功效(图1C)。尽管MBZ-B显示与MBZ-C相似的存活率，但它在6只处理的小鼠中引起更多的毒性，伴随1例治疗相关的死亡(图1C)。功效数据在以下意义上恰当地反映了MBZ片剂的多形体组成：S2015无效，而MBZ-C制成的其他片剂都显示了显著功效，将对照组的29天平均存活期延长至42-45天(图1E)。
实施例3
MBZ以显著水平到达脑
在口服给药50mg/kg之后，MBZ-C达到16,039h*ng/ml的血浆AUC0-24h(图2A和表1A)。相比之下，MBZ-B达到26,474h*ng/ml的血浆AUC0-24h，而MBZ-A血浆AUC0-24h仅达到3,052h*ng/ml，目前在所有三种多形体中最低(对于AUC0-24h，P<0.05，其中MBZ-B>MBZ-C>MBZ-A；表1A)。彻底灌注之后的脑组织的测量显示MBZ-C跨越一段时间过程显著存在，与血浆MBZ水平密切相关，其中脑/血浆(B/P)比在8小时期间保持相对稳定为平均0.75(图2B-2C)。在口服管饲之后6h时比较多形体，我们发现MBZ-C和MBZ-B达到相似的脑水平，尽管在血浆中MBZ-B有较高的水平和AUC0-24h(图2D和图6，表1A)，导致MBZ-C的平均B/P比比MBZ-B略微更有利(C为0.80，对比，B为0.64，以及A为0.29，p＝0.055)(图2E)。这充分证实了图1C中的功效数据，其中MBZ-B和MBZ-C在GL261模型中显示出相似的存活率益处(平均存活期：MBZ-B 45天对比MBZ-C 48.5天)。然而，值得注意的是，MBZ-B显示更大的毒性，导致六只被治疗的动物中一只小鼠的早期死亡(图2D)。GL261脑肿瘤和对侧脑组织的分析指示MBZ-C在脑肿瘤和正常脑组织中的同等分布(图2D)。
实施例4
MBZ代谢物的药代动力学
我们确定了MBZ多形体的主要代谢物MBZ-NH2和MBZ-OH的血浆水平(对于MBZ-NH2的AUC0-24h，P<0.05，其中MBZ-B>MBZ-C>MBZ-A；对于MBZ-OH的AUC0-24h，P<0.05，其中MBZ-B与MBZ-C>MBZ-A；Table1A)。血浆和脑中MBZ-C代谢物的水平大体遵循MBZ-C浓度的相同模式(图3A和B)。MBZ-NH2在血浆中显示出比MBZ-OH高的水平(图3A)，其中AUC0-24h与MBZ-OH的5,781h*ng/ml相比为10,516h*ng/ml(表1A)。明显地，以相反的模式，在C最大和AUC0-24h方面，测量到MBZ-NH2在脑中的水平比MBZ-OH低得多(图3B和表1A)。有趣地，在GL261神经胶质瘤中，MBZ-NH2达到比对侧脑中的显著更高的水平(图3C)。为了阐明MBZ代谢物的抗肿瘤作用，我们比较了GL261细胞中MBZ、MBZ-OH和MBZ-NH2的IC50，并确定了MBZ-NH2为MBZ的体外细胞毒性最小的衍生物(图3D)。
实施例5
MBZ与依克立达的组合。
在肿瘤和周围脑组织中达到足够的治疗浓度为几乎所有脑癌治疗所面临的关键挑战。口服施用之后4小时，我们发现MBZ-C脑浓度以2,016ng/g(相当于7.1μM)达到峰值(表1A)，这远高于培养的神经胶质瘤和成神经管细胞瘤细胞的IC50(0.11-1μM)，并且也高于MBZ对VEGFR2激酶的4.3μM的体外抑制IC50。相对高的脑浓度可能有助于解释脑肿瘤模型中的MBZ功效。然后，我们推测，MBZ的脑分布的进一步增加将是期望的，因为它可以增加治疗功效。除了纯机械屏障以外，BBB采用主动外排机制来限制药物进入，诸如P-糖蛋白(P-gp)。依克立达(ELD)为抑制P-gp以及乳腺癌耐药蛋白(BCRP)的有效的第三代抑制剂，并且依克立达的共施用已经增加了几种药物的脑渗透(15,19)。我们首先检查了依克立达在GL261小鼠神经胶质瘤细胞中的细胞毒性，并确定其IC50为5.8μM(图4A)。将依克立达与0.25μM MBZ组合仅极小地增加体外细胞毒性(图4B)。在MBZ-C之前两小时，口服施用50mg/kg依克立达就AUC0-8h来看未显著改变MBZ的脑浓度，同时2.5h、4h和8h的B/P比平均值从0.75轻微升高到1.03，然而，这是统计学上不显著的(表1B和图4C)。有趣地，这伴随着MBZ-NH2的显著增加，并且当用依克立达和MBZ-C组合治疗时脑中B/P比从0.12提高至0.30(表1B)。
实施例6
与依克立达组合改进MBZ的治疗
依克立达和MBZ的联合疗法增加了GL261同系神经胶质瘤和D425异种移植物成神经管细胞瘤模型的存活率受益(图5)。这通过将7天或14天的50mg/kg依克立达治疗添加至50mg/kg的标准MBZ(MBZ-C)方案来实现。具体地，在GL261中，取决于治疗长度，联合疗法将生存中值提高到92.5天和110.5天，这是从单独的MBZ的53天以及29.5天(对照)和34天(单独的依克立达)的显着增加(图5B)。类似地，在原位D425成神经管细胞瘤异种移植物模型中，依克立达与MBZ的组合将生存中值增加至77天(图5D)。这是对具有53天存活率的仅MBZ治疗和单独的依克立达的显著改进，单独的依克立达在该特定动物模型中显示9天的极小存活率受益。
尝试用依克立达和MBZ进行延长的治疗过程，然而增加的毒性诸如严重的体重损失和死亡率限制了这些研究(数据未示出)。
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Claims (59)
1.一种甲苯哒唑的药物制剂，其中所述制剂中所述甲苯哒唑的至少90％为多形体C，并且其中所述制剂为粒状的。
2.如权利要求1所述的药物制剂，其中所述粒状的制剂为包衣的。
3.如权利要求1所述的药物制剂，其中所述制剂中所有甲苯哒唑的至少95％为多形体C。
4.如权利要求1所述的药物制剂，其中所述制剂中所有甲苯哒唑的至少98％为多形体C。
5.如权利要求1所述的药物制剂，其中所述制剂中所有甲苯哒唑的至少99％为多形体C。
6.如权利要求1所述的药物制剂，所述药物制剂还包含P-糖蛋白的抑制剂。
7.如权利要求6所述的药物制剂，其中所述P-糖蛋白的抑制剂为依克立达。
8.如权利要求1所述的药物制剂，所述药物制剂还包含非甾族抗炎药物(NSAID)。
9.如权利要求8所述的药物制剂，其中所述NSAID为舒林酸。
10.一种甲苯哒唑的药物制剂，所述药物制剂包含多形体C和P-糖蛋白的抑制剂。
11.如权利要求10所述的药物制剂，其中所述制剂为粒状的。
12.如权利要求11所述的药物制剂，其中所述制剂为包衣的。
13.如权利要求10所述的药物制剂，其中所述P-糖蛋白的抑制剂为依克立达。
14.一种甲苯哒唑和NSAID的药物制剂。
15.如权利要求14所述的药物制剂，其中所述制剂为粒状的。
16.如权利要求15所述的药物制剂，其中所述制剂为包衣的。
17.如权利要求14所述的药物制剂，其中所述NSAID为舒林酸。
18.如权利要求14所述的药物制剂，其中所述甲苯哒唑包含多形体C。
19.一种施用如权利要求1、10和14之一所述的药物制剂的方法，所述方法包括：
在摄入食物之前将所述制剂应用于所述食物。
20.如权利要求19所述的方法，其中所述食物包括脂质。
21.如权利要求19所述的方法，其中所述药物组合物包含P-糖蛋白抑制剂，并且所述P-糖蛋白抑制剂为依克立达。
22.如权利要求19所述的方法，其中所述药物组合物包含NSAID，并且所述NSAID为舒林酸。
23.如权利要求19所述的方法，其中所述食物被癌症患者摄入。
24.如权利要求19所述的方法，其中所述食物被患有脑肿瘤的癌症患者摄入。
25.如权利要求19所述的方法，其中所述食物被患有乳腺癌、结肠直肠癌和肺肿瘤中的一种的癌症患者摄入。
26.如权利要求19所述的方法，其中所述食物被患有具有多重耐药泵的肿瘤的癌症患者摄入。
27.如权利要求19所述的方法，其中所述食物被处于提高的发展结肠直肠癌的风险的个体摄入。
28.如权利要求27所述的方法，其中所述个体具有家族性腺瘤性息肉病。
29.如权利要求27所述的方法，其中所述个体具有非遗传性结肠息肉病。
30.一种监测甲苯哒唑的药物制剂的抗癌效力的方法，所述方法包括：
测定所述药物制剂以及确定多形体C的量和多形体A的量。
31.如权利要求30所述的方法，其中测定步骤包括红外光谱法。
32.如权利要求30所述的方法，其中测定步骤被多次进行。
33.一种治疗人类肿瘤或降低人类发展肿瘤的风险的方法，所述方法包括：
将如权利要求1、10和14之一所述的药物制剂施用至所述人类或分配以便被所述人类口服摄入。
34.如权利要求33所述的方法，其中所述肿瘤为脑肿瘤。
35.如权利要求34所述的方法，其中所述脑肿瘤为成神经管细胞瘤。
36.如权利要求34所述的方法，其中所述脑肿瘤为神经胶质瘤。
37.如权利要求33所述的方法，其中所述肿瘤选自由乳腺肿瘤、结肠直肠肿瘤和肺肿瘤组成的组。
38.如权利要求33所述的方法，其中所述肿瘤具有多重耐药泵。
39.一种用于治疗肿瘤或降低肿瘤的风险的试剂盒，所述试剂盒包括：
甲苯哒唑；和
P-糖蛋白的抑制剂或非甾族抗炎药物。
40.如权利要求39所述的试剂盒，其中所述甲苯哒唑包含多形体C。
41.如权利要求39所述的试剂盒，其中所述多形体C构成所述试剂盒中所有甲苯哒唑的至少90％。
42.如权利要求39所述的试剂盒，所述试剂盒包含P-糖蛋白的抑制剂。
43.如权利要求39所述的试剂盒，所述试剂盒包含NSAID。
44.如权利要求42所述的试剂盒，其中所述P-糖蛋白的抑制剂为依克立达。
45.如权利要求43所述的试剂盒，其中所述NSAID为舒林酸。
46.一种治疗人类肿瘤或降低人类的肿瘤风险的方法，所述方法包括：
将以下施用或分配至所述人类用于口服摄入：
甲苯哒唑的多形体C，和
P-糖蛋白的抑制剂或非甾族抗炎药物。
47.如权利要求46所述的方法，其中P-糖蛋白的抑制剂被施用或分配。
48.如权利要求47所述的方法，其中所述P-糖蛋白的抑制剂为依克立达。
49.如权利要求46所述的方法，其中所述多形体C构成被施用的所有甲苯哒唑的至少90％。
50.如权利要求46所述的方法，其中脑肿瘤被治疗。
51.如权利要求50所述的方法，其中所述脑肿瘤为成神经管细胞瘤。
52.如权利要求50所述的方法，其中所述脑肿瘤为神经胶质瘤。
53.如权利要求46所述的方法，其中肿瘤被治疗，所述肿瘤选自由乳腺肿瘤、结肠直肠肿瘤和肺肿瘤组成的组。
54.如权利要求53所述的方法，其中所述肿瘤具有多重耐药泵。
55.如权利要求46所述的方法，其中NSAID被施用或分配。
56.如权利要求55所述的方法，其中所述NSAID为舒林酸。
57.如权利要求46所述的方法，其中所述人类具有提高的发展癌症的风险。
58.如权利要求46所述的方法，其中所述人类具有提高的发展结肠直肠癌的风险。
59.一种降低人类的肿瘤风险的方法，所述方法包括：
将以下施用或分配至所述人类用于口服摄入：
甲苯哒唑，和
非甾族抗炎药物。
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| CN113398122A (zh) * | 2020-03-17 | 2021-09-17 | 中国医学科学院药物研究所 | 三个唑类化合物在制备抗神经胶质瘤药物中的应用 |
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2016127168A3 (en) | 2016-10-06 |
| EP3253384A4 (en) | 2018-08-22 |
| JP6796586B2 (ja) | 2020-12-09 |
| IL253854B (en) | 2021-03-25 |
| US20240115552A1 (en) | 2024-04-11 |
| IL253854A0 (en) | 2017-09-28 |
| WO2016127168A2 (en) | 2016-08-11 |
| JP2018504440A (ja) | 2018-02-15 |
| EP3253384A2 (en) | 2017-12-13 |
| US11110079B2 (en) | 2021-09-07 |
| ES2907468T3 (es) | 2022-04-25 |
| EP3253384B1 (en) | 2021-12-15 |
| CN107635547B (zh) | 2021-06-25 |
| US20180021310A1 (en) | 2018-01-25 |
| US20210369679A1 (en) | 2021-12-02 |
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