CN101277707A - 意欲用于治疗泌尿生殖器癌症及其转移的包含亚砷酸、其钠盐及其衍生物的药用组合物 - Google Patents
意欲用于治疗泌尿生殖器癌症及其转移的包含亚砷酸、其钠盐及其衍生物的药用组合物 Download PDFInfo
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Abstract
本申请涉及治疗人的泌尿生殖器疾病和骨转移的药用组合物和方法,所述药用组合物含有效量的亚砷酸碱金属盐或碱土金属盐和/或药学上可接受的辅助剂。依据本发明,碱性亚砷酸碱金属盐是偏亚砷酸钠(AsO2Na)或偏亚砷酸钾(AsO2K)。有效量的亚砷酸碱金属盐或碱土金属盐是0.0001-1500mg/kg,优选1-1000mg/kg,更优选1-150mg/kg和最优选50-100mg/kg体重/天。本发明药用组合物的给药形式优选口服,诸如含药学上可接受的载体、稀释剂或赋形剂的片剂、胶囊剂、粉剂和/或溶液剂。
Description
1.导言
癌症是世界上重大的健康问题。虽然在癌症的检测和治疗上已经取得进展,但是现在没有可用的疫苗或其它普遍意义上的成功的预防或治疗方法。目前对该疾病的诊治依赖于早期诊断和积极性治疗的结合,其包括一种或多种疗法诸如手术、放射疗法、化学疗法和激素疗法。虽然这样的疗法给许多患者提供益处,但是对于许多癌症可继续观察到高死亡率。开发改良的抗肿瘤剂将会促进癌症的预防和治疗。
不幸的是,癌症是男性和女性中仅次于心脏疾病的主要死因。在抗击癌症的过程中,已经开发众多技术,目前研究的主题涉及了解该种疾病的性质和成因,以及提供控制或治愈其的方法。
虽然已经评价了数以千计的潜在的抗癌药,但是人癌症的治疗仍然充满复杂性,其经常表现为次佳疗法选项的矩阵组合。因此,对于肿瘤学家而言,具有很小的毒性甚或没有毒性、廉价获得或制备、患者耐受性好、易于服用的化学治疗剂,将是当前可利用的治疗药征的附加条件。将选择性对癌变组织敏感以降低射线或疗法的剂量,实现同样的治疗效应而对健康组织较少伤害的药物也是迫切需要的。同样地,预防癌症发生或复发的药物也是迫切需要的。通过提供这样的化疗剂和敏感剂,本发明满足这些需求。
因此,本发明潜在的技术上的问题是提供可选的或更多的具有抗癌活性的化合物和临床应用的方法。
通过提供在权利要求书中限定的实施方案,解决该问题。
本发明化合物用于治疗癌症。它们有效抑制癌症细胞的生存和/或生长,和/或通常用于抑制不合需要的细胞生长。
本发明还提供含药学上或治疗学上有效量的这些化合物的药物和治疗剂组合物和治疗方法,以及应用这样的化合物的治疗方法。尤其是,本发明涉及通过口服给予本文公开的亚砷酸钠盐治疗癌症的方法。
如由几位发明人描述的三氧化二砷在癌症治疗中的作用与本发明不同,然而用于治疗恶性肿瘤的含砷化合物的作用(WO 800245;Komipharm International)限定于原发性肿瘤。
还要求保护用于抑制非正常细胞生长的药剂盒,其包含亚砷酸钠盐和/或合成的类似物、修饰物及其药理学活性片段。
在描述本化合物、组合物、制剂和方法之前,应该理解,本发明并不限制在本文描述的具体的化合物、方法、组合物和治疗适应症,当然,这样的方法、组合物和治疗适应症不同。还应该理解,本文使用的术语是仅为了描述具体实施方案的目的,并不意欲限制本发明的范围,该范围仅由所附的权利要求书限定。
如在本文包括所附的权利要求书中使用的,除非在上下文另有明确所指,单数形式的单词诸如“一”、“一个”、“该”包括其相应的复数指示物。因而,例如当涉及“有机物”时包括一个或多个不同的有机物,当涉及“细胞”时包括一个或多个这样的细胞,以及当谈到“方法”时包括涉及本领域普通专业技术人员已知的等同的步骤和方法等。
除非另有定义,所有在本文使用的技术和科学术语具有本发明所属领域内普通专业技术人员所通常理解的相同含义。虽然在实施或测试本发明中可使用与本文中所描述的相似或等同的方法和材料,但是以下描述了适宜的方法和材料。仅提供在本申请的提交日之前公开的以上讨论的所有出版物、专利申请、专利和其它参考文献。本文中的一切并不解释为许可本发明不经授权由于其在先发明的优点而使这样的公开提前。本文提到的所有出版物、专利申请、专利和其它参考文献通过全文(包括所有数据和附图)引用结合于本文。
在陈述本发明之前,列出某些将在下文中使用的术语的定义,对于理解本发明可能是有帮助的。
用于本发明的目的的“患者”包括人和其它动物,尤其是哺乳动物,以及其它有机体。因此,本方法可适用于人的疗法和兽医。在优选的实施方案中,患者是哺乳动物,在最优选的实施方案中,患者是人。
术语“动物”指具有封闭的血管循环系统的有机体,包括鸟类、哺乳动物和鳄鱼。本文所用的术语“动物”也包括人。
术语“血管生成”指新的血管的产生进入细胞、组织、器官或肿瘤。
术语“转移”指肿瘤细胞经扩散至身体远端部分的过程。该术语还用于本文是指通过转移过程发展的肿瘤。
术语“接触”在本文与以下词互换使用:与…结合,加入,与…混合,通过,与…一起孵育,流过等。此外,可通过任何常规方法例如,胃肠外、口服和局部以及如本文描述的吸入途径“给予”本发明化合物。
如在本文中使用的,术语“安全和有效量”指足以产生想要的治疗反应而不产生过度的不利副作用(诸如毒性、刺激性或变态反应)的成分的量,当以本发明的方式使用时,其与合理的利益/风险比相当。“有效治疗量”的含义是有效产生所需治疗反应的本发明化合物的量。该量例如可有效使癌症(或者肉瘤或者淋巴瘤)的生长延迟、转移延迟、血管生成和/或端粒受到抑制和/或使癌症缩小。特定的安全和有效量或有效治疗量将因被治疗的具体病情、患者的身体状况、被治疗的哺乳动物的类型、治疗的持续时间、同时进行的疗法(如果存在任何治疗)的性质以及所用的特定制剂和化合物或其衍生物的结构等此类因素的不同而异。
“抗血管生成”的量指有效削弱、降低或抑制血管生成或导致与血管生成性疾病相关症状改善的化合物或组合物的量。想要的结果可或者是症状的主观上的减轻,或是客观上可确认的、如由临床医生或其它有资质的观察者所注意到的在接受者中的剂量改善、血管内皮细胞减少和血管生成速率降低。
术语“治疗癌症”、“疗法”等一般指患有癌症的哺乳动物的任何改善,其中改善可归因于用本发明化合物治疗。改善可或者为主观的或者为客观的。例如,如果哺乳动物是人,那么患者可注意到提高精力和生存活力,或者减少疼痛作为主观症状的改善或对治疗的反应。或者,临床医生根据物理检查、实验室参数、肿瘤标记物或放射影像结果可注意到的肿瘤尺寸或肿瘤负载量缩小。临床医生可观察到对于治疗的反应的一些实验室指标包括检验诸如白细胞计数、红细胞计数、血小板计数、红血球沉降率和多种酶水平的正常化。还有,临床医生可观察到可检测到的肿瘤标记物的减少。或者,可用其它检验评估客观改善诸如声像图(sonograms)、核磁共振检验和正电子发射测试。
可由任何公认的检测肿瘤细胞生长是否已经减慢或减少的方法评价“抑制肿瘤细胞生长”。所述方法包括直接观察和间接评估诸如以上讨论的主观症状或客观指标(signs)。
因此,将本发明的组合物给予细胞。“给予”在本文意思是给予有效治疗剂量的本发明侯选药物至或者细胞培养基中的细胞或者是患者体内的细胞。“有效治疗剂量”在本文意思是产生其给药想要的效应的剂量。确切的剂量将依赖于治疗的目的并可由本领域专业技术人员采用已知技术确定。如本领域已知的,对于系统相对于局部的传递、年龄、体重、一般健康状况、性别、饮食、给药次数、药物相互作用和病症的严重程度进行调节可能是必需的,并且将可由本领域专业技术人员通过常规试验确定。“细胞”在本文意思是其中有丝分裂或减数分裂可改变的几乎任何细胞。
因此,本发明涉及包含有效治疗量的由下式(I)表示的亚砷酸钠盐的药用抗癌症组合物:
O=As-O-Na+ I
2.发明领域
本发明涉及用于治疗原发性和转移性肿瘤性疾病,包括,但不限于泌尿生殖器癌的化合物、方法和组合物。
更具体地说,本发明涉及新的亚砷酸钠盐的化学治疗组合物、口服含砷化合物的用于治疗前列腺癌、泌尿生殖系统原发性和转移性肿瘤和膀胱癌、肾癌、睾丸癌和转移性骨癌的新的使用方法。
3.发明背景
目前已开发的大多数化学治疗药物是静脉使用的。然而,用抗癌药进行口服治疗现在引起兴趣,因为其易于给药的便利、较好的患者依从性和成本的降低并且提高患者的生活品质。例如,患者将能够象门诊患者一样进行口服治疗。
因此,已经清楚,用于癌症治疗的口服药物具有前景并且将比它们在之前所起的作用更加重要。患者的偏好和生活品质问题,在治标的治疗方案中将变为主要的考虑,领先于口服给予药物的发展。静脉(iv)给药是癌症患者不适和紧张的主要根源,且约90%的被问患者表示优选口服而不是iv化学疗法,主要是因为在诊所外给药的便利性或目前涉及的之前用静脉途径给药的问题。
本发明的一个关键目的是提供用于治疗癌症的化学治疗产品,并且所述产品在口服给药后表现出高的生物利用度、增强的抗癌活性和高水平的安全性。
3.1泌尿生殖器癌症
泌尿生殖器的恶性肿瘤包括(尤其是)前列腺癌、膀胱癌、肾癌和睾丸癌。由这些恶性肿瘤呈现的挑战与研究者和临床医生在在治疗所有其它类型的癌症中所面临的挑战类似。与肺癌的发展强烈相关的吸烟,是三分之一的膀胱癌主要因素,几项研究暗示肥胖与增加的结肠癌、乳腺癌和肾癌的风险有关。
3.2膀胱癌
泌尿道癌症中90%的病例直接发生在膀胱,8%发生在肾盂和2%发生在输尿管或尿道。膀胱癌是男性第四位和女性第八位最常见的癌症。估计男性中25%的膀胱癌与职业暴露有关而50%与吸烟有关。吸烟是关键的决定性风险,其持续至停止吸烟后最高至10年。治疗的选择基于疾病的程度:浅表性、入侵性或转移性。采用联合化学疗法治疗转移性疾病。尿路上皮性肿瘤对化疗敏感,一些单一药物可引起20-30%病例的短期恢复。一个给药方案称为MVAC方案。其由甲氨蝶呤、长春碱、多柔比星(阿霉素)和顺铂的联合治疗组成。给予几种药物几天,然后每几周重复给予所述药物数月。
3.3肾癌
肾细胞癌占发生于肾脏的恶性肿瘤的90-95%。在美国,肾细胞癌每年侵袭30,000多美国人并且造成每年约12,000死亡。尽管也有报告肾细胞癌在如3岁的婴孩中发生,但最常发生在50-70岁的成人。肾癌占成人恶性肿瘤的约3%,且男性与女性6的比例是1.5∶1。吸烟与肾细胞癌的发生之间存在很强的相关性。可增加患肾细胞癌风险的未经证实的因素包括多囊性肾病、糖尿病和慢性透析。最多至85%的肾细胞癌是透明细胞型的;5%-15%的肾细胞癌是乳头状组织变异型的(papillary histologic variant)。虽然也可推荐放射疗法,但是对于肾癌的主要治疗类型是手术。在一些人中,或者在手术后或者在癌症不能通过手术去除时,可使用激素疗法或生物学疗法。非常偶然的是,肾癌将不经任何治疗而自发改善,但这是罕见的。化学疗法至今未显示对肾癌的治疗有帮助。
3.4睾丸癌
睾丸癌主要侵袭20-44岁年龄组的年轻男性,在他们中间这是最常见的癌症。总的来说,睾丸癌症并不非常常见。睾丸癌症对治疗的反应特别地好,超过十分之九的患者被治愈。由原始生殖细胞的恶性转化而发生的睾丸的原发性生殖细胞细胞肿瘤(GCTs),占睾丸肿瘤的95%。该疾病由于其罹患的患者年轻、肿瘤细胞分化的全能性(totipotent)能力及其可治愈型性而值得注意;超过90%的全部新诊断的患者将被治愈,并且由于基于顺铂的化学疗法的进展,约70-80%的患有转移性疾病的患者被治愈。
手术、放射疗法和化学疗法是常用的治疗方法,依据癌症的不同阶段和是否已经扩散选用。化学疗法是更常用于非精原细胞瘤睾丸癌,然而其也用于已经扩散的精原细胞瘤。可用药物的不同组合治疗睾丸癌症,最常见的联合是BEP,博来霉素、依托泊苷(Etoposide)和顺铂。
3.5前列腺癌
前列腺癌是美国男性中最常见的恶性肿瘤和55岁以上男性第三位最常见的癌症死亡原因(排在肺癌和结肠癌之后)。对于早期的前列腺癌,手术是最常见的疗法,其次为放射疗法。也有不同的形式的激素疗法。前列腺癌细胞不象某些其它类型的癌症那样趋向于快速生长。由此理由,传统的化学治疗药物并不证明如它们在某些其它多数癌症那样十分有用。虽然如此,一些标准的化学疗法已经显示是有用的,特别是在晚期前列腺癌症中。尽管有三个化学治疗药物被美国食品药品管理局批准用于前列腺癌-泰素帝(Taxotere)(多西他赛)、诺消灵(Novantrone)(盐酸米托恩醌)和艾去适(Emcyt)(雌莫司汀磷酸钠),许多最常见的用于其它癌症的化学治疗剂基于标示外使用(Off-Label)方式用于晚期前列腺癌。化学疗法是典型地用于对激素疗法不再响应的后期前列腺癌症患者。这些药物对该病均不具有一贯地帮助。前列腺癌症患者的最常见的转移部位是骨和淋巴结。骨转移是特别麻烦的,因为其可使患者产生剧烈的疼痛。
3.6继发性骨癌
继发性骨癌并非始于骨,而是癌症细胞从原发性肿瘤扩散至骨的结果。有时仅骨的一个地方受到侵袭,但在其它人中,常常在身体中不同的骨发生许多骨的继发病症。尽管任何类型的癌症均可扩散至骨,但是最常见的类型是乳腺癌、前列腺癌、肺癌、肾癌和甲状腺癌。继发性骨癌的治疗根据原发性癌症的类型而定。例如,前列腺癌细胞可从前列腺脱出,沿着血流运行到骨并开始在那里生长和繁殖。故在骨中的癌细胞会对用于前列腺癌细胞的治疗类型产生同样的反应。虽然继发性骨癌可在体内任何骨中发生,最常见受侵袭的骨是那些脊骨、肋骨、骨盆、头骨和手臂和腿的上骨。
3.7砷及其医学应用
砷作为药物使用已超过2400年,以治疗包括癌症的很多种疾病,但其也是毒物和致癌剂。随着20世纪医学的快速发展,药用砷的应用迅速衰退。当显示每天静脉单独给予三氧化二砷引起大多数新近诊断并复发的急性早幼粒细胞性白血病的患者产生完全的反应时,对含砷化合物的兴趣重新恢复。另外的试验已在血液性恶性肿瘤和实体瘤诸如前列腺和胰腺癌患者中进行。三氧化二砷的缺点是每天静脉给药1-4-hr输液,持续最多至6周。正在进行采用三氧化二砷口服制剂用于急性早幼粒细胞性白血病患者的试验性研究。初步的结果显示功效和副作用与静脉给予三氧化二砷相当。同样值得注意的是采用口服四硫化四砷(tetra-arsenic tetrasulphide)给予急性早幼粒细胞性白血病患者的试验性的研究。因而,口服含砷药物在白血病和实体瘤中具有相似或更好的功效并且更少的副作用,特别是在需要长期治疗的患者中,将降低费用和获得生活品质的利益。
砷以三价和五价的氧化状态作为化学上不稳定的硫化物或氧化物,或者作为钠盐、钾盐或钙盐存在。包括亚砷酸钠和三氧化二砷的三价含砷化合物(arsenical),通过与具有可利用的硫基团的生物学配体反应抑制许多酶。五价砷是线粒体氧化磷酸化的解偶联剂。因此不足为奇的是,三氧化二砷通过激活细胞凋亡,诱导活性氧物质,抑制血管生成,并且在急性早幼粒细胞性白血病细胞中还使PML-RARα融合蛋白降解,发挥抗肿瘤作用。该反应取决于细胞类型和砷的形式。
在1991,美国国立癌症研究所报告,在许多不同的癌症细胞系中三氧化二砷抑制生长和促进细胞凋亡,并且开始研究程序以评估其在血液性恶性肿瘤中的临床活性,所述血液性恶性肿瘤有诸如急性早幼粒细胞性白血病、急性骨髓性白血病、急性淋巴细胞性白血病、慢性骨髓性白血病、非霍奇金氏淋巴瘤、霍奇金氏病、慢性淋巴细胞性白血病、骨髓异常增殖综合征和多发性骨髓瘤。在实体瘤诸如晚期激素-难治的前列腺癌和肾细胞癌中和在宫颈癌以及难治的膀胱移行细胞癌中也得到支持性研究。
正在进行其它的临床研究,包括在实体瘤中的II期研究。基于有前景的临床前资料,正在进行NCI-赞助的临床试验以考察三氧化二砷对实体瘤的治疗效力,或该项工作已在最后计划阶段。
4.发明简述
本发明涉及意欲用于治疗泌尿生殖器疾病和骨转移的药用组合物以及治疗这样的疾病的方法。
因此,本发明提供意欲用于治疗人的泌尿生殖器疾病和骨转移的药用组合物,其中所述药用组合物含有效量的亚砷酸碱金属盐或碱土金属盐和/或药学上可接受的辅助剂。
依据本发明,所述亚砷酸碱金属盐是偏亚砷酸钠(AsO2Na)或偏亚砷酸钾(ASO2K)。
亚砷酸碱金属盐或碱土金属盐的有效量是0.0001-1500mg/kg,优选1-1000mg/kg,更优选1-150mg/kg和最优选50-100mg/kg体重/天。
所述药用组合物优选以口服给药形式出现,其中所述口服给药形式为例如含药学上可接受的载体、稀释剂或赋形剂的片剂、胶囊剂、粉剂和/或溶液剂。
所述泌尿生殖器疾病基本上包括前列腺癌、膀胱癌、肾癌和睾丸癌。
依据本发明,含亚砷酸钠盐的化学治疗产物具有式(I):
O=As-O-Na+
此外,本发明包括含这样的产物与药学上可接受的载体或稀释剂一起的药用组合物。适宜的载体和稀释剂是熟悉的,作为以单位剂型和用于口服给药的组合物的制剂成分。
在还一方面,本发明包括用于治疗动物或人身体癌症的方法,该方法包括同时、分开或序贯给予所述身体以亚砷酸钠盐。
本发明人已经在体外经专题讨论小组考察了三种不同价的和甲基化的含砷化合物,亚砷酸钠盐(As3+)、二甲基次胂酸(As5+)和砷酸(As5+),对人肿瘤细胞系的效价。令人惊奇的是,亚砷酸钠盐最具潜力并且在体外人肿瘤模型中显示抗肿瘤活性,有理由开发亚砷酸钠盐作为再一个新的含砷化合物。令人惊奇的是,亚砷酸钠盐在体外比AS2O3更具效力并且在白血病、黑色素瘤和乳腺癌系中显示特异性活性。令人惊奇的是,亚砷酸钠盐能够使人癌症细胞的端粒缩短,包括细胞衰老和染色体异常,但不直接抑制端粒酶(telomerase)活性。该作用预示,亚砷酸钠盐是端粒抑制剂。亚砷酸钠盐在i.v.和p.o.给药后均被迅速吸收并长时期维持在血浆中。令人惊奇的是,口服亚砷酸钠盐的生物利用度为约100%。动物毒性研究显示,主要靶器官是骨髓和淋巴器官。这样,亚砷酸钠盐可口服给药,可能用于实体瘤或白血病癌症患者的长期治疗,其剂量水平低于最大耐受剂量(MTD),单独或联合另一种治疗形式,维持优良的生活品质。
已经开发本发明的这种化合物(NaAsO2)作为新的抗癌药。该化合物在体外一组43个人肿瘤细胞系中具有好的细胞毒活性,IC50值为0.6μM。在来源于白血病、乳腺癌和黑色素瘤的肿瘤细胞系中观察到显著的选择性。在平行的直接(head-to-head)比较中,令人惊奇的是,亚砷酸钠盐的效力至少15-倍于临床上所用的药物三氧化二砷,并且也具有较好的特异性活性。亚砷酸钠盐与5-氟尿嘧啶(5-FU)或长春碱联合可导致相加效应。亚砷酸盐中的钾降低细胞毒活性。
令人惊奇的是,在体内亚砷酸钠盐(口服和腹膜内)为在2/7皮下移植人肿瘤异种移植物(肾细胞癌RXF 944LX和乳腺癌MAXF 401)中的临界活性。一般,以最大耐受剂量(MTD)的1/3-2/3的剂量,得到亚砷酸钠盐的最高功效。与间歇给药方案(每4天x3,每周x3)比较,该化合物的功效在采用每天给药,持续5天或更多天的给药方案时较好。
令人惊奇的是,在患有泌尿生殖器癌症,主要是前列腺癌和骨转移的癌症患者中,随后以2.5、10、12.5、15、17.5和20mg的亚砷酸钠盐胶囊剂治疗连续14天,口服亚砷酸钠盐显示高治疗功效。
令人惊奇的是,患者均对亚砷酸钠盐非常好地耐受,没有不良事件(AE′s)或严重的不良事件(SAE′s)发生。研究药物不引起对任何患者的安宁感的任何干扰。在整个研究过程中患者的ECG活动、听力测定或神经学测试没有变化。
令人惊奇的是,本发明化合物亚砷酸钠盐,与三氧化二砷比较,具有非常好的治疗和安全性优点。已经显示三氧化二砷AS2O3使校正心率(QTC)的QT和QT间期延长,其可使患者易受潜在地致命性非典型心室心动过速的影响并产生完全性房室阻滞。
再有,在用三氧化二砷治疗的10%或更多的患者中,发生不良事件,包括乏力、发热、水肿、胸痛、寒战、注射部位的反应(即疼痛、红斑、水肿)、虚弱、体重增加、恶心、厌食、食欲减退、腹泻或稀的大便、呕吐、腹痛、消化不良、咽痛、便秘、低钾血症、低血镁症、血清AST(SGOT)和/或ALT(SGPT)升高、血钾过多、低血钙症、头痛、失眠、感觉异常、眩晕、震颤、咳嗽、呼吸困难、鼻出血、缺氧、胸膜腔积液、鼻后滴漏、喘鸣、呼吸音降低、肺部捻发音(crepitations)、罗音、皮炎、搔痒症、瘀斑、皮肤干燥、红斑、发汗、心动过速、ECG异常、窦炎、单纯疱疹、上呼吸道感染、关节痛、肌痛、骨痛、背痛、颈痛、肢体痛、白细胞增多、贫血、血小板减少、中性粒细胞减少(neutopenia)(可能是发热)、血压过低、高血压、潮红、苍白、焦虑、抑郁、眼睛刺激、视物模糊和阴道出血。
令人惊奇的是,使用口服为本发明化合物的亚砷酸钠盐,没有观察到这些不良事件。
5.发明详述
治疗原发性和转移性泌尿道肿瘤和/或骨转移的方法和组合物在本文中描述。
本发明部分基于口服给予含亚砷酸钠盐的组合物的给药方案。也部分基于本发明亚砷酸钠盐对抗某些癌症的治疗功效。
本发明包括治疗哺乳动物的原发性实体瘤的方法,该方法包括将非致死量的有效治疗量的亚砷酸钠盐单独给予或与一个或多个治疗剂联合给予需要此疗法的哺乳动物。
本发明还包括治疗哺乳动物中血液疾病的方法,该方法包括将亚砷酸钠盐或者单独给予或者与一个或多个治疗剂联合给予感染的哺乳动物。
本发明的含砷化合物,亚砷酸钠盐,可以多种已知的形式,例如作为盐、作为有机/无机复合物、作为有机螯合物或装入药物靶向系统的胶囊中应用。
应该认识到,本发明包括在体内转化为生物学活性形式的亚砷酸钠盐的亚砷酸钠盐前药或化合物。这样的前药可用于减少或避免常用药物的毒性或使治疗和功效优化。可合成或经商业途径购买亚砷酸钠盐。
在本发明的实施方案中,将亚砷酸钠盐制备成胶囊剂。一般专业技工将认可,所要应用的亚砷酸钠盐的形式将会是治疗上有效的而没有过度的毒性。
按照本发明,可使用任何适宜的给予亚砷酸钠盐的途径,所述给予途径包括,但不限于口服给药、胃肠外给药诸如静脉、皮下、肌肉和胸内和鼻内、直肠或阴道给药。也可直接向肿瘤内部给药或通过透皮贴片或植入装置(特别是用于缓慢释放)给药。也可采用局部给药。
将要使用的药用组合物可以为生理上可接受的灭菌(水性的或有机的)溶液剂、胶质混悬剂、乳膏剂、软膏剂、糊剂、胶囊剂、囊片剂、片剂和扁囊剂的形式。应该认识到,也包括延迟缓慢或持续释放的给药形式。
本发明含砷化合物可用于对抗多种原发性和转移性肿瘤性疾病,所述疾病包括,但不限于中枢神经系统、乳房、结肠、卵巢、肾、肺、肝脏、膀胱、前列腺以及头和颈的原发性和转移性肿瘤。
5.1药用制剂
因此,本发明涉及药用抗癌组合物,所述组合物含用于制备治疗细胞增殖性疾病的药物的、以下式(I)表示的、有效治疗量的亚砷酸钠盐及其药学上可接受的盐
O=As-O-Na+ I
和一个或多个药学上可接受的辅助剂、赋形剂、载体、缓冲剂、稀释剂和/或惯用的药用辅剂。在本发明优选的实施方案中,可以药学上可接受的制剂给予本发明化合物。本发明适合于任何药学上可接受的制剂,诸如以大分子复合物、纳米胶囊剂、微球体或珠形式的合成或天然的聚合物,和包括水包油乳剂、胶束、混合胶束、合成的膜小泡(membrane vesicles)的脂-基质制剂,和再封(resealed)红血球。除了本化合物和药学上可接受的聚合物,用于本发明的方法中的药学上可接受的制剂可包括额外的药学上可接受的载体和/或赋形剂。如在本文中使用的药学上可接受的载体,包括生理上相容的任何和所有溶剂、分散介质、包衣材料、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂等。例如,载体可适宜于注射入血液。赋形剂包括药学上可接受的稳定剂和崩解剂。在另一个实施方案中,药学上可接受的制剂包括脂-基质制剂。任何已知的脂-基质的药物传递系统可用于本发明的实践中。例如,多泡脂质体(MVL)、多层脂质体(也被称作多层囊泡或MLV)、包括小单层脂质体(也被称作单层囊泡或SUV)和大单层脂质体(也被称作大单层囊泡或LUV)的单层脂质体,只要封囊化合物的持续释放速率可确立,则均可被使用。在一个实施方案中,脂-基质制剂可为多泡脂质体系统。合成的膜小泡的组合物通常是磷脂联合体,通常与类固醇,特别是cholcompoundol联合。也可使用其它磷脂或其它脂质。用于产生合成的膜小泡脂质的实例包括磷脂酰丙三醇、磷脂酰胆碱、磷脂酰丝氨酸、磷脂酰乙醇氨基(phosphatidylethanolaminos)、鞘脂、脑苷脂和神经节苷脂。可优选使用磷脂包括卵磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二油酰磷脂酰胆碱、二棕榈酰磷脂酰丙三醇和二油酰磷脂酰丙三醇。在另一个实施方案中,可将含本化合物的组合物掺入或浸渗到生物可吸收的基质中。此外,所述基质可由所述生物聚合物组成。用于本发的适宜的生物聚合物也可包含一个或多个大分子,其选自胶原质、弹性蛋白、纤连蛋白、玻连蛋白(vitronectin)、层粘连蛋白(laminin)、聚乙二醇酸、透明质酸、硫酸软骨素、硫酸软骨素(dermatan)、硫酸肝素、肝素、纤维蛋白、纤维素、明胶、多熔素、海胆粘连蛋白(echinonectin)、副层连蛋白(entactin)、凝血酶致敏蛋白、桑椹胚粘着蛋白(uvomorulin)、双糖链蛋白多糖(biglycan)、核心蛋白聚糖(decorin)和右旋糖苷。这些大分子进入生物聚合物的制剂为本领域内所熟悉。在优选的实施方案中,当给予病人作治疗目的时,治疗组合物不是免疫原性的。
本发明的治疗性组合物可包含其中各成分的药学上可接受的盐。药学上可接受的盐包括与无机酸例如,盐酸或磷酸,或此类有机酸诸如乙酸、酒石酸、扁桃酸等形成的酸加成盐。生理上可耐受的载体为本领域内所熟悉。典型的液体载体为不含除了活性成分之外的物质的灭菌水溶液和水,或含缓冲剂诸如生理pH值的磷酸钠、生理盐水或两者,诸如磷酸盐-缓冲的盐水。再有,水性载体可含多余一种缓冲剂盐,以及盐诸如氯化钠和氯化钾、右旋糖、丙二醇、聚乙二醇和其它溶质。液体组合物也可含除了并且排除水的液体相。这样的额外的液体相的实例是丙三醇、植物油诸如棉籽油、有机化合物诸如油酸乙酯和水-油乳剂。治疗性组合物含本发明的多肽,典型地含量以重量比计为总治疗性组合物的至少0.1%重量的多肽。重量百分率是多肽重量与组合物总重量之比。因而,例如,0.1重量百分率是每100克的总组合物含0.1克的多肽。
术语“药学上可接受的盐”指那些保留生物学有效性和游离碱特性、并且由与无机酸反应获得的化合物的盐,所述无机酸有诸如盐酸、氢溴酸、硫酸、硝酸、磷酸、甲烷磺酸、乙烷磺酸、甲苯磺酸、水杨酸等。含活性成分的药用组合物可以为适宜于口服使用的形式,例如片剂、锭剂(troches)、糖锭剂(lozenges)、水性或油性混悬剂、可分散的粉剂或颗粒剂、乳剂、硬或软胶囊剂或糖浆剂或酏剂。可依据任何本领域已知用于制备药用组合物的方法,制备意欲用于口服使用的组合物,并且这样组合物可含一个或多个选自甜味剂、矫味剂、着色剂和防腐剂的试剂以提供药学上美观可口的制剂。片剂中含与适宜制备片剂的、无毒性的药学上可接受的赋形剂混合的活性成分。这些赋形剂可例如为惰性稀释剂,诸如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;粒化剂和崩解剂,例如玉米淀粉或褐藻酸;粘合剂,例如淀粉、明胶或阿拉伯树胶,和润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。片剂可包衣或可将它们用已知技术包衣以延缓崩解和在肠道吸收,并因此提供在较长时期内的持续作用。例如,可应用延时材料诸如单硬脂酸丙三醇酯或双硬脂酸丙三醇酯。也可通过在美国专利号4,256,108;4,166,452;和4,265,874中描述的技术,对它们进行包衣,形成用于控制释放的渗透性的治疗性片剂。药用组合物也可,或者可选择地,含一种或多种可与调节剂连结或可在组合物中游离的药物。实际上可与如本文描述的调节剂联合给予任何药物,用于以下描述的目的。可与调节剂一起给予的药物类型的实例,包括止痛剂、麻醉剂、抗心绞痛剂、抗真菌剂、抗菌剂、抗癌症药物(如,紫杉醇(taxol)或丝裂霉素C)、抗炎药(如,布洛芬和吲哚美辛)、驱虫剂、抗抑郁剂、解毒剂、催吐剂、抗组胺药、抗高血压药、抗疟药、抗微管剂(如,秋水仙碱或长春花生物碱)、抗偏头痛剂、抗微生物剂、抗精神病药、退热药、防腐剂、抗信号传导剂(anti-signalling agents)(如,蛋白激酶C抑制剂或细胞内钙移动抑制剂)、抗关节炎药、抗凝血酶剂、抗结核药、抗咳嗽药、抗病毒剂、食欲抑制剂、作用于心脏的药物、化学依赖药物、泻药、化学治疗剂、冠脉、脑血管或外周血管扩张剂、避孕药、镇静剂、利尿剂、祛痰药、生长因子、激素药物、催眠药、免疫抑制剂、麻醉剂拮抗剂(narcotic antagonists)、拟副交感剂、镇定剂、兴奋剂、拟交感剂、毒素(如,霍乱毒素)、安定药和抗尿道感染剂。
口服使用的制剂也可以作为其中活性成分与惰性固体稀释剂,例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊剂呈现,或作为其中活性成分与水或油介质,例如例如花生油、液体石蜡或橄榄油混合的软明胶胶囊剂呈现。
水性混悬剂含与适宜制备水性混悬剂的赋形剂混合的活性物质。这样的赋形剂为助悬剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠聚乙烯吡咯烷酮、黄蓍胶和阿拉伯树胶;分散剂或湿润剂可为天然存在的磷脂,例如卵磷脂或烯化氧与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或氧化乙烯与长链脂族醇的缩合产物,例如十七碳亚乙基氧基(heptadecaethyleneoxy)鲸蜡醇,或环氧乙烷与由脂肪酸和己糖醇衍生的部分化合物的缩合产物,例如聚环氧乙烷与衍生自脂肪酸和己糖醇酐的部分化合物的缩合产物,例如聚环氧乙烷脱水山梨醇单油酸酯。水性混悬剂也可含一种或更多种防腐剂,例如乙基或正-丙基、对-羟基苯甲酸酯,一种或更多种着色剂,一种或更多种矫味剂和一个或多个甜味剂,诸如蔗糖或糖精。
可通过将活性成分悬浮于植物油,例如落花生油、橄榄油、芝麻油或椰子油或矿物油诸如液体石蜡中,配制油性混悬剂。油性混悬剂可含增稠剂,例如蜂蜡、硬石蜡或十六烷醇。可添加诸如以上所列的甜味剂和矫味剂以提供可口的口服制剂。可通过添加抗氧化剂诸如抗坏血酸保存这些组合物。
适宜于通过添加水制备水性混悬剂的可分散的粉剂和颗粒剂,提供与分散剂或润湿剂、助悬剂和一种或更多种防腐剂混合的活性成分。适宜的分散剂或润湿剂和助悬剂已举例说明,也可存在例如甜味剂、矫味剂和着色剂。
本发明药用组合物也可为水包油乳剂的形式。油相可为植物油,例如橄榄油或落花生油,或矿物油,例如液体石蜡,或这些物质的混合物。适宜的乳化剂可为天然存在的树胶,例如阿拉伯树胶或黄蓍胶,天然存在的磷脂,例如大豆、卵磷脂和衍生自脂肪酸和己糖醇酐的化合物或部分化合物,例如山梨醇酐单油酸酯和所述部分化合物与氧化乙烯的缩合产物,例如聚氧乙烯山梨醇酐单油酸酯。乳剂也可含甜味剂和矫味剂。
可用甜味剂,例如丙三醇、丙二醇、山梨醇或蔗糖配制糖浆剂和酏剂。这样的制剂也可含缓和剂、防腐剂、矫味剂和着色剂。药用组合物可为可注射的灭菌水性或油质混悬剂的形式。依据已知技术采用那些以上已经提到的适宜的分散剂或甜味剂和助悬剂,可配制该混悬剂。可注射的灭菌制剂也可为在无毒性的胃肠外可接受的稀释剂或溶剂,例如象溶解于(absolution)1,3-丁烷二醇中的可注射灭菌溶液剂或混悬剂。在可使用的可接受的溶媒和溶剂之中的是水、林格(Ringer′s)溶液和等渗氯化钠溶液。再有,灭菌的不挥发油常作为溶剂或助悬介质使用。为此目的,可使用任何温和的不挥发油,包括合成的甘油单酯或甘油二酯。另外,发现脂肪酸如油酸用于可注射的制剂中。
每天每千克体重约0.05mg至约140mg的定制剂量水平在治疗上述指出的病症中是有用的(每患者每天约2.5mg至约7g)。例如,通过每千克体重每天给予约0.01-50mg(每患者每天约0.5mg至约3.5g)化合物,可有效治疗炎症。可与载体物质混合产生单一剂型的活性成分的量,将根据被治疗的对象和具体给药模式的不同而异。例如,意欲用于人口服给药的制剂,可占总组合物量的约5至约95%。剂量单位形式一般将含约1mg至约500mg的活性成分。然而,应该明白,对于任何具体患者的特定剂量水平将根据多种因素而定,这些因素包括所用的特定化合物的活性,年龄、体重、一般健康状况、性别、规定的给药时间、给药途径、排泄速率、联合用药和被治疗的疾病的严重程度。依据本发明化合物的有效剂量,将根据以下因素变化,所述因素包括具体的化合物、毒性、和抑制活性、被治疗的病症以及是单独给予化合物还是与其它疗法联用。典型地,有效的剂量范围将在约0.0001mg/kg-1500mg/kg体重,更优选1-1000mg/kg体重,更优选约1-150mg/kg体重和最优选约50-100mg/kg体重。本发明还涉及治疗以上提及的病症的过程或方法。本发明化合物可预防性或治疗性地给药,优选以有效对抗已提及的疾病的量,给予需要此种治疗的温血动物,例如人,该化合物优选以药用组合物的形式使用。
制药上可接受的赋形剂和载体溶液的配制为本领域内专业技术人员所熟悉,如开发用于在多种治疗方案中的本文描述的具体组合物,包括,如,口服、胃肠外、静脉、鼻内和肌肉给药和制剂的适宜的给药和治疗方案。
5.1.1口服传递
在某些应用中,可经口服传递给予动物本文公开的药用组合物。如此,可将这些组合物与惰性稀释剂或能被吸收的可食用的载体一起配制,或者可将它们包裹在硬-或软-壳明胶胶囊剂中,或者可将它们压制成片剂,或者可将它们直接掺入定制的食物中。
甚至可将活性化合物与赋形剂混合并以可吸收的片剂、口颊含片、锭剂、胶囊剂、酏剂、混悬剂、糖浆剂、糯米纸囊剂等的形式使用。可加入片剂、锭剂、丸剂、胶囊剂等也可含以下成分:粘合剂,如黄蓍胶、阿拉伯树胶、玉米淀粉、或明胶;赋形剂,如磷酸氢钙;崩解剂,如玉米淀粉、马铃薯淀粉、褐藻酸等;滑润剂,如硬脂酸镁;和甜味剂,如蔗糖、乳糖或糖精,或者可加入矫味剂,如薄荷油、冬青油或樱桃调味料。当剂量单位形式是胶囊剂时,除了以上类型的材料外,其可含液体载体。可存在多种其它材料作为包衣,或另外修饰剂量单位的物理形式。例如,可用紫胶、糖或此两者对片剂、丸剂或胶囊剂进行包衣。酏剂的糖浆剂可含活性化合物蔗糖作为甜味剂,羟苯甲酯和羟苯丙酯作为防腐剂,染料和矫味剂,诸如樱桃味剂或橙味剂。当然,任何用于制备任何单位剂型中的材料应该在使用的剂量中是药学纯的并且是基本无毒性的。再有,可将活性化合物掺入缓释制剂和配方中。
典型地,这些制剂可含至少约0.1%或更多的活性化合物,当然,尽管活性成分的百分含量可不同,并且方便地在总制剂重量或体积的约1%或2%和约60%或70%或更多之间变化。无疑,在每个治疗上有用的组合物中的活性化合物的量可以这样的方式制备,即适宜的剂量将以任何给定化合物的单位剂量获得。诸如溶解度、生物利用度、生物半衰期、给药途径、产品货架存放期以及其它药理学上需要考虑的事项等因素将预期为制备此类药用制剂领域的专业技术人员所考虑,并且,如此而来,可需要多种给药和治疗方案的。
为了口服给药,可选择性地本发明的组合物与一种或多种赋形剂混合成漱口水、牙粉、口颊含片、口腔喷雾剂或舌下经口给药的制剂的形式。例如,将需要量的活性成分掺入适当的溶剂诸如硼酸钠溶液(Dobell′s溶液)中,可制备漱口水。或者,可将活性成分掺入口服溶液,诸如含硼酸钠、丙三醇和碳酸氢钾中,或分散于牙粉中,或以有效治疗量加至组合物中,所述组合物可包含水、粘合剂、研磨剂、矫味剂、发泡剂和湿润剂。或者,可将组合物塑成可置于舌头之下或在口腔溶解的片剂或溶液剂形式。
5.1.2注射用传递
在某些情况下,将需要经胃肠外、静脉、肌肉甚或腹膜内传递本文公开的药用组合物。可在水中与表面活性剂诸如羟丙基纤维素适宜地混合,制备作为游离碱或药理学可接受的盐的活性化合物的溶液剂。也可在丙三醇、液体聚乙二醇及其混合物和在油中制备分散剂。在常规储存和使用条件下,这些制剂含防腐剂以预防微生物的生长。
适宜于注射用的药用形式包括灭菌水溶液剂或分散剂和用于临用时配制灭菌可注射的溶液剂或分散液的灭菌粉剂。在所有情况下,该形式必须是灭菌的并且必须为易于用针筒注射(syringability exists)的程度的流体。在制备和储存条件下必须是稳定的,并且必须防止微生物,诸如细菌和真菌的污染作用。载体可为含,例如,水、乙醇、多元醇(如,丙三醇、丙二醇和液体聚乙二醇等)的溶剂或分散介质、其适宜的混合物和/或植物油。例如,通过使用包衣料,诸如卵磷脂,通过在分散剂中维持所需的粒子大小,和通过使用表面活性剂,可维持适当的流动性。采用多种抗菌剂和抗真菌剂,例如,苯甲酸酯类、三氯叔丁醇、苯酚、山梨酸、硫汞撒等,可促进预防微生物的作用。在许多情况下,可优选包括等渗剂,例如,糖或氯化钠。通过在组合物中使用延时吸收的试剂例如,单硬脂酸铝和明胶,可实现使可注射组合物的延时吸收。
对于以水溶液胃肠外给药,例如,如果需要,应使溶液适当地缓冲并用足量的盐水或葡萄糖首先使该液体稀释剂等渗。这些具体的水溶液特别适宜于静脉、肌肉、皮下和腹膜内给药。在此关系下,可用的灭菌水性介质将为根据本公开的领域内专业技术人员已知的。例如,可将一个剂量溶解于1ml的等渗NaCl溶液中并且或者将其加至1000ml的皮下输液中或者将其注入输注的计划部位。根据被治疗的对象的不同,将必需出现某些剂量的变更。在任何情况下,负责给药的人将确定个体患者的适当的剂量。此外,对于向人给药,制剂应该符合国家或地区生物标准当局所要求的无菌、致热性以及一般的安全和纯度标准。
通过将必需量的活性化合物,如果需要时,与以上列举的几个其它成分在适当的溶剂中混合,随后过滤灭菌,制备可注射的灭菌溶液剂。通常,通过将多种灭菌的活性成分掺入含碱性分散介质的灭菌载体和来自以上列举的其它必需成分中,制备分散剂。在用于制备可注射的灭菌溶液剂的灭菌粉剂的情况下,优选的制备方法是真空干燥和冷冻干燥技术,得到活性成分加上自其前述灭菌过滤溶液剂的任何另外的所需成分的粉剂。
可以中性或盐的形式配制本文公开的组合物。药学上可接受的盐,包括酸加成盐(与蛋白质的游离氨基形成),且其与无机酸例如,盐酸或磷酸,或这样的有机酸诸如乙酸、草酸、酒石酸、扁桃酸等形成。与游离羧基形成的盐也可由无机碱例如,氢氧化钠、氢氧化钾、氢氧化铵、氢氧化钙或氢氧化铁,和这样的有机碱诸如异丙胺、三甲胺、组氨酸、普鲁卡因等衍生。至于制剂,应该以与给药制剂相容的方式和有效治疗的量给予溶液剂。该制剂易于以多种剂型诸如可注射的溶液剂、药物释放型胶囊剂等给药。
如在本文中使用的,“载体”包括任何和所有溶剂、分散介质、溶媒、包衣材料、稀释剂、抗菌剂和抗真菌剂、等渗剂和吸收延迟剂、缓冲剂、载体溶液、混悬剂、胶质等。这样的介质和试剂的作为药学活性物质的应用已为本领域内所熟悉。除非任何常规介质或试剂与活性成分不相容,否则其在治疗性组合物中的应用是可预见的。也可将辅助活性成分掺入组合物中。
词组“药学上可接受的”指给予人时不产生过敏或类似的不利反应的分子实体和组合物。含作为活性成分的蛋白质的水性组合物的制剂已为本领域所充分理解。典型地,这样的组合物制备为可注射的或者液体溶液或者混悬剂;也可制备适宜在注射前成为在液体中的溶液或在液体中的混悬液的固体形式。也可使制剂乳化。
5.1.3经鼻传递
在某些实施方案中,鼻内喷雾、吸入和/或其它的气雾剂传递溶媒可传递药用组合物。同样地,采用微粒树脂和溶血性磷脂酰-丙三醇化合物进行鼻内药物传递也为药学领域所熟悉。
5.2靶向治疗癌症
被治疗的患者将典型地包括哺乳动物并最优选是病人如癌症病人。本发明化合物可单独使用或联合用药。另外,治疗化合物可与其它类型的治疗一起应用。例如,本化合物可与其它化学疗法如他莫西芬、紫杉醇、甲氨蝶呤,生物制剂诸如抗生素、生长因子或淋巴因子、放射线等一起使用。联合疗法可导致协同效果。优选的适应症是癌症,特别是之前已经指出的癌症。
本文提供的组合物和方法特别被认为对治疗原发性和转移性肿瘤性肿瘤有用,所述肿瘤包括诸如乳房、中枢神经系统、结肠、卵巢、肾、肺、肝脏、膀胱、前列腺、头和颈等的实体瘤。更具体地,可通过本发明的组合物和方法治疗的肿瘤包括上皮来源的肿瘤,诸如,但不限于:
肺:支气管原性癌(鳞状细胞癌、未分化的小细胞癌、未分化的大细胞癌、腺癌)、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨瘤样错构瘤、间皮瘤;胃肠:食管(鳞状细胞癌、腺癌)、胃癌、结肠直肠癌;泌尿生殖道:肾(腺癌、Wilm’s肿瘤[肾母细胞瘤]、淋巴瘤、白血病)、膀胱和尿道(鳞状细胞癌、移行细胞癌、腺癌)、前列腺(腺癌、肉瘤)、睾丸(精原细胞瘤);肝脏:肝细胞瘤(肝细胞癌);骨:成骨肉瘤(骨肉瘤);神经系统:神经母细胞瘤、视网膜神经胶质瘤、成胶质细胞瘤、少突神经胶质细胞瘤;妇科:子宫颈(宫颈癌、肿瘤前期宫颈发育异常);血液系统:血液(骨髓性白血病[急性和慢性]、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病)、霍奇金氏病、非霍奇金氏淋巴瘤[恶性淋巴瘤];皮肤:恶性黑色素瘤、基底细胞癌、鳞状细胞癌、Karposi′s肉瘤和腺和导管:腺癌、乳头状癌和乳头状腺癌。因而,如在本文中提供的术语“癌症细胞”包括感染任何一种以上指出病症的细胞。
术语“白血病”广义地指形成血液的器官的进行性恶性疾病,并且一般以白细胞的扭曲地增殖和生成为特征以及它们的前体在血液和骨髓中。临床上一般基于以下因素将白血病分类:(1)疾病的持续时间和特征-急性或慢性;(2)所累及的细胞的类型;骨髓的(源于骨髓的)、淋巴的(源于淋巴的)或单核细胞的和(3)非正常细胞在血液中的数量的增多或不增多-白血病或白细胞不增多性白血病(aleukaemic(亚白血病(subleukaemic)))。P388白血病模型作为体内抗白血病活性预兆已被广泛接受。相信在P388测试中被检测为阳性的化合物将通常表现某些体内抗白血病活性的水平,而不论被治疗的白血病的类型如何。因此,本发明包括治疗白血病的方法,且优选为治疗以下白血病的方法:急性非淋巴细胞性白血病、慢性淋巴细胞性白血病、急性粒细胞性白血病、慢性粒细胞性白血病、急性早幼粒细胞性白血病、成人T-细胞性白血病、白细胞不增多性白血病、非白血性白血病(aleukocythemic)、basophylic白血病、胚细胞性白血病、牛白血病、慢性髓细胞性白血病、皮肤白血病、胚胎性白血病、嗜酸粒细胞性白血病、葛氏(Gross′)白血病、毛-细胞性白血病、血小板性白血病、血胚细胞性白血病(hemocytoblastic)、组织细胞性白血病、干细胞性白血病、急性单核细胞性白血病、白细胞减少性白血病、淋巴性白血病、淋巴母细胞性白血病、淋巴细胞性白血病、成淋巴性白血病、淋巴性白血病、淋巴肉瘤细胞性白血病、肥大细胞性白血病、巨核细胞性白血病、微小髓细胞性白血病、单核细胞性白血病、髓细胞性白血病、粒细胞性白血病、髓样粒细胞性白血病、骨髓单核细胞性白血病、奈格利氏(Naegeli)白血病、血浆细胞性白血病、浆细胞性白血病、早幼粒细胞性白血病、多形核(Rieder)细胞性白血病、希林氏(Schilling′s)白血病、干细胞性白血病、亚白血性白血病和未分化细胞性白血病。
术语“肉瘤”通常指由类似胚胎结缔组织物质组成的肿瘤并且通常包含在纤维状或均一物质中紧密充满的细胞。可用本发明化合物和任选增效剂和/或化学治疗剂治疗的肉瘤包括软骨肉瘤、纤维肉瘤、淋巴肉瘤、黑色素肉瘤、粘液肉瘤、骨肉瘤、Abemethy′s肉瘤、脂肉瘤、类脂肉瘤、腺泡状软组织肉瘤、成釉细胞肉瘤、葡萄簇状肉瘤、绿色癌肉瘤、绒毛膜癌、胚胎性肉瘤、Wilms′肿瘤肉瘤、子宫内膜肉瘤、乳腺间质(stromal)肉瘤、尤文氏(Ewing′s)肉瘤、筋膜肉瘤、成纤维细胞性肉瘤、巨大细胞肉瘤、粒细胞性肉瘤、霍奇金氏肉瘤、特发性多发性色素沉着出血性肉瘤、B细胞的免疫母细胞性肉瘤、淋巴瘤、T-细胞的免疫母细胞性肉瘤、詹恩逊氏(Jensen′s)肉瘤、卡波济氏(Kaposi′s)肉瘤、枯否氏细胞肉瘤、血管肉瘤、白血病性肉瘤、恶性间质瘤肉瘤、骨膜外肉瘤、网织细胞性肉瘤、鲁斯氏肉瘤、浆液囊性肉瘤、滑液性肉瘤和毛细血管扩张性(telangiectaltic)肉瘤。
术语“黑色素瘤”的意思是源于皮肤和其它器官的黑素细胞系的肿瘤。可用所述化合物和任选增效剂和/或另一个化学治疗剂治疗的黑色素瘤,包括,例如,肢端雀斑样痣黑色素瘤、无黑素性黑色素瘤、良性青少年黑色素瘤、Cloudman′s黑色素瘤、S91黑色素瘤、Harding-Passey黑色素瘤、青少年黑色素瘤、恶性小痣黑色素瘤、恶性黑色素瘤、结节黑色素瘤、甲下黑色素瘤和浅表扩散的黑色素瘤。
术语“癌”指由上皮细胞产生的新的恶性生长,倾向于浸润周围组织并且发生转移。可用所述化合物和任选增效剂和/或化学治疗剂治疗的典型的癌包括,例如,腺泡癌、腺泡状癌、腺囊肿性癌、腺样囊性癌、癌性腺瘤(adenomatosum)、肾上腺皮质癌、肺泡癌、肺泡细胞癌、基底细胞癌、基底细胞癌(basocellulare)、基底细胞样癌、基底鳞状细胞癌、支气管肺泡癌、支气管癌、支气管源性癌、脑形癌、胆管细胞癌、绒膜上皮癌、胶样癌、粉刺癌、子宫体(corpus)癌、筛状癌、en cuirasse癌、上皮瘤、柱状细胞癌、圆柱状细胞癌、导管癌、硬癌、胚胎性癌、髓样癌、epiermoid癌、腺样上皮癌、外生性(exophytic)癌、ex ulcere癌、纤维癌、胶样癌、胶状癌、巨大细胞癌、巨细胞癌、腺状癌、粒层细胞癌、毛基质癌、血样癌、肝细胞癌、许尔特累氏细胞瘤、玻璃样(hyaline)癌、hypemephroid癌、幼稚型胚胎细胞癌、原位癌、表皮内癌、上皮内癌、Krompecher′s癌、Kulchitzky-细胞癌、大细胞癌、豆状癌、扁豆状(lenticulare)癌、脂肪瘤性癌、淋巴上皮癌、髓样癌、髓样癌、黑色素癌、软癌、粘液癌、粘液样癌、粘液细胞性癌、粘液表皮样癌、粘液癌、粘液癌、粘液瘤性癌、鼻咽癌、燕麦形细胞癌、骨化性癌、骨样癌、乳头状癌、门脉周癌、原位癌(preinvasive癌)、棘细胞癌、髓样癌、肾细胞肾癌、贮备细胞(reserve cell)癌、肉瘤样癌、鼻粘膜癌、硬癌、阴囊癌、印指环状细胞癌、单纯癌、小细胞癌、马铃薯状癌、球状细胞癌、梭形细胞癌、阴茎海绵体癌、鳞状癌、鳞状细胞癌、线样(string)癌、毛细血管扩张性癌、细血管扩张性癌、移行细胞癌、结节性皮癌、结节性癌、疣状癌和绒毛状癌。
可用依据本发明的化合物治疗的其它的癌症包括,例如,霍奇金氏病、非霍奇金氏淋巴瘤、多发性骨髓瘤、神经母细胞瘤、乳房癌、卵巢癌、肺癌、横纹肌肉瘤、原发性血小板增多症、原发性巨球蛋白血症、小细胞肺肿瘤、原发性脑肿瘤、胃癌、结肠癌、恶性胰腺胰岛素瘤(insulanoma)、恶性类癌(carcinoid)、尿道膀胱癌、恶性病变前的皮肤损害、睾丸癌、淋巴瘤、甲状腺癌、神经母细胞瘤、食道癌、泌尿生殖道癌、恶性血钙过多、宫颈癌、子宫内膜癌、肾上腺皮质癌和前列腺癌。
在特别的实施方案中,本发明提供在罹患转移至肝脏的结肠直肠癌的个体中增强肿瘤特异性免疫的组合物和方法,以抑制肿瘤性疾病的恶化。治疗这些肿瘤性疾病的优选方法包括给予引起针对肿瘤细胞免疫反应的含砷组合物。
在另一个特别的实施方案中,本发明提供用于在罹患肝细胞肝癌的个体中增强特异性免疫的组合物和方法,以抑制肿瘤性疾病的恶化和最终所有的辐射癌前细胞和肿瘤性细胞。
最后,本发明提供用于在妇女中增强对癌前细胞和肿瘤性乳腺细胞的特异性免疫的组合物和方法。本发明还提供抑制癌症细胞增殖和转移的组合物和方法。这些组合物可单独使用或相互联合或与生物反应修饰剂联合使用。
6.工作实施例
以下部分描述应用癌症患者的包含亚砷酸钠盐的药用组合物的体内试验。结果证明亚砷酸钠盐口服给药对治疗泌尿生殖器癌症有效。
6.1方法和材料
在ICH-GCP临床研究中,采用口服亚砷酸钠盐对罹患前列腺和/或泌尿生殖器癌症的癌症患者进行治疗。所述患者罹患泌尿生殖器癌症,主要是前列腺癌症和骨转移,不依从任何已建立的治疗方法,用超过7个不同剂量水平的亚砷酸钠盐治疗。考虑亚砷酸钠盐作为端粒毒物起作用,因为其可使人癌症细胞的端粒缩短,导致染色体异常但不抑制端粒酶活性。
依据以下治疗方案的剂量水平,连续14天每天给予亚砷酸钠盐:
治疗水平1:每天(每24小时)早餐前1粒胶囊,
每粒含2.5mg偏亚砷酸钠
治疗水平2:每天2粒胶囊,每粒含2.5mg亚砷酸钠盐,
早餐、中餐前各1粒
治疗水平3:每天4粒胶囊,每粒含2.5mg亚砷酸钠盐,
早餐前1粒、中餐前2粒、晚餐前1粒
治疗水平4:每天5粒胶囊,每粒含2.5mg亚砷酸钠盐,
早餐前2粒、中餐前2粒、晚餐前1粒
治疗水平5:每天6粒胶囊,每粒含2.5mg亚砷酸钠盐,
早餐前2粒、中餐前2粒、晚餐前2粒
计划安排患者就诊,以控制依从性、毒性和安全性,照如下进行:
第1次就诊:在(治疗开始)之前第7天和0天之间进行
第2次就诊:在用偏亚砷酸钠治疗的第1天
第3次就诊:在用亚砷酸钠盐治疗的第8天
第4次就诊:第15天,即在用亚砷酸钠盐连续治疗14天完成
后的(约24小时)
第5次就诊:在第22天(约在用亚砷酸钠盐连续治疗14天完成
后的第7天)
第6次就诊:在第42天,在用亚砷酸钠盐连续治疗14天完成
后的(约28天)
在该研究中,就以下目标参数进行评估:毒性概况、功效、肝脏酶参数(GOT、GPT、α-GT、AP)、肾功能、血液学功能、肿瘤标记物评价(CEA和PSA)和亚砷酸钠盐的药动学。
6.2结果
以下是被纳入该研究中的每个患者临床结果的概要。结果报告包括肿瘤标记物CEA(癌胚抗原)和PSA(前列腺特异性抗原)的值和功效、毒性和安全性的结果。
表1和2表示患者的详细PSA和CEA值的概要:
表1亚砷酸钠盐给药组1、3和5:
表2亚砷酸钠盐给药组2和4
令人惊奇的是,患者均非常好地耐受亚砷酸钠盐。没有发生不良事件(AE′s)或严重不良事件(SAE′s)。该研究药物治疗不对任何患者的安宁感造成任何影响。在任何患者的ECG活性、听力测定或神经学检查的研究的过程中没有变化。在用亚砷酸钠盐治疗前,没有患者经历放射疗法。亚砷酸钠盐显示高水平的功效。
6.2.1实施例1:患者K.F.
病史:晚期的,不宜动手术的,伴直肠粘膜壁浸润的实体前列腺癌,2004年2月11日
阶段:Dukes C,pT 4 Gleason评分6分
疗法
由于患者罹患冠心病伴心肌梗死,并且植入冠脉支架,不能行根除的前列腺精囊切除术并用LHRH拮抗剂(one profact每3个月s.c注射)和口服抗雄激素剂(色普龙片剂,剂量lxl/d,午餐后)开始进行完全雄激素去除。于2004年5月施行经尿道前列腺切除术(TURP)以改善频尿。
该患者参加亚砷酸钠盐剂量水平1、3和5的研究。该患者的结果表示在所有3个药物剂量水平上,PSA水平具有临床意义的显著性变化。剂量水平1(2.5mg亚砷酸钠盐)表示PSA从0.29ng/ml显著性降低至0.16ng/ml。此降低与肿瘤活性减少44.83%相应。剂量水平3(10mg亚砷酸钠盐)表示PSA从0.16增加至0.18ng/ml。剂量水平5(12.5mg亚砷酸钠盐)还表示增加,此次是从0.17至0.18ng/ml。剂量水平3或5均未显示肿瘤活性的任何显著性变化。
剂量水平1显示肿瘤尺寸从20x35mm缩小至20x34mm。剂量水平3也显示尺寸从20x35mm缩小至20x34mm,而剂量水平5则显示肿瘤在20x34mm尺寸没有变化。
次要的参数(安全性参数)在任何剂量水平显示无临床显著意义的结果。在给药组III和V(第3次和第4次就诊)摄入亚砷酸钠盐期间,观察到肝转氨酶sGPT和sGOT的可逆性增加。第5次就诊中转氨酶几乎回到正常值。此增加似乎与给予研究性药物亚砷酸钠盐有关。
对于剂量水平1的临床反应/进展的评价/判断是部分反应。对于剂量水平3和5,显示疾病的稳定性。
6.2.2实施例2:患者G.R.
病史:晚期的,不宜动手术的,伴腺外肿瘤生长的实体前列腺癌
阶段:Dukes C,pT 4 Gleason评分4分
疗法
除了罹患前列腺癌,该患者还罹患过肾细胞癌(以前经根治性肾切除术治愈)和浅表性膀胱癌(无肿瘤复发)。将该患者纳入该项研究是由于用LHRH拮抗剂(one profact每3个月s.c注射)和口服抗雄激素剂(康士德片剂,剂量lxl/d,午餐后)进行完全雄激素去除后,PSA水平持续上升。
该患者参加亚砷酸钠盐剂量水平1、3和5的研究。该患者的结果表示在所有3个亚砷酸钠盐剂量水平上,PSA水平具有临床意义的显著性变化。剂量水平1表示PSA从1.61ng/ml显著性降低至0.37ng/ml。此降低与肿瘤活性减少77.1%相应。剂量水平3和剂量水平5表示PSA分别从0.37降低至0.12ng/ml和从0.11降低至0.07ng/ml。剂量水平3显示肿瘤活性还降低67.56%,而剂量水平5显示无显著性变化。
剂量水平1显示肿瘤尺寸从12.5x65mm缩小至0.8x30mm。剂量水平3也显示前列腺肿瘤尺寸从60x25mm缩小至50x25mm,而剂量水平5则显示尺寸没有变化。
次要的参数(安全性参数)在任何剂量水平显示无临床显著意义的结果。先前研究升高的甘油三酸酯和胆固醇水平已经检测,且在本研究过程中没有变化。葡萄糖水平始终表现为不能由食物原因解释的升高,因为总是在早晨丰富的早餐后取血液探针。
对于所有三个剂量水平的临床反应/进展的评价/判断是部分反应。
6.2.3实施例3:患者E.S.
病史:晚期的,不宜动手术的,伴囊外肿瘤生长的雄激素抵抗的实体前列腺癌。
阶段:Dukes C,pT 4 Gleason评分4分
疗法
除了罹患前列腺癌,该患者还罹患直肠癌。将该患者纳入该项研究是因为晚期的和不宜动手术的情况。用LHRH拮抗剂(one profact每3个月s.c注射)进行雄激素去除。
该患者参加亚砷酸钠盐剂量水平1、3和5的研究。该患者的结果表示在所有3个药物剂量水平上,PSA水平具有临床意义的显著性变化。剂量水平1和3表示PSA分别从0.24ng/ml降低至0.11ng/ml和0.11ng/ml降低至0.08ng/ml。剂量水平5显示自0.09ng/ml无变化。剂量水平1显示肿瘤活性降低54.12%,而水平3还降低67.56%。剂量水平5显示无显著变化。
剂量水平1显示肿瘤尺寸从30x35mm缩小至30x30mm。剂量水平3和5则显示尺寸没有变化。
次要的参数(安全性参数)在任何剂量水平显示无临床意义的结果。检测到可逆的和轻微的sGPT升高。
对于剂量水平1和3的临床反应/进展的评价/判断是部分反应。剂量水平5显示疾病的稳定性。
6.2.4实施例4:患者J.S.
病史:晚期的,不宜动手术的,伴腺外肿瘤生长的雄激素抵抗的实体前列腺癌。
阶段:Dukes C,pT 4 Gleason评分8分
疗法
将该患者纳入该项研究是由于采用囊下睾丸切除术使雄激素去除后,PSA水平持续上升。
该患者参加亚砷酸钠盐剂量水平1、3和5的研究。该患者的结果表示在所有3个药物剂量水平上,PSA水平具有临床意义的显著性变化。剂量水平1表示PSA从0.19ng/ml显著性增加至0.21ng/ml。剂量水平3和5分别表示PSA从0.21ng/ml增加至0.27ng/ml和从0.27ng/ml降低至0.24ng/ml。剂量水平1和3显示肿瘤进展增强,而剂量水平5显示无显著性变化。
剂量水平1显示肿瘤尺寸从30x30mm增大至35x35mm。剂量水平3和5在30x35mm时没有变化。
次要的参数(安全性参数)在任何剂量水平显示无临床显著性意义的结果。先期研究表现的sGGT升高和血小板增多在本研究过程中仍然不变。
对于剂量水平1和3的临床反应/进展的评价/判断是疾病的进展。剂量水平5显示对亚砷酸钠盐的部分反应。
6.2.5实施例5:患者D.B.
病史:根除性前列腺切除术(阶段pT2C Gleason 6分)后,伴膀胱颈浸润,不宜动手术的实体前列腺癌的局部复发。
阶段:Dukes C,pT 4 Gleason评分6分
疗法
将该患者纳入该项研究是由于采用根除性前列腺切除术和用LHRH拮抗剂(one profact每3个月s.c注射)和口服抗雄激素剂(康士德(casodex)片剂,剂量lxl/d,午餐后)进行完全雄激素去除后,PSA水平持续上升。
该患者参加亚砷酸钠盐剂量水平1、3和5的研究。该患者的结果表示在药物剂量水平1时PSA水平具有临床意义的显著性变化。剂量水平1表示PSA从0.45ng/ml显著性降低至0.04ng/ml。此降低与肿瘤活性下降91.11%相对应。剂量水平3和剂量水平5显示维持在0.04ng/ml而没有变化。
采用任何标准的检测方法得不到肿瘤损害的测量值。
次要的参数(安全性参数)在任何剂量水平显示无临床显著意义的结果。观察到肝转氨酶sGOT、sGPT和sGGT可逆性升高。
对于剂量水平1的临床反应/进展的评价/判断是部分反应。对于剂量水平3和5,疾病均显示对亚砷酸钠盐的完全反应。
6.2.6实施例6:患者H-W.S.
病史:晚期的,不宜动手术的,伴在膀胱颈和盆壁的腺外肿瘤生长和骨转移扩散的实体前列腺癌。
阶段:Dukes C,pT 4 Gleason评分9分M2
疗法
将该患者纳入该项研究是因为晚期状态检测到的前列腺癌症,伴侵袭所有骨骼的多处骨转移。用LHRH拮抗剂(one profact每3个月s.c注射)和口服抗雄激素剂(康士德片剂,剂量lxl/d,午餐后)进行完全雄激素去除。
该患者参加亚砷酸钠盐剂量水平2和4的研究。该患者的结果表示在此两个药物剂量水平,PSA水平均具有临床意义的显著性变化。剂量水平2表示PSA从725ng/ml降低至6.15ng/ml,而肿瘤活性下降99.15%,而剂量水平4表示PSA从6.15ng/ml降低至3.67ng/ml,伴有进一步的肿瘤活性下降40.32%。
剂量水平2显示肿瘤尺寸从65x40mm缩减至15x30mm,而剂量水平显示在15x40mm维持没有变化。
次要的参数(安全性参数)显示在任何剂量水平均无临床显著意义的结果。通过亚砷酸钠盐强有力地改善患者的生活品质。先前研究sGGT的升高由于研究过程中饮酒恶化所致。血红蛋白浓度从10.0增加至11.1g/l,而PSA从725降低至3.67ng/ml。
对于两个剂量水平的临床反应/进展的评价/判断是对亚砷酸钠盐的部分反应。
6.3结论
所有那些参加剂量水平1、3和5的患者在大部分情况下显示,其PSA水平降低和肿瘤尺寸缩小。大多数患者显示至少对亚砷酸钠盐具有部分反应,其中一个患者显示稳定的疾病状态。在剂量水平2和4中的患者H-W.S.,显示对亚砷酸钠盐治疗的非常清晰的反应,其PSA水平急剧降低(肿瘤活性降低99.15%)以及肿瘤尺寸相当可观地缩小。安全性(实验室)参数显示无具有临床意义的显著性结果。令人惊奇的是,亚砷酸钠盐具有非常好的耐受性,并没有发生AE′s或SAE′S。所有口服亚砷酸钠盐,即使在低剂量和相当短的治疗期时,对于治疗前列腺和/或泌尿生殖器癌症和骨转移,显示令人惊奇的非常积极的反应。
Claims (19)
1.意欲用于治疗人的泌尿生殖器疾病和骨转移的药用组合物,其特征是所述药用组合物含有效量的亚砷酸碱金属盐或碱土金属盐和/或药学上可接受的辅助剂。
2.依据权利要求1的药用组合物,其特征是所述亚砷酸碱金属盐是偏亚砷酸钠(AsO2Na)或偏亚砷酸钾(AsO2K)。
3.依据权利要求1或2的药用组合物,其特征是所述亚砷酸碱金属盐或碱土金属盐的有效量是0.0001-1500mg/kg,优选1-1000mg/kg,更优选1-150mg/kg和最优选50-100mg/kg体重/天。
4.依据权利要求1-3的任一项的药用组合物,其特征是所述药用组合物以口服给药形式呈现。
5.依据权利要求1-4的任一项的药用组合物,其特征是所述口服给药形式为含药学上可接受的载体、稀释剂或赋形剂的片剂、胶囊剂、粉剂和/或溶液剂。
6.依据权利要求1-5的任一项的药用组合物,其特征是所述泌尿生殖器疾病包括前列腺癌、膀胱癌、肾癌和睾丸癌。
7.一种治疗人的转移性泌尿生殖器癌症的方法,其中所述泌尿生殖器癌症包括前列腺癌、膀胱癌、肾癌和睾丸癌,其特征是给予被感染的人有效治疗量的权利要求1-6中任一项的药用组合物。
8.一种治疗人的黑色素瘤、乳房癌、结肠癌、卵巢癌、肾癌、中枢神经系统癌症或肺癌的方法,其特征是给予被感染的人有效治疗量的权利要求1-6中任一项的药用组合物。
9.一种治疗人的实体瘤的方法,其特征是给予被感染的人有效治疗量的权利要求1-6中任一项的药用组合物。
10.一种治疗人的转移性实体瘤的方法,其特征是给予被感染的人有效治疗量的权利要求1-6中任一项的药用组合物。
11.权利要求9的方法,其中所述肿瘤是上皮组织、淋巴组织、结缔组织、骨或中枢神经系统的肿瘤。
12.权利要求11的方法,其中所述肿瘤是食管鳞状细胞癌、食管腺癌、结肠直肠癌或胃癌。
13.权利要求11的方法,其中所述上皮组织的肿瘤是上皮腺肿瘤、上皮导管肿瘤、肝脏肿瘤、胆道肿瘤、胃肠道肿瘤、呼吸道肿瘤或泌尿生殖道肿瘤。
14.权利要求11的方法,其中所述淋巴组织的肿瘤是霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、滤泡性淋巴瘤、弥漫性淋巴瘤、淋巴母细胞性淋巴瘤、大细胞淋巴瘤或小细胞淋巴瘤。
15.权利要求11的方法,其中所述中枢神经系统肿瘤选自神经母细胞瘤、视网膜神经胶质瘤、成胶质细胞瘤或少突神经胶质细胞瘤。
16.一种治疗人的肿瘤性疾病的方法,其特征是联合给予被感染的人有效治疗量的权利要求1-6中任一项的药用组合物或其药学上可接受的盐或衍生物,以及有效量的至少一种其它治疗剂。
17.权利要求16的方法,其中所述其它治疗剂是化学治疗剂或放射治疗剂。
18.权利要求11-15的任一项的方法,其中所述给药通过胃肠外、局部、经皮、直接进入肿瘤或经由植入装置实施。
19.一种在哺乳动物中治疗造血系统性疾病的方法,该方法包括联合给予所述被感染的人有效治疗量的亚砷酸钠盐以及一个或多个含砷化合物,其中所述造血系统性疾病选自急性淋巴细胞性白血病、慢性淋巴细胞性白血病、毛细胞性白血病、骨髓组织变形、骨髓发育异常综合征、多发性骨髓瘤和浆细胞瘤。
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SI (2) | SI3067068T1 (zh) |
TW (5) | TWI539957B (zh) |
WO (1) | WO2006121280A1 (zh) |
ZA (1) | ZA200710559B (zh) |
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CN112336746A (zh) * | 2020-10-23 | 2021-02-09 | 内蒙古科技大学包头医学院 | 一种膀胱癌灌注化疗药物及其应用 |
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EP1721615A1 (en) | 2005-05-09 | 2006-11-15 | Komipharm International Co., Ltd. | Pharmaceutical compositions comprising sodium or potassium arsenite for the treatment of urogenital cancer and its metastasis |
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US20090246291A1 (en) | 2008-03-27 | 2009-10-01 | Angelika Burger | Method and compositions for treatment of cancer |
US20120045520A1 (en) * | 2008-08-21 | 2012-02-23 | Sang Bong Lee | Pharmaceutical composition comprising arsenite for the treatment of malignancy |
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DK2042182T3 (da) * | 2002-04-10 | 2013-08-26 | Komipharm Int Co Ltd | Farmaceutisk sammensætning, der omfatter arsen, til behandling af malignitet. |
KR100632250B1 (ko) * | 2004-02-16 | 2006-10-11 | 정태호 | 비소 화합물을 유효성분으로 하는 항암제 |
US20060104292A1 (en) | 2004-11-15 | 2006-05-18 | Gupta Vivek G | System and methods for supporting multiple communications interfaces with single client interface |
EP1721615A1 (en) | 2005-05-09 | 2006-11-15 | Komipharm International Co., Ltd. | Pharmaceutical compositions comprising sodium or potassium arsenite for the treatment of urogenital cancer and its metastasis |
US8945505B2 (en) | 2007-02-02 | 2015-02-03 | Panaphix, Inc. | Use of arsenic compounds for treatment of pain and inflammation |
US20090246291A1 (en) | 2008-03-27 | 2009-10-01 | Angelika Burger | Method and compositions for treatment of cancer |
MX2012002855A (es) | 2009-09-10 | 2012-07-20 | Kominox Inc | Terapia de cancer dirigida a celula madre de cancer y resistente a farmaco. |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102753164A (zh) * | 2009-09-10 | 2012-10-24 | 柯密纳克斯公司 | 靶向癌症干细胞的耐药性癌症疗法 |
CN107412771A (zh) * | 2009-09-10 | 2017-12-01 | 柯密纳克斯公司 | 靶向癌症干细胞的耐药性癌症疗法 |
CN112135608A (zh) * | 2018-03-22 | 2020-12-25 | 科米药物国际澳大利亚公司 | 包含偏亚砷酸盐的药物组合物及其制造方法 |
CN115243692A (zh) * | 2020-02-16 | 2022-10-25 | 科微范国际澳大利亚私人有限公司 | 使用偏亚砷酸盐的治疗方法 |
CN112336746A (zh) * | 2020-10-23 | 2021-02-09 | 内蒙古科技大学包头医学院 | 一种膀胱癌灌注化疗药物及其应用 |
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