CN104168957A - 用于治疗中风的佛波醇酯的组合物和使用方法 - Google Patents
用于治疗中风的佛波醇酯的组合物和使用方法 Download PDFInfo
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- CN104168957A CN104168957A CN201380014858.7A CN201380014858A CN104168957A CN 104168957 A CN104168957 A CN 104168957A CN 201380014858 A CN201380014858 A CN 201380014858A CN 104168957 A CN104168957 A CN 104168957A
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- phorbol
- deoxidation
- acetas
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- phorbol ester
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Abstract
本发明提供用于治疗和预防中风和中风后遗症的方法以及含有佛波醇酯或佛波醇酯衍生物的组合物。本发明提供另外的组合物和方法,这些组合物和方法联合使用佛波醇酯或衍生化合物与至少一种另外的药剂,以得到治疗或预防哺乳动物受试者的中风和中风的长期影响更有效的治疗手段。
Description
相关申请
本申请是美国实用新型专利申请,要求2012年1月18日提交的美国临时专利申请序列号61/588,167的优先权权益,所述临时专利申请通过引用整体并入本文。
其它公开
与本申请相关的其它公开可参见授予Richard L.Chang等的于2008年1月31日提交的美国专利申请序列号12/023,753“CompositionsAnd Methods Of Use Of Phorbol Esters,”该专利申请要求2007年1月31日提交的美国临时专利申请序列号60/898,810的优先权权益,所述专利申请各自出于所有目的通过引用整体并入本文。
技术领域
本发明大体上涉及佛波醇酯在治疗和预防中风和中风的影响中的医疗用途。
背景
植物长久以来已提供了许多医疗用途。世界卫生组织(WHO)估计目前有40亿人(世界人口的80%)使用草药药品进行某一方面的初级卫生保健。(WHO情况说明书N°134情况说明书,2008年12月)然而,植物中具有期望医疗效果的特定化合物可能难以分离并以商业规模再造。另外,尽管可将所述活性化合物从植物中分离出来,但植物的其它部分诸如矿物质、维生素、挥发油、糖苷、生物碱、生物类黄酮和其它物质也可以参与活性化合物的作用发挥或该植物的已知医疗效果,从而对基于植物的药剂的使用、纯化和商业化提出了挑战。
佛波醇是一种天然植物来源有机化合物,属巴豆烷家族二萜类。其于1934年作为自巴豆(Croton tiglium)(东南亚本土大戟科家族的一种多叶灌木)的种子产出的巴豆油的水解产物首次被分离出来。佛波醇的各种酯具有重要的生物性质,包括已报道的模拟二酰甘油和活化蛋白激酶C(PKC)的能力;以及调节下游细胞信号传导途径(包括促***原活化蛋白激酶(MAPK)途径)的能力。另外认为佛波醇酯能结合嵌合蛋白(chimaerin)Ras活化子RasGRP和囊泡启动蛋白Munc-13((Brose N,Rosenmund C.,JCell Sci;115:4399–411(2002))。一些佛波醇酯还可诱导细胞核因子-κB(NF-κB)。佛波醇酯最显著的生理学性质是已经报道的其充当肿瘤促进剂的能力。(Blumberg,1988;Goel,G等,Int,Journal of Toxicology 26,279-288(2007))。
12-O-十四烷酰佛波醇-13-乙酸酯(TPA)(也称为佛波醇-12-肉豆蔻酸酯-13-乙酸酯(PMA))是一种在致癌作用模型中被用作多种细胞系和原代细胞的分化和/或凋亡的诱导剂的佛波醇酯。TPA也被报道能使骨髓功能受到化疗抑制的患者中的循环白血细胞和中性粒细胞增加(Han Z.T.等Proc.Natl.Acad.Sci.95,5363-5365(1998)),且能抑制HIV诱发的对MT-4细胞的致细胞病变效应。(Mekkawy S.等,Phytochemistry 53,47-464(2000))。然而,由于多种因素,包括在与皮肤接触时的腐蚀性反应和其潜在毒性等问题,目前尚未显示TPA是用于治疗、管理或预防疾病的有效手段。事实上,由于佛波醇酯在蛋白激酶C活化中发挥关键作用,使得蛋白激酶C触发各种细胞反应而导致炎性反应和肿瘤形成(Goel等,Int,Journal of Toxicology 26,279-288(2007)),故佛波醇酯通常被排除在涉及炎性反应的病况(诸如中风)的可能治疗候选物之外。
每年有约1700万人因心脏病和中风而死亡,占全球所有死亡近三分之一。预计它们将成为世界范围内死亡和残疾的首要原因,且预计截至2020年死亡人数增加至每年超过2000万且截至2030增加至每年2400万。(Atlas of Heart Disease and Stroke,World HealthOrganization 2004)。
尽管有300余种风险因素与冠心病和中风相关(Atlas of HeartDisease and Stroke,World Health Organization 2004),但在发达国家,至少1/3的心血管疾病可归因于吸烟、饮酒、高血压、高胆固醇和肥胖。
当前用于管理和预防中风的治疗通常是下列的组合:诸如ACE抑制剂、阿司匹林、β阻断剂和降脂药物的药物;诸如起博器、植入式除颤器、冠状动脉支架、人工瓣膜和人工心脏的装置;以及诸如冠状动脉分流术、气囊血管成形术、瓣膜修复及置换术、心脏移植术和人造心脏手术的手术。“相较于不太昂贵但仍有效的策略,人们越来越多地选择尖端技术程序”(Atlas of Heart Disease and Stroke,WorldHealth Organization 2004)促使卫生保健的成本升高并造成不同群体的个体间在治疗质量方面的显著差异。
然而,即便在可获得先进技术和设备的情况下,仍有60%的中风患者死亡或产生依赖性,且每次中风均显著增加其它事件的风险。“在世界范围内,对心血管疾病及其风险因素采取的治疗仍不适于大多数患者。”(Atlas of Heart Disease and Stroke,World Health Organization2004)。因此,显然需要一种新的且更有效的措施来治疗和预防中风以及治疗或预防中风引起的长期效应。
发明概述
本发明涉及含有佛波醇酯的组合物和其使用方法。本文所述组合物和方法可有效预防和治疗中风以及管理中风后遗症,包括急性缺血事件。
可通过使用如本文所述的佛波醇酯和佛波醇酯衍生物来预防或治疗的中风的影响包括但不限于麻痹、空间障碍、判断力受损、左侧忽视、记忆丧失、失语、协调与平衡问题、恶心、呕吐、认知障碍、知觉障碍、定向力障碍、同侧偏盲和冲动。在一些实施方案中,使用佛波醇酯和佛波醇酯衍生物可防止中风初发和继发。
可按照常规方法判定是否成功治疗,诸如中风的严重程度或后遗症减轻、中风影响减少或消除、易致个体患中风风险因素减少和/或中风(包括继发中风)的次数或严重程度减少。
在另一个实施方案中,如本文所述的佛波醇酯和佛波醇酯衍生物可用于调节细胞信号传导途径。该调节可具有多种结果,例如,在一些实施方案中,使用含有佛波醇酯和佛波醇酯衍生物的组合物可改变哺乳动物受试者中Th1细胞因子的释放。在又一个实施方案中,含有佛波醇酯和/或佛波醇酯衍生物的组合物可改变哺乳动物受试者中白细胞介素2(IL-2)的释放。在另一个实施方案中,含有佛波醇酯和/或佛波醇酯衍生物的组合物可改变哺乳动物受试者中干扰素的释放。在又一个实施方案中,含有佛波醇酯和/或佛波醇酯衍生物的组合物可改变ERK磷酸化的速率。
本发明通过提供新颖且十分有效的方法和组合物来治疗和预防中风、调节细胞信号传导途径和/或管理、治疗和预防中风后遗症,从而实现以上方面并满足另外的目标及优点,所述方法和组合物使用含有下文式I的佛波醇酯:
其中R1和R2可独立地为氢;羟基;其中所述烷基含有1至15个碳原子;其中低级烯基含有1个至7个之间的碳原子; 和其经取代的衍生物。R3可独立地为氢或和其经取代的衍生物。本发明的方法和组合物进一步包含式I的组合物的任何药用盐、对映异构体、异构体、多晶型物、前药、水合物和溶剂化物。
在一些实施方案中,R1和R2中至少一者不同于氢且R3为氢或和其经取代的衍生物。在另一个实施方案中,R1或R2为其余R1或R2为其中低级烷基为1个与7个之间的碳,且R3为氢。
本文式I的各式的烷基、烯基、苯基和苄基可未被取代或被卤素,优选地,氯、氟或溴;硝基;氨基;和/或类似类型的基团取代。
在如本文所述的方法和组合物中所使用的示例性佛波醇酯组合物是下文式II的12-O-十四烷酰佛波醇-13-乙酸酯(TPA):
可用于本发明的制剂和方法中的式I的佛波醇酯和相关化合物和衍生物包括但不限于所述化合物的其它药学上可接受的活性盐以及所述化合物的活性异构体、对映异构体、多晶型物、糖基化衍生物、溶剂化物、水合物和/或前药。可用于本发明的组合物和方法中的佛波醇酯的示例性形式包括但不限于佛波醇13-丁酸酯;佛波醇12-癸酸酯;佛波醇13-癸酸酯;佛波醇12,13-二乙酸酯;佛波醇13,20-二乙酸酯;佛波醇12,13-二苯甲酸酯;佛波醇12,13-二丁酸酯;佛波醇12,13-二癸酸酯;佛波醇12,13-二己酸酯;佛波醇12,13-二丙酸酯;佛波醇12-肉豆蔻酸酯;佛波醇13-肉豆蔻酸酯;佛波醇12-肉豆蔻酸酯-13-乙酸酯(也称为TPA或PMA);佛波醇12,13,20-三乙酸酯;12-脱氧佛波醇13-当归酸酯;12-脱氧佛波醇13-当归酸酯20-乙酸酯;12-脱氧佛波醇13-异丁酸酯;12-脱氧佛波醇13-异丁酸酯-20-乙酸酯;12-脱氧佛波醇13-苯乙酸酯;12-脱氧佛波醇13-苯乙酸酯20-乙酸酯;12-脱氧佛波醇13-十四烷酸酯;佛波醇12-顺芷酸酯13-癸酸酯;12-脱氧佛波醇13-乙酸酯;佛波醇12-乙酸酯;和佛波醇13-乙酸酯。
根据本发明的方法,适于用式I的佛波醇酯或所述式I的佛波醇酯的衍生物、特别是TPA治疗的哺乳动物受试者包括但不限于已患中风或处于中风风险中的个体。适于用式I的佛波醇酯、特别是TPA治疗的受试者还包括遭受中风的影响(包括但不限于麻痹、空间障碍、判断力受损、左侧忽视、记忆丧失、失语、协调与平衡问题、恶心、呕吐、认知障碍、知觉障碍、定向力障碍、同侧偏盲和冲动)的受试者。
通过向这些及其它受试者施用有效量的式I的佛波醇酯或式I的佛波醇酯衍生物对所述受试者进行有效地预防性和/或治疗性治疗,所述量应足以调节NF-κB活性、增加Th1细胞因子活性、预防或治疗麻痹、增加空间意识、减少记忆丧失、减少失语、增加协调与平衡、预防或降低中风的发生率和严重程度、以及改善认知能力。
本发明的治疗上可用的方法和制剂将有效地使用呈各种形式的式I的佛波醇酯或该式I的佛波醇酯的衍生物,如上文所述,包括所述化合物的任何活性药学上可接受的盐、以及活性异构体、对映异构体、多晶型物、溶剂化物、水合物、前药和/或其组合。在下文实施例中使用式II的TPA作为本发明的说明性实施方案。
在本发明的其它方面,提供组合制剂和方法,所述组合制剂和方法联合使用有效量的式I的佛波醇酯或式I的佛波醇酯的衍生物与一种或多种次要或辅助活性剂,将所述次要或辅助活性剂与所述式I的佛波醇酯化合物组合配制或协同施用以在受试者中产生有效反应。
在中风的治疗中,组合制剂和协同治疗方法联合使用式I的佛波醇酯化合物或式I的佛波醇酯的衍生物与一种或多种另外的预防中风的、治疗中风的或其它所示次要或辅助治疗剂。在这些实施方案中,与佛波醇酯(例如,TPA)联合使用的次要或辅助治疗剂单独或与佛波醇酯(例如,TPA)联合时可对中风的预防或恢复具有直接或间接影响;与例如TPA联合时可展现其它有用的辅助治疗活性(诸如抗凝血、抗胆固醇血症、舒张血管、抗高血压、降低小动脉阻力、增加静脉容量、减少心脏需氧量、降低心律、稳定心律或神经保护);或单独或与例如TPA联合时可展现可用于治疗或预防中风或相关症状的辅助治疗活性。此类次要或辅助治疗剂可在施用式I的佛波醇酯或式I的佛波醇酯的衍生物之前、同时或之后施用。
在这些组合制剂和协同治疗方法中可用于预防或治疗哺乳动物受试者中风的辅助或次要治疗剂包括但不限于组织型纤溶酶原激活剂、抗凝血剂、抑制素、血管紧张素II受体阻断剂、血管紧张素转化酶抑制剂、抗血小板剂、β阻断剂、阿司匹林、贝特类药物、钙通道阻断剂或利尿剂。另外,可使用辅助或次要疗法,诸如但不限于手术干预,包括颈动脉内膜切除术、血管成形术、气囊血管成形术、瓣膜修复及置换术、冠状动脉分流术、支架置入术、开颅术、血管内弹簧圈栓塞术或卵圆孔未闭封堵术。
本发明的上述和其它目标、特征、方面和优点将从以下详细说明中变得显而易见。
详述
新颖方法和组合物已经鉴定为可用于预防和/或治疗哺乳动物受试者(包括人类)的中风和中风后遗症。
在各种实施方案中,如本文所述的组合物和方法可增加Th1细胞因子释放、增加ERK磷酸化、调节NF-κB活性、预防或治疗麻痹、增加空间意识、减少记忆丧失、减少失语、增加协调与平衡、改善认知能力、改善定向力、减少继发中风的流行和减少冲动。
本文提供的制剂和方法使用式I的佛波醇酯或式I的佛波醇酯的衍生化合物作为用于治疗慢性或复发性病况的新颖组合物,如在2008年1月31日提交的美国专利申请号12/023,753中更详细地描述,该专利申请要求2007年1月31日提交的美国临时专利申请序列号60/898,810及_________提交的美国临时专利申请号____________的优先权权益,每篇专利均通过引用整体并入本文,
其中R1和R2可为氢;羟基;其中所述烷基含有1至15个碳原子;;其中低级烯基含有1个至7个之间的碳原子; 和其经取代的衍生物。R3可为氢或
在一些实施方案中,R1和R2中至少一者不同于氢且R3为氢或和其经取代的衍生物作为用于治疗慢性或复发性病况的新颖组合物。在另一个实施方案中,R1或R2为其余R1或R2为其中低级烷基为1个与7个之间的碳,且R3为氢。
本文各式的烷基、烯基、苯基和苄基可未被取代或被卤素,优选地,氯、氟或溴;硝基;氨基;和/或类似类型的基团取代。
本文提供的治疗中风的制剂和方法使用上文式I的佛波醇酯或式I的佛波醇酯的衍生化合物(包括本说明书的所有活性药学上可接受的化合物以及各种可预见的和容易提供的这些化合物的复合物、盐、溶剂化物、异构体、对映异构体、多晶型物和前药及其组合)作为抗中风剂。
本文提供的增加Th1细胞因子的制剂和方法使用上文式I的佛波醇酯或其衍生化合物(包括本说明书的所有活性药学上可接受的化合物以及各种可预见的和容易提供的这些化合物的复合物、盐、溶剂化物、异构体、对映异构体、多晶型物和前药及其组合)作为新颖增加Th1细胞因子的药剂。多种哺乳动物受试者(包括人类受试者)适于使用本发明的制剂和方法进行治疗。这些受试者包括但不限于患有中风或处于中风风险中的个体。
本文提供的增加ERK磷酸化的制剂和方法使用上文式I的佛波醇酯或其衍生化合物(包括本说明书的所有活性药学上可接受的化合物以及各种可预见的和容易提供的这些化合物的复合物、盐、溶剂化物、异构体、对映异构体、多晶型物和前药及其组合)作为新颖增加ERK磷酸化的药剂。多种哺乳动物受试者(包括人类受试者)适于使用本发明的制剂和方法进行治疗。这些受试者包括但不限于患有中风或处于中风风险中的个体。
在本发明的方法和组合物中,如本文所公开的一种或多种式I的佛波醇酯化合物或式I的佛波醇酯的衍生化合物被有效地配制或施用为药剂以有效治疗和预防中风或中风后遗症。在示例性实施方案中,出于说明性目的,证明TPA在药物制剂和治疗方法中单独或与一种或多种辅助治疗联合时为有效药剂。本公开进一步提供了其它药学上可接受的呈天然或合成化合物形式的佛波醇酯化合物,包括本文公开的化合物的复合物、衍生物、盐、溶剂化物、异构体、对映异构体、多晶型物及前药,其在中风和中风后遗症的治疗和预防中有效作为本发明的方法和组合物中的治疗剂。
中风是因脑部供血中断引起的。这可能缘于血管的堵塞(缺血性中风)或破裂(出血性中风)。中风的症状包括突然麻木或虚弱,特别是身体单侧的突然麻木或虚弱;突然意识模糊或讲话困难或无法理解谈话内容;双眼或单眼突然无法视物;突然无法行走、头晕或丧失平衡或协调;或突然的没有原因的剧烈头痛。中风风险因素包括高血压、血脂异常、吸烟、身体活动不足、肥胖、压力、糖尿病、饮酒、血液中高半胱氨酸过量、炎症和凝血异常。还存在不可更改的风险因素,诸如年龄、遗传、性别和种族。
中风的治疗具有三个不同的阶段:预防、中风发生后立即采取的治疗以及中风后的康复。本文所述的组合物和方法可在中风治疗的任何阶段使用,独立地或联合一种或多种另外的疗法,包括其它药剂、装置或手术干预。
佛波醇是一种天然植物来源多环状醇,属巴豆烷家族二萜类。其于1934年作为自巴豆种子产出的巴豆油的水解产物首次被分离出来。其极易溶于大多数极性有机溶剂和水。佛波醇的酯具有下文式I的一般结构:
其中R1和R2是选自由以下组成的组:氢;羟基;其中所述烷基含有1至15个碳原子;其中低级烯基含有1个至7个之间的碳原子; 和其经取代的衍生物,且R3可为氢、或其经取代的衍生物以及式I化合物和其经取代的衍生物的药学上可接受的盐、对映异构体、多晶型物、前药、溶剂化物和水合物。
如本文所使用的术语"低级烷基"或"低级烯基"意指含有1至7个碳原子的部分。在式I化合物中,所述烷基或烯基可为直链或支链。在一些实施方案中,R1或R2中任一者或二者为长链碳部分(即,式I为癸酸酯或肉豆蔻酸酯)。
本文各式的烷基、烯基、苯基和苄基可未被取代或被卤素,优选地,氯、氟或溴;硝基;氨基和类似类型的基团取代。
有机和合成形式的佛波醇酯(包括任何草药来源诸如巴豆的制剂或提取物)均被认为是对于在本文实施方案中使用为可用的包含佛波醇酯(或佛波醇酯类似物、相关化合物和/或衍生物)的组合物。对于在本文实施方案中使用为可用的佛波醇酯和/或相关化合物通常将具有如式I中所说明的结构,但本领域技术人员还应了解,所述化合物的功能上等效类似物、复合物、缀合物和衍生物在本发明的范围内。
在更详细的实施方案中,将选择符合上文式I的说明性结构修改以提供可用的候选化合物用以在哺乳动物受试者(包括人类)中治疗和/或预防中风、中风造成的损伤和/或管理中风影响或后遗症,其中:R1和R2中至少一者不同于氢且R3是选自由氢、和其经取代的衍生物组成的组。在另一个实施方案中,R1或R2为其余R1或R2为且R3为氢。
在哺乳动物受试者(包括人类)中治疗或预防中风、中风造成的损伤和/或管理中风影响或后遗症时可用于治疗的式I的佛波醇酯化合物的示例性实施方案参见下文式II所示的佛波醇12-肉豆蔻酸酯-13-乙酸酯(也称为PMA或12-O-十四烷酰-佛波醇-13-乙酸酯(TPA))。
在本发明的制剂和方法中可用的其它佛波醇酯和相关化合物和衍生物包括但不限于所述化合物的其它药学上可接受的活性盐以及所述化合物的活性异构体、对映异构体、多晶型物、糖基化衍生物、溶剂化物、水合物和/或前药。式I的佛波醇酯衍生物可为或可不为佛波醇酯自身。可用于本发明的组合物和方法的其它示例性形式的佛波醇酯包括但不限于佛波醇13-丁酸酯;佛波醇12-癸酸酯;佛波醇13-癸酸酯;佛波醇12,13-二乙酸酯;佛波醇13,20-二乙酸酯;佛波醇12,13-二苯甲酸酯;佛波醇12,13-二丁酸酯;佛波醇12,13-二癸酸酯;佛波醇12,13-二己酸酯;佛波醇12,13-二丙酸酯;佛波醇12-肉豆蔻酸酯;佛波醇13-肉豆蔻酸酯;佛波醇12,13,20-三乙酸酯;12-脱氧佛波醇13-当归酸酯;12-脱氧佛波醇13-当归酸酯20-乙酸酯;12-脱氧佛波醇13-异丁酸酯;12-脱氧佛波醇13-异丁酸酯-20-乙酸酯;12-脱氧佛波醇13-苯乙酸酯;12-脱氧佛波醇13-苯乙酸酯20-乙酸酯;12-脱氧佛波醇13-十四烷酸酯;佛波醇12-顺芷酸酯13-癸酸酯;12-脱氧佛波醇13-乙酸酯;佛波醇12-乙酸酯;和佛波醇13-乙酸酯,如表1中所示。
表1
示例性佛波醇酯
如本文所述的组合物包含治疗中风的组合物,其包含减轻或预防中风损伤有效量的式I的佛波醇酯化合物或式I的佛波醇酯的衍生化合物,所述化合物在哺乳动物受试者中有效预防和/或治疗中风或中风相关症状或后遗症。在指定治疗干预期内,“治疗中风”、“抗凝血”、“抗胆固醇血症”、“舒张血管”、“抗高血压”、“降低小动脉阻力”、“增加静脉容量”、“减少心脏需氧量”、“降低心律”、“稳定心律”或“神经保护”有效量的所述活性化合物呈单一或多个单位剂型时在治疗上有效,从而在受试者中适度地减轻中风的一种或多种症状或后遗症。在示例性实施方案中,本发明的组合物在治疗方法中有效预防或减轻易患或已患中风的人类及其它哺乳动物受试者的中风症状或中风后遗症。
本发明的佛波醇酯治疗组合物通常包含有效量或单位剂量的式I的佛波醇酯化合物或式I的佛波醇酯的衍生化合物,,所述化合物可与一种或多种药学上可接受的载体、赋形剂、媒介物、乳化剂、稳定剂、防腐剂、缓冲剂和/或其它可增强稳定性、递送、吸收、半衰期、功效、药物代谢动力学和/或药效学、减少不良副作用或提供其它药用优点的添加剂一起配制。本领域普通技术人员根据临床和患者特异性因素将容易地判定式I的佛波醇酯化合物或其相关或衍生化合物的有效量(例如,包含有效浓度/量的TPA或所选药学上可接受的TPA的盐、异构体、对映异构体、溶剂化物、多晶型物和/或前药的单位剂量)。用于施用至哺乳动物受试者(包括人类)的活性化合物的适合有效单位剂量范围可为约10μg至约1500μg、约20μg至约1000μg、约25μg至约750μg、约50μg至约500μg、约150μg至约500μg、约125μg至约500μg、约180μg至约500μg、约190μg至约500μg、约220μg至约500μg、约240μg至约500μg、约260μg至约500μg、约290μg至约500μg。在某些实施方案中,式I的佛波醇酯化合物或相关或衍生化合物治疗疾病的有效剂量可选择在较窄范围内,例如,10μg至25μg、30μg至50μg、75μg至100μg、100μg至300μg或150μg至500μg。这些和其它有效单位剂量可以单一剂量或以每日、每周或每月多个剂量的形式施用,例如在一种给药方案中包括每天、每周或每月施用1个至5个或者2个至3个剂量。在一个示例性实施方案中,每天一次、两次、三次、四次或五次施用10μg至30μg、30μg至50μg、50μg至100μg、100μg至300μg或300μg至500μg的剂量。在更详细的实施方案中,每日一次或两次施用50-100μg、100-300μg、300-400μg或400-600μg的剂量。在又一个实施方案中,每隔一天施用50-100μg、100-300μg、300-400μg或400-600μg的剂量。在替代实施方案中,剂量是基于体重计算,且可以例如下述量施用,每天约0.5μg/m2至约300μg/m2、约1μg/m2至约200μg/m2、每天约1μg/m2至约187.5μg/m2、每天约1μg/m2至每天约175μg/m2、每天约1μg/m2至每天约157μg/m2、每天约1μg/m2至约125μg/m2、每天约1μg/m2至约75μg/m2、每天1μg/m2至约50/μg/m2、每天2μg/m2至约50μg/m2、每天2μg/m2至约30μg/m2或者每天3μg/m2至约30μg/m2。
在其它实施方案中,剂量可以更低的频率施用,例如,每隔一天0.5μg/m2至约300μg/m2、约1μg/m2至约200μg/m2、每隔一天约1μg/m2至约187.5μg/m2、每隔一天约1μg/m2至约175μg/m2、每天约1μg/m2至每隔一天约157μg/m2、每隔一天约1μg/m2至约125μg/m2、每隔一天约1μg/m2至约75μg/m2、每隔一天1μg/m2至约50μg/m2、每隔一天2μg/m2至约50μg/m2、每天2μg/m2至约30μg/m2或者每天3μg/m2至约30μg/m2。在另外的实施方案中,视临床和患者特异性因素,剂量可3次/周、4次/周、5次/周、仅在工作日、仅与其它治疗方案一致、连续数天或以任何适当的剂量方案施用。
包含一(或者“治疗中风”、“抗凝血”、“抗胆固醇血症”、“舒张血管”、“抗高血压”、“降低小动脉阻力”、“增加静脉容量”、“减少心脏需氧量”、“降低心律”、“稳定心律”、“诱导ERK磷酸化”“调节IL-2”和/或“神经保护”)有效量的式I的佛波醇酯化合物或式I的佛波醇酯的衍生化合物的本发明组合物的递送量、时程和模式将根据个体的基本情况(根据诸如个体的体重、年龄、性别和个人情况)、疾病和/或相关症状的剧烈程度、预防性抑或治疗性施用、并且依据其它已知影响药物递送、吸收、药物代谢动力学(包括半衰期)和功效的因素进行常规地调整。
本发明的用于治疗紧急疾病(或者,“治疗中风”、“抗凝血”、“抗胆固醇血症”、“舒张血管”、“抗高血压”、“诱导ERK磷酸化”、“降低小动脉阻力”、“增加静脉容量”、“减少心脏需氧量”、“降低心律”、“稳定心律”、“减少凝血”、“神经保护”、“调节IL-2”或“调节NFκB”)的制剂的有效剂量或多剂量治疗方案将通常选择为接近必要且足够有效的最小给药方案以实质上预防或减轻受试者的中风症状。剂量和施用方案通常将包括在数天或甚至一或多周或者一或多年期间内重复给药疗法。有效治疗方案还可涉及在某一天或者在数天、数周、数月或甚至数年期间内持续每天多剂量施用预防剂量。
可使用多种模型***来证明本发明的组合物和方法在中风治疗中的效果,包括如实施例9中所示的暂时性大脑中动脉闭塞、如实施例8中所示的永久性大脑中动脉闭塞、血管内长丝大脑中动脉闭塞、如实施例7中所示的栓塞性大脑中动脉闭塞、内皮缩血管肽-1-诱导的动脉和静脉收缩或脑皮质光栓疗法。使用本发明的佛波醇酯组合物将使所述模型***所展现的症状或长期效应相较于对照动物减少0%、20%、30%、50%或更多,多达75-90%、96%或更多的减少。
本发明的组合物和方法在中风治疗中的效果可进一步通过已患中风的个体中所展现的症状的减少来证明。这些症状包括但不限于麻痹、空间障碍、判断力受损、左侧忽视、记忆丧失、失语、协调与平衡问题、恶心、呕吐、认知障碍、知觉障碍、定向力障碍、同侧偏盲和冲动。使用本发明的佛波醇酯组合物将使个体所展现的症状相较于初始状态减少0%、20%、30%、50%或更多,多达75-90%、96%或更多的减少。
在本发明其它方面,提供治疗组合疾病(“治疗中风”、“抗凝血”、“抗胆固醇血症”、“舒张血管”、“抗高血压”、“诱导ERK磷酸化”、“降低小动脉阻力”、“增加静脉容量”、“减少心脏需氧量”、“降低心律”、“稳定心律”或“调节NFκB”)的制剂和协同施用方法,这些制剂和协同施用方法使用有效量的式I的佛波醇酯化合物或式I的衍生化合物和一种或多种次要或辅助药剂,所述一种或多种次要或辅助药剂是与所述式I的佛波醇酯化合物组合配制或协同施用以得到复方多重活性治疗疾病的组合物或协同治疗方法。
在中风的预防或治疗中,示例性组合制剂和协同治疗方法使用所述式I的佛波醇酯化合物或式I的佛波醇酯的衍生化合物,联合一种或多种另外的可用于治疗或预防目标疾病、病况和/或症状的神经保护剂或其它所示次级或辅助治疗剂。对于本发明的大多数组合制剂和协同治疗方法,式I的佛波醇酯化合物或相关或衍生化合物是联合一种或多种次要或辅助治疗剂配制或协同施用,以产生可组合时有效或协同地用于预防或治疗中风或中风影响的复方制剂或协同治疗方法。在此背景下,示例性组合制剂和协同治疗方法使用式I的佛波醇酯化合物或式I的佛波醇酯的衍生化合物,联合一种或多种选自以下的次要或辅助治疗剂:组织纤溶酶原激活物、抗凝血剂、抑制素、血管紧张素II受体阻断剂、血管紧张素-转化酶抑制剂、抗血小板剂、贝特类药物、β阻断剂、钙通道阻断剂或利尿剂。示例性抗凝血剂包括但不限于肝素、华法林(warfarin)、类肝素、苯茚二酮、阿托门丁(atomentin)、醋硝香豆素(acenocoumarol)、苯丙香豆素(phenprocoumon)、依达肝素(idraparinux)、磺达肝素(fondaparinux)和凝血酶抑制剂。示例性抑制素包括但不限于洛伐他汀(lovastatin)、氨氯地平(amlodipine)、阿托伐他汀(atorvastatin)、罗舒伐他汀(rosuvastatin)、辛伐他汀(simvastatin)、氟伐他汀(fluvastatin)、匹伐他汀(pitavastatin)和普伐他汀(pravastatin)。示例性血管紧张素II受体阻断剂包括但不限于坎地沙坦(candesartan)、依普罗沙坦(eprosartan)、厄贝沙坦(irbesartan)、氯沙坦(losartan)、奥美沙坦(olmesartan)、替米沙坦(telmisartan)和缬沙坦(valsartan)。血管紧张素转化酶抑制剂包括但不限于艾那普利(enazepril)、卡托普利(captopril)、依那普利(enalapril)、福辛普利(fosinopril)、赖诺普利(isinopril)、莫昔普利(moexipril)、培哚普利(perindopril)、喹那普利(quinapril)、雷米普利(ramipril)和群多普利(trandolapril)。示例性β-阻断剂包括但不限于阿普洛尔(alprenolol)、布新洛尔(bucindolol)、卡替洛尔(carteolol)、卡维地洛(carvedilol)、拉贝洛尔(labetalol)、纳多洛尔(nadolol)、氧烯洛尔(oxprenolol)、喷布洛尔(penbutolol)、吲哚洛尔(pindolol)、***(propranolol)、索他洛尔(sotalol)、噻吗洛尔(timolol)、杜仲(eucommia)、醋丁洛尔(acebutolol)、阿替洛尔(atenolol)、倍他洛尔(betaxolol)、比索洛尔(bisoprolol)、塞利洛尔(celiprolol)、艾司洛尔(esmolol)、美托洛尔(metoprolol)和奈必洛尔(nebivolol)。示例性钙通道阻断剂包括但不限于氨氯地平(amlodipine)、氯维地平(clevidipine)、地尔硫卓(diltiazem)、非洛地平(felodipine)、伊拉地平(isradipine)、硝苯地平(nifedipine)、尼卡地平(nicardipine)、尼莫地平(nimodipine)、尼索地平(nisoldipine)和维拉帕米(verapamil)。示例性利尿剂包括但不限于***(chlorothiazide)、氢***(hydrochlorothiazide)、布美他尼(bumetanide)、依他尼酸(ethacrynic acid)、呋塞米(furosemide)、阿米洛利(amiloride)、依普利酮(eplerenone)、螺内酯(spironolactone)和氨苯蝶啶(triamterene)。示例性贝特类药物包括但不限于苯扎贝特(benzafibrate)、环丙贝特(ciprofibrate)、氯贝丁酯(clofibrate)、吉非贝齐(gemfibrozil)或非诺贝特(fenofibrate)。示例性抗血小板剂包括但不限于氯吡格雷(clopidogrel)和噻氯匹定(ticlopidin)。
协同治疗方法可进一步使用手术干预,包括但不限于使用起搏器、植入式除颤器、冠状动脉支架、人工瓣膜、冠状动脉分流术、气囊血管成形术、瓣膜修复及置换术、颈动脉内膜切除术、血管成形术、支架置入术、开颅术、血管内弹簧圈栓塞术、卵圆孔未闭封堵术和心脏移植术。
在某些实施方案中,本发明提供治疗组合疾病(“治疗中风”、“抗凝血”、“抗胆固醇血症”、“舒张血管”、“抗高血压”、“诱导ERK磷酸化”、“降低小动脉阻力”、“增加静脉容量”、“减少心脏需氧量”、“降低心律”、“稳定心律”或“调节NFκB”)的制剂,其包含佛波醇酯和一种或多种具有疾病治疗活性的辅助药剂。在此类组合制剂中,式I的佛波醇酯和所述具有疾病治疗活性的辅助药剂将单独或组合以有效治疗疾病(“治疗中风”、“抗凝血”、“抗胆固醇血症”、“舒张血管”、“抗高血压”、“诱导ERK磷酸化”、“降低小动脉阻力”、“增加静脉容量”、“减少心脏需氧量”、“降低心律”、“稳定心律”或“调节NFκB”)的量存于复方制剂中。在示例性实施方案中,式I的佛波醇酯化合物和一种(多种)非佛波醇酯药剂将各自以治疗/预防疾病的量(即,以将单独引发受试者可检测的症状减轻的单剂量)存在。或者,所述组合制剂可以低于单剂量的治疗量包含所述式I的佛波醇酯化合物和所述非佛波醇酯药剂中的一者或两者,其中同时包含这两种药剂的组合制剂的特征在于这两种药剂的组合剂量共同地有效引发减轻疾病、病况或症状的反应。因此,所述式I的佛波醇酯或式I的佛波醇酯的衍生化合物和非佛波醇酯药剂中的一者或两者可低于治疗剂量在所述制剂中存在或在协同施用方案中施用,但在所述制剂或方法中它们在受试者中共同地引发可检测的疾病症状、中风复发的出现或中风后遗症的减少。在又一个实施方案中,所述组合制剂可包含一种或多种神经保护剂。在另一个实施方案中,所述组合制剂可包含一或多种抗炎剂或其它如本文所述的次要或另外的治疗剂。
为了实施本发明的协同施用方法,在协同治疗方案中式I的佛波醇酯化合物或式I的佛波醇酯的衍生化合物可与一种或多种本文所涵盖的次要或辅助治疗剂同时或依次施用。因此,在某些实施方案中,一种化合物是与非佛波醇酯药剂或任何其它本文所涵盖的次要或辅助治疗剂协同施用,使用分别的制剂或如上文所述的组合制剂(即,同时包含式I的佛波醇酯化合物或相关或衍生化合物和非佛波醇酯治疗剂)。该协同施用可同时或依次以任何顺序进行,且可存在供仅一种或两种(或所有)活性治疗剂个别地和/或共同地发挥其生物学活性的一段时间。
在另一个实施方案中,此类协同治疗方法可例如遵循或源自各种中风治疗方案。例如,协同治疗方法可包括一种佛波醇酯和/或用于预防或治疗中风造成的损害的治疗。所有此类协同治疗方法的突出方面在于式I的佛波醇酯化合物或式I的佛波醇酯的衍生化合物发挥至少一定程度的活性,从而使得联合补充的预防或治疗中风的药剂能产生有利的临床反应;或由次要或辅助治疗剂提供的显著临床反应。通常,将式I的佛波醇酯化合物或式I的佛波醇酯的衍生化合物与次要或辅助治疗剂协同施用将在受试者中产生改善的治疗或预防结果,该结果超过单独施用式I的佛波醇酯化合物或式I的佛波醇酯的衍生化合物或次要或辅助治疗剂所引起的疗效。该评定涵盖直接效果以及间接效果。
在示例性实施方案中,式I的佛波醇酯化合物或式I的佛波醇酯的衍生化合物将与一种或多种次要治疗中风的化合物或其它所示治疗剂或辅助治疗剂(例如组织纤溶酶原激活物、抗凝血剂、抑制素、血管紧张素II受体阻断剂、血管紧张素-转化酶抑制剂、贝特类药物、β-阻断剂、钙通道阻断剂、降血脂药物、抗血小板剂或利尿剂)协同施用(同时或依次,以复方制剂或单独的制剂)。另外,在中风或中风影响的治疗中可使用辅助或次要疗法,诸如但不限于起搏器、植入式除颤器、冠状动脉支架、人工瓣膜、人工心脏、冠状动脉分流术、气囊血管成形术、瓣膜修复及置换术、心脏移植术、颈动脉内膜切除术、血管成形术、支架置入术、开颅术、血管内弹簧圈栓塞术或卵圆孔未闭封堵术。
如上文所述,在本文所涵盖的所有本发明的各种实施方案中,治疗所述疾病的方法和制剂可以使用呈各种形式中的任一种的式I的佛波醇酯化合物,包括标的化合物的药学上可接受的盐、溶剂化物、异构体、对映异构体、多晶型物、溶剂化物、水合物和/或前药中的任一者或组合。在本发明的示例性实施方案中,出于说明的目的在治疗制剂和方法中使用TPA。
本发明的药物组合物可通过能实现其所需的治疗或预防目的的任何方式施用。本发明的组合物的适合施用途径包括但不限于常规递送途径、装置和方法(包括注射方法),例如但不限于静脉内、肌肉内、腹膜内、脊柱内、鞘内、脑室内、动脉内、皮下和鼻内途径。
本发明的组合物可进一步包括适合于所使用的具体施用模式的药学上可接受的载体。本发明的组合物的剂型包括在药物配混领域中被公认为适于制备如上文所述的剂量单位的赋形剂。这些赋形剂包括但不欲限于粘合剂、填充剂、润滑剂、乳化剂、助悬剂、甜味剂、调味剂、防腐剂、缓冲剂、润湿剂、崩解剂、泡腾剂和其它常规赋形剂和添加剂。
视需要,本发明的组合物可通过使用缓释载体(诸如亲水性缓释聚合物)以控释形式施用。在此背景下示例性控释剂包括但不限于粘度在约100cps至约100,000cps范围内的羟丙基甲基纤维素或其它生物相容性基质诸如胆固醇。
一些本发明式I的佛波醇酯组合物被设计用于肠胃外施用,例如被设计为静脉内、肌内、皮下或腹腔内施用,包括水性和非水性无菌注射溶液,同本发明所涵盖的许多其它组合物一样,其可任选地含有抗氧化剂、缓冲剂、抑菌剂和/或赋予制剂与哺乳动物受试者血液等渗的溶质;以及水性和非水性无菌悬浮液,其可包括助悬剂和/或增稠剂。所述制剂可存于单位剂量或多剂量容器中。本发明的其它组合物和制剂可包括用于在肠胃外施用后延长释放的聚合物。肠胃外制剂可为适于此类施用的溶液、悬浮液或乳液。还可将标的药剂配制到用于在肠胃外施用后延长释放的聚合物中。药学上可接受的制剂和成分将通常是无菌或容易灭菌的、生物学上惰性的且易于施用。此类聚合材料为药物配混领域普通技术人员所熟知。肠胃外制剂通常含有缓冲剂和防腐剂、和药学和生理学可接受的可注射流体,诸如水、生理盐水、平衡盐溶液、葡萄糖水溶液、甘油等。临时注射溶液、乳液和悬浮液可由先前所述种类的无菌粉剂、颗粒和片剂制备。优选的单位剂量制剂是含有如上文所述的日剂量或单位日次剂量或其适当分量的活性成分的那些。
在更详细的实施方案中,本发明组合物可包含为达成递送而包埋于以下中的式I的佛波醇酯化合物或式I的佛波醇酯的衍生化合物:例如通过凝聚技术或通过界面聚合制备的微胶囊、微粒或微球,例如分别为羟甲基纤维素或明胶微胶囊和聚-(甲基丙烯酸甲酯)微胶囊;胶体药物递送***(例如,脂质体、白蛋白微球、微乳剂、纳米颗粒和纳米胶囊);或粗乳剂。
如上所述,在某些实施方案中,本发明的方法和组合物可使用药学上可接受的盐,例如,上述式I的佛波醇酯化合物和/或相关或衍生化合物的酸加成盐或碱式盐。药学上可接受的加成盐的实例包括无机和有机酸加成盐。适合的酸加成盐是由形成无毒盐(例如,盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、硝酸盐、磷酸盐和磷酸氢盐)的酸形成。其它药学上可接受的盐包括但不限于金属盐,诸如钠盐、钾盐、铯盐等;碱土金属,诸如钙盐、镁盐等;有机胺盐,诸如三乙胺盐、吡啶盐、甲基吡啶盐、乙醇胺盐、三乙醇胺盐、二环己胺盐、N,N'-二苄基乙二胺盐等;有机酸盐,诸如乙酸盐、柠檬酸盐、乳酸盐、琥珀酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐、乙酸盐、二氯乙酸盐、三氟乙酸盐、草酸盐和甲酸盐;磺酸盐,诸如甲磺酸盐、苯磺酸盐和对-甲苯磺酸盐;和氨基酸的盐,诸如精氨酸盐、天冬酰胺酸盐、谷氨酸盐、酒石酸盐和葡糖酸盐。适合的碱式盐由形成无毒盐(例如铝盐、钙盐、锂盐、镁盐、钾盐、钠盐、锌盐和二乙醇胺盐)的碱形成。
本发明的其它具体实施方案、方法和组合物使用式I的佛波醇酯的前药。前药被认为是体内释放活性母体药物的任何共价结合的载体。可用于本发明的前药的实例包括以羟烷基或氨基烷基作为取代基的酯或酰胺,并且它们可通过使如上文所述的此类化合物与酸酐(诸如琥珀酸酐)反应来制备。
本文公开的发明还应理解为涵盖使用所述化合物的体内代谢产物(在施用受试者前体化合物后体内产生或直接以代谢产物自身形式施用)的方法和包含式I的佛波醇酯的组合物。此类产物可能例如因所施用化合物的氧化、还原、水解、酰胺化、酯化等而产生,主要由于酶促过程。因此,本发明包括使用通过包括使式I的佛波醇酯化合物与哺乳动物受试者接触足以得到其代谢产物的一段时间的方法而产生的化合物的本发明的方法和组合物。此类产物通常如下鉴定:制备放射性标记的本发明化合物,将其以可检测的剂量肠胃外施用至动物,诸如大鼠、小鼠、豚鼠、猴或人,允许代谢进行足够长的时间并从尿液、血液或其它生物样本中分离其转化产物。
本文公开的发明还应理解为涵盖用于诊断哺乳动物的疾病(包括但不限于中风)的风险水平、存在、严重程度或治疗指标或者管理所述疾病的诊断组合物,其包括使标记的(例如,同位素标记的、荧光标记的或允许使用常规方法检测标记化合物的以其它方式标记的)式I的佛波醇酯化合物与处于中风风险中或表现出一或多种中风症状的哺乳动物受试者(例如细胞、组织、器官或个体)接触,且此后使用众多已知测定和标记/检测方法中的任一种来检测标记化合物的存在、位置、代谢和/或结合状态。在示例性实施方案中,式I的佛波醇酯化合物是由具有不同原子质量或质量数的原子代替一种或多种原子的同位素标记的。可纳入所公开的化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,诸如分别为2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。然后将同位素标记的化合物施用至个体或其它受试者,且随后如上文所述根据常规技术进行检测,得到有用的诊断和/或治疗管理数据。
实施例
下文所述实验证明佛波醇酯和衍生化合物作为治疗和预防中风的药剂的新颖且强效的用途。将在以下实施例中进一步详述并阐明这些和其它发现。
实施例I
TPA对注射S180细胞的小鼠的外周白血细胞(WBC)和
血红蛋白(Hb)计数的影响:
将肉瘤180(S180)细胞注入Kwen-Ming小鼠中。在第三天,小鼠以50、100或200μg/kg/天腹膜内(i.p.)给予TPA,持续7天。在完成治疗后的第二天,从所治疗小鼠的尾部获取血液样本用于WBC和Hb分析。治疗组(50、100或200ug/kg/天,持续7天)的WBC计数分别为16.1±7.4、18.7±.3.0和20.7±.3.4×109/L;对照组的WBC计数为13.6±1.8×109/L。治疗组的Hb为136±11、149±12和149±10g/L,且对照组的Hb为134+-15g/L。结果表明腹膜内注射TPA可以剂量依赖性方式增加小鼠的外周WBC计数,而TPA治疗的小鼠的Hb水平与对照小鼠相比未受太大影响。
实施例II
剂量范围研究.
因TPA施用时会引起强烈的局部刺激,故TPA是通过静脉内(i.v.)输注给予患者。将无菌注射器中的TPA溶液注入200ml无菌盐水中并充分混合以供静脉内输注。
临床上施用不同TPA剂量的毒性和副作用:
(1)以1mg/患者/周给予TPA:
将溶液中的1mg TPA与200ml无菌盐水充分混合以供静脉内输注,静脉内输注是以16μg/min的速率在1h内完成。TPA施用后一小时,患者开始有持续约30分钟的畏寒,接着发烧(患者体温达到37.5-39.5℃并持续3-5h,然后恢复到正常)且伴有轻重不等的出汗。上述症状可通过给予患者糖皮质激素得以减轻。此剂量的TPA造成少数患者出血,一些患者遭受短期呼吸困难,并在尿液中检测到Hb。然而,这些副作用是短暂的且可恢复的。发现心脏、肝、肾和肺功能均正常。
(2)以0.5mg/患者×2/周给予TPA:(每周给药两次)
将溶液中的0.5mg TPA与200ml盐水充分混合以供静脉内输注,静脉内输注是以8μg/min的速率在1h内完成。施用后的反应类似于1mg TPA剂量的反应,但程度轻于1mg剂量。患者更易耐受较低剂量。偶尔在患者的尿液中检测到Hb。并未观察到呼吸困难。心脏、肝、肾和肺功能均正常。
(3)以0.25mg/患者×4/周给予TPA:
将溶液中的0.25mg TPA与200ml盐水充分混合以供静脉内输注,静脉内输注是以4μg/min的速率在1h内完成。施用后,也观察到诸如畏寒和发烧的症状,但程度远轻于使用较高剂量。在尿液中没有检测到Hb,且患者未感到呼吸困难。心脏、肝、肾和肺功能均正常。
实施例III
用TPA治疗复发性/难治性恶性肿瘤
用TPA(Xichuan Pharmaceuticals,Nan Yang,Henan,China)、***和三水杨酸胆碱镁联合治疗经组织学证实患有复发性/难治性血液恶性肿瘤/骨髓病症的患者。将运用与下文用于证明TPA在治疗急性髓性白血病(AML)中的治疗性用途所述类似的方法来证明TPA用于治疗其它瘤形成病况和恶性肿瘤的用途。除了本文特定方案以外,将使用众多种熟知癌症检测和评估方法中的任一种来判定不同的目标瘤形成和恶性病况的成功治疗和/或缓解,例如通过测定实体瘤的尺寸减小,进行组织病理研究以评价肿瘤生长、阶段、转移潜力、组织学癌症标记物的存在/表达水平等。
AML是通常需要进行紧急和强化治疗的一种侵袭性疾病。被诊断为AML的患者的平均年龄为64-68岁,且60岁以上以标准化疗治疗的患者当次疾病治愈的机率<20%。患有AML的患者在患有前期血液病症之后,或是在引起白血病的化疗/放疗之前,具有类似不好的结果,患有与特定不良细胞遗传及临床特征相关疾病的患者同样如此。因此,大多数经诊断患有AML的患者具有与极差的预后相关的患者和/或疾病连带特征。对于有复发疾病的患者,尚无标准的非移植疗法经证实具有治愈的能力。对这些患者,AML常常是致命的疾病。需要新的治疗AML的方法。
使用本发明的方法和组合物将TPA发展为用于治疗AML患者的治疗剂,此是基于TPA在调节细胞内信号途径中的新颖作用、其诱导细胞系分化和/或凋亡的能力、以及表明TPA在治疗瘤形成和恶性病症(包括骨髓性恶性肿瘤)中的有效性的临床数据。
迄今,TPA的临床评价已证实,TPA在至少一个AML病例子集中产生直接的治疗性细胞毒性作用,如通过细胞活力和凋亡测定所测量。在通过Western分析进行分析的所有原代培养物中,在培养1小时后TPA强烈诱导ERK磷酸化。TPA对原代AML细胞的细胞毒性作用与在24小时先体外后体内暴露后磷酸化-ERK促存活信号随后消失相关。该观察结果与其它报道通过MEK抑制剂(诸如PD98059、U0126和PD 184352)药理上干扰ERK信号传导后原代AML存活率减少的研究很好地相符。在我们的研究中,ERK信号传导的损失与ERK磷酸酶的诱导相关。
除了活化蛋白激酶C和ERK,TPA还是已知的NF-κB诱导物,NF-κB是在AML母细胞和白血病干细胞中时常持续活化的促存活转录因子。我们实验室最近的工作已证实,用***+三水杨酸胆碱镁(CMT)治疗48h可体内抑制AML细胞NF-κB。另外,我们已证实***可诱导MKP-1ERK磷酸酶表达并增强TPA对原代AML样本的细胞毒性。在该背景下,我们已在下文示例性实施方案中选择使用***和CMT作为在TPA治疗前24h和治疗后24h使用的辅助药物。这些药物良好耐受且预期减少治疗的炎性副作用并通过增加ERK磷酸酶表达和抑制NF-κB而增强TPA细胞毒性。将***和CMT用作辅助药物另外因为它们具抗炎性,可改善副作用,并且可通过抑制组成型NF-κB表达的抗细胞凋亡作用和诱导磷酸酶降低信号传导途径活性而增强抗白血病活性。
初步的TPA 1期研究招募35名患者[23名患有复发性/难治性AML,2名患有其它骨髓性恶性肿瘤(CML-母细胞危象、母细胞过多的脊髓发育不良),3名患有霍奇金氏病(Hodgkin's Disease),3名患有非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)且4名患有实体瘤]。大部分患者有复发性/难治性AML。我们的临床结果包括一名接受8次TPA输注持续>5个月病情稳定的AML患者。在又一名AML患者中,在TPA施用后看到循环母细胞数显著(5倍)下降。白血病母细胞的此下降持续4周,且所述患者最终死于真菌感染。最后,患有复发性和难治性霍奇金氏病的患者尽管被施予高剂量的化学疗法联合自体干细胞解救,但TPA施用后胸壁肿块仅部分缓解。TPA剂量增加已经完成,在最后一个小组中3名患者中的2名第1-5天以0.188mg/m2的剂量治疗,第8-12天经历III级非血液学剂量限制性毒性(DLT),确立了在第1-5天和第8-12天单一药剂时的最大耐受TPA剂量为0.125mg/m2/天。
在AML和其它血液恶性肿瘤的情况下,给予患者初始剂量为1mg/周×3周(第1天、第8天、第15天)的TPA并配以连续/间歇脉搏血氧测定法施用6小时。在开始TPA疗法之前24小时,对患者持续每6小时给予10mg***并每8小时给予1500mg三水杨酸胆碱镁(CMT)直到施用TPA之后24小时。施用初始剂量的TPA后,患者有2周的休息时间,此后他们会接受重新评价。具有疾病反应或通过初始剂量的TPA稳定病情的患者按照以下方案治疗长达6个28天的周期。
2周的休息时间过后,患者在施用TPA之前30分钟以650mgTylenol及25-50mg Benadryl(视患者体型和年龄而定)进行前驱用药。然后,他们通过中心静脉导管每天接受TPA静脉内输注,每周5天,连用2周,接着为2周的休息时间。TPA是以1mg的剂量于200ml生理盐水中在1小时内施用。在开始TPA疗法之前24小时,对患者持续每6小时给予10mg***并每8小时给予1500mg三水杨酸胆碱镁直到施用TPA之后24小时。
使用测量有机溶剂可提取的分化活性的生物测定测量TPA输注前后TPA的血液水平。将1ml血液用5ml乙酸乙酯萃取两次,将萃取残余物重新溶于50μL乙醇中并加入等分的HL60细胞。48小时后,测量粘附细胞。
也对TPA输注前后的血液样本进行了测试,以判定白血细胞、血小板和中性粒细胞的水平。另外还对样本中髓母细胞和奥氏小体(Auer rod)的出现进行了分析。这些实验和后续实验将进一步阐明在AML和其它瘤形成和恶性病况中TPA对瘤形成细胞引发的治疗性细胞毒性作用和其它效应。
实施例IV
ERK活化的调节的测量
测量白血患者者的循环恶性细胞中和淋巴瘤/实体瘤患者的外周血单核细胞中的磷酸化-ERK水平。在施用TPA之前和之后,自依照实施例III的方案治疗的患者取得血液样本。
在WBC≥1000个/μL的白血患者中,使用与荧光团直接辍合的细胞表面抗原特异性抗体和磷酸化-ERK特异性抗体(BD Biosciences,San Jose,CA)对血液样本实施流式细胞术。在施用TPA之前、在按照实施例III的方案的初始治疗的第1天、第2天和第11天输注TPA 1小时之后以及在后续周期的第1天和第11天采集样本。在绝对白血病母细胞数目≥2500个/μL的白血患者者和其它非白血患者者中,在按照实施例III的首个周期的第1天、第8天和第15天在输注前和输注后1小时和4小时采集外周血液样本。还使用Western印迹分析来分析了样本中的磷光化-ERK和总ERK1/2水平以判定获自流式细胞术和与临床反应相关的结果。
上述分析进一步阐明TPA在治疗瘤形成和恶性病况中的作用,包括TPA对恶性细胞(以原代AML细胞为例)的细胞毒性作用、以及相关因TPA而降低的磷酸化-ERK促存活信号。
实施例V
NF-κB调节的测量
在先前的研究中,我们已证实在施用TPA与***后可调节患者中的NF-κB活性。另外,已证实***诱导MKP-1ERK磷酸酶表达并增强TPA细胞毒性。设计以下研究以进一步阐明如何在用TPA+***治疗的患者中治疗性地调节NF-κB活性。
使用基于ELISA的测定(BD Bioscience,San Jose,USA)测量基线时和输注前以及输注后患者外周血液样本中的NF-κB结合情况,所述患者外周血液样本来自按照实施例III用TPA治疗的患者。使用供以在使用96孔形式的限定量的细胞萃取物中检测结合情况的化学发光强度对NF-κB水平进行定量。另外,实施电泳迁移率变化测定以测量绝对白血病母细胞数目≥2500个/μL的白血患者者和其它具有正常白血细胞计数的非白血患者者外周血液样本中的NF-κB结合情况。
上述研究将进一步说明TPA为NF-κB诱导物;然而这些实验证明可通过用***和三水杨酸胆碱镁治疗来抑制AML细胞中的NF-κB。
实施例VI
已患中风的个体的治疗。
患者N.C.,男性,68岁,在用TPA治疗之前患中风18个月。在开始TPA治疗时,他需依靠拐杖行走,左手和左腿均活动困难并感到疲倦且虚弱。他接受1安瓿的含有以下物质的注射:0.19mg TPA(0.125mg/m2),每隔一天,持续4周;然后0.24mg TPA(1.25×0.125mg/m2),每隔一天,持续2周;且然后0.26mg TPA(1.5×0.125mg/m2),每隔一天,再持续3周。所述患者已完全康复。
患者M.C.,男性,年龄为65岁,在开始用TPA治疗之前患中风7年。他每周接受3至4次的0.19mg TPA(0.125mg/m2)注射,持续10周,总计35次注射。他的面部已恢复灵活性且右侧的灵活性改善80%。
实施例VII
用TPA治疗的栓塞性中风模型
使用雄性Sprague-Dawley大鼠(Charles River,Japan),每只的体重为280-350g。按照经过改进的Kudo等(1982)的方法诱导栓塞性中风。将欲进行血液采集的大鼠于自发呼吸下用1.0%氟烷(FluorothaneTM;Takeda,Osaka,Japan)麻醉。将24号SurfloTM(Terumo MedicalProducts,Elkton,MD)固定在股动脉中并用1-mL注射用注射器(TerumoMedical Products,Elkton,MD)采集0.1mL动脉血。将注射器中的动脉血在30℃下孵育2天以形成血凝块。此后,将0.1mL生理盐水加入到所述注射用注射器中并使其通过26号注射针头(Terumo MedicalProducts,Elkton,MD)(两次)以使血凝块破碎。
将已诱发栓塞性中风的大鼠于自发呼吸下用1.0%氟烷麻醉。对大鼠颈部做一正中切口并用双极电凝器(T-45;Keisei MedicalIndustrial Co.Ltd,Tokyo,Japan)电灼颈外动脉、甲状腺上动脉、枕动脉和翼腭动脉。通过将0.1mL粉碎的血凝块注入颈内来诱发脑栓塞。
使用激光多普勒血流测定仪(laser Doppler flowmetry)(FloC1;Omegawave,Tokyo,Japan)评价脑栓塞的形成。脑血流量下降到30%或更少的水平被视为形成栓塞的确凿证据。在输注血凝块30分钟后监测脑血流量且直到监测到血流量保持在血凝块输注前的流量的50%或更少。此后,将用于施用药物的插管(PE50)固定在颈静脉中并唤醒动物。
将已成功地形成脑栓塞的大鼠分成四组。第一组大鼠每隔一天给予盐水注射。第2-4组每隔一天给予0.125mg/m2的TPA注射,持续四周。然后将第2组处死。第3-4组每隔一天另外给予0.156mg/m2的TPA,持续两周且然后处死第3组。第4组每隔一天给予0.18775mg/m2的TPA,持续三周,且然后处死。
处死动物后切下脑后并使用McIwain组织切碎机(MickleLaboratory Engineering,U.K.)以1mm间隔切成10段,并通过在37℃下在2%TTC(2,3,5-三苯基氯化四唑;Tokyo Kasei)中浸泡20分钟进行染色。使用数码相机(HC-2500;Fuji PhotoFilm)和Phatograb-2500(Fuji Photo Film)将TTC-染色切片的图像上载到计算机中,并使用Mac Scope(Mitani,Japan)计算梗塞体积。梗塞体积由平均值±标准误差给出。关于梗塞体积结果的统计学检验,通过对对照组以及每个TPA施用组进行Dunnett's检验,与对照组进行比较,且然后对TPA施用组进行t-检验。
每日观察神经学症状直到处死并根据三个测试评价大鼠:(1)轻提大鼠尾部,悬吊于距地面一米处,并观察前肢弯曲;(2)将大鼠放置于一大张软的塑料涂布纸上,使其爪可牢牢抓住纸。拉住鼠尾,在大鼠肩部后施加轻微的侧向压力直到前肢滑行数英寸;(3)使大鼠自由移动并观察转圈行为。根据Bederson等开发的量表(1986)如下进行神经学症状的评分:0分:没有观察到缺陷;1分∶前肢弯曲;2分:侧推抵抗力下降,不转圈;3分:与2分等级相同的行为,转圈。
使用Steel检验评价对照组以及每个TPA施用组的神经学症状,与对照组进行比较且然后对TPA施用组进行Wilcoxon检验。在任一所述检验中,p<0.05的值均被定义为统计上显著的。
实施例VIII
TPA在使用永久性大脑中动脉闭塞模型的中风治疗中的效果
对本研究使用雄性Wistar大鼠(250-320g)。用异氟烷麻醉动物(3%诱导,1-2%维持)。通过挤压脚趾监测麻醉。在本研究期间所有程序均使用无菌技术。夹住手术部位并用酒精和外科擦洗液清洗。将动物放置于温水加热垫上以维持体温。在颈动脉上方的颈部上做一旁正中切口。钝性切除组织以露出颈动脉和分叉部。将缝线放置于近端部分或颈总动脉和颈外动脉附近。将这些缝线打结。在结扎部位远端的颈总动脉中做一切口。预先制备的长丝(4-0单丝缝线或类似材料)放置于颈动脉中并前进至颈内动脉内。使长丝前进约20mm通过颈动脉分叉部直到其楔入大脑中动脉中时感觉到轻微阻力。在***长丝时必须小心不要破坏动脉。将长丝原位打结并封闭皮肤切口。在动物清醒时使用Bederson量表评价成功闭塞。(参见Bederson等,(1986)Stroke,17:1304-1308.)每15分钟量取体温以维持正常体温。已经历大脑中动脉闭塞程序的动物在手术后数小时可能难以进行体温调节,故视动物的体温将其放置于冷却或加热箱中。维持体温在37.5℃下。在大脑中动脉后监测动物6小时且然后置于笼中过夜。
将大鼠分成四组。第一组大鼠每隔一天给予盐水注射。第2-4组每隔一天给予0.125mg/m2的TPA注射,持续四周。然后将第2组处死。第3-4组每隔一天另外给予0.156mg/m2的TPA,持续两周,且然后处死第3组。第4组每隔一天给予0.18775mg/m2的TPA,持续三周,且然后处死。
处死动物后切下脑后并使用McIwain组织切碎机(MickleLaboratory Engineering,U.K.)以1mm间隔切成10段,并通过在37℃下在2%TTC(2,3,5-三苯基氯化四唑;Tokyo Kasei)中浸泡20分钟进行染色。使用数码相机(HC-2500;Fuji PhotoFilm)和Phatograb-2500(Fuji Photo Film)将TTC-染色切片的图像上载到计算机中。对脑切片拍照并分析梗塞面积、梗塞体积、半影和水肿。
每日观察神经学症状直到处死。每日观察神经学症状直到处死并根据三个测试评价大鼠。(1)轻提大鼠尾部,悬吊于距地面一米处,并观察前肢弯曲。(2)将大鼠放置于一大张软的塑料涂布纸上,使其爪可牢牢抓住纸。拉住鼠尾,在大鼠肩部后施加轻微的侧向压力直到前肢滑行数英寸。(3)使大鼠自由移动并观察转圈行为。根据Bederson等开发的量表(1986)如下进行神经学症状的评分:0分:没有观察到缺陷;1分∶前肢弯曲;2分:侧推抵抗力下降,不转圈;3分:与2分等级相同的行为,转圈。
使用Steel检验评价对照组以及每个TPA施用组的神经学症状,与对照组进行比较且然后对TPA施用组进行Wilcoxon检验。在任一所述检验中,p<0.05的值均被定义为统计上显著的。
实施例IX
TPA在使用暂时性大脑中动脉闭塞模型的中风治疗中的效果
在本研究中使用雄性C57B16小鼠(25-30g)。用异氟烷麻醉小鼠(3%诱导,1-2%维持)。夹住手术部位并用酒精和外科擦洗液清洗。在颈动脉上方做一正中颈部切口,并将该动脉切开至其分叉部。将单丝缝线穿引至颈内动脉中并前进直到其停留在大脑中动脉内。将缝线原位打结并封闭切口。在闭塞后两小时,将小鼠重新麻醉并将缝线从MCA中去除。在手术期间和手术后均利用加热垫维持体温。在中脑动脉闭塞后监测动物4小时。
将大鼠分成四组。第一组大鼠每隔一天给予盐水注射。第2-4组每隔一天给予0.125mg/m2的TPA注射,持续四周。然后将第2组处死。第3-4组每隔一天另外给予0.156mg/m2的TPA,持续两周,且然后处死第3组。第4组每隔一天给予0.18775mg/m2的TPA,持续三周,且然后处死。
处死动物后切下脑后并使用McIwain组织切碎机(MickleLaboratory Engineering,U.K.)以1mm间隔切成10段,并通过在37℃下在2%TTC(2,3,5-三苯基氯化四唑;Tokyo Kasei)中浸泡20分钟进行染色。使用数码相机(HC-2500;Fuji PhotoFilm)和Phatograb-2500(Fuji Photo Film)将TTC-染色切片的图像上载到计算机中。对脑切片拍照并分析梗塞面积、梗塞体积、半影和水肿。
每日观察神经学症状直到处死并根据三个测试评价大鼠。(1)轻提大鼠尾部,悬吊于距地面一米处,并观察前肢弯曲。(2)将大鼠放置于一大张软的塑料涂布纸上,使其爪可牢牢抓住纸。拉住鼠尾,在大鼠肩部后施加轻微的侧向压力直到前肢滑行数英寸。(3)使大鼠自由移动并观察转圈行为。根据Bederson等开发的量表(1986)如下进行神经学症状的评分:0分:没有观察到缺陷;1分∶前肢弯曲;2分:侧推抵抗力下降,不转圈;3分:与2分等级相同的行为,转圈。
使用Steel检验评价对照组以及每个TPA施用组的神经学症状,与对照组进行比较且然后对TPA施用组进行Wilcoxon检验。在任一所述检验中,p<0.05的值均被定义为统计上显著的。
实施例X
使用TPA治疗中风的临床效果
招募先前患中风不足一个月的年龄在30-72岁之间的男性和女性参与10周的TPA试验。
被招募的个体签署知情同意书评价并使用下述予以评价:计算机体层摄影术(CT)、物理和神经学测试、神经学检查、镇静程度、美国国立卫生研究所中风调查(National Institute of Health Stroke Survey,NIHSS)、12导联心电图、心电图遥测术、脉搏氧值测量、生命体征、体重、患者的背景、怀孕测试、测量尿液中药物、血液学测试、凝固操作盘、一般临床测试、尿检。临床实验室测试包括全套代谢功能检测(Complete Metabolic Panel)(Na、K、Cl、CO2、Glu、BUN、Cr、Ca、TP、Alb、TBili、AP、AST、ALT)、血液学CBC(Hgb、Hct、RBC、WBC、Plt、Diff)和针对所有女性的血清hCG。
个体每隔一天施用0.125mg/m2TPA或安慰剂,持续4周,然后第5周和第6周每隔一天施用1.25×0.125mg/m2或安慰剂,且第7至9周每隔一天施用1.5×0.125mg/m2或安慰剂。在TPA或安慰剂施用期间监测个体并在施用后监测2小时。
在第5周和第10周,使用NIHSS(NIH中风量表(NIH StrokeScale))、Barthel ADL指数(Granger,1979)和改进的Rankin量表(Farrell,1991)评价受试者,
通过测量相比于安慰剂用TPA治疗的个体的NIHSS自基线的变化来测定功效。次要功效变量为Barthel ADL指数和改进的Rankin量表。通过所述试验收集并评价安全措施,特别是通过测量自基线访问至第5周的变化。这些措施包括不良事件报告、体检、生命体征、重量测量、ECG、临床实验室测试结果和生命体征以及***行为和/或意念的分数。不良事件是在施用研究药物的受试者中出现的任何不利医学事件,不论其是否与所述研究药物有因果关系。不良事件因此可为任何不利的或不期望的体征(包括例如实验室异常发现)、症状或暂时伴随研究药物的病症,不论这种病症是否与所述试验药物有关。
如果受试者完成了全部访问,则认为其已完成研究。如果其不符合纳入/排除标准;遭受不良事件、治疗反应不足、撤回同意、违反方案、停止到来或死亡,则可终止对其的研究。
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Claims (20)
1.一种预防或治疗哺乳动物受试者的一或多种中风影响的方法,其包括向所述受试者施用有效量的式I的佛波醇酯或其药学上可接受的盐、异构体或对映异构体
其中R1和R2是选自由氢、羟基、 和其经取代的衍生物组成的组;且R3是氢、和其经取代的衍生物。
2.根据权利要求1所述的方法,其中R1或R2为其余R1或R2为且R3为氢。
3.根据权利要求1所述的方法,其中所述佛波醇酯是佛波醇13-丁酸酯、佛波醇12-癸酸酯、佛波醇13-癸酸酯、佛波醇12,13-二乙酸酯、佛波醇13,20-二乙酸酯、佛波醇12,13-二苯甲酸酯、佛波醇12,13-二丁酸酯、佛波醇12,13-二癸酸酯、佛波醇12,13-二己酸酯、佛波醇12,13-二丙酸酯、佛波醇12-肉豆蔻酸酯、佛波醇13-肉豆蔻酸酯、佛波醇12,13,20-三乙酸酯、12-脱氧佛波醇13-当归酸酯、12-脱氧佛波醇13-当归酸酯20-乙酸酯、12-脱氧佛波醇13-异丁酸酯、12-脱氧佛波醇13-异丁酸酯-20-乙酸酯、12-脱氧佛波醇13-苯乙酸酯、12-脱氧佛波醇13-苯乙酸酯20-乙酸酯、12-脱氧佛波醇13-十四烷酸酯、佛波醇12-顺芷酸酯13-癸酸酯、12-脱氧佛波醇13-乙酸酯、佛波醇12-乙酸酯或佛波醇13-乙酸酯。
4.根据权利要求1所述的方法,其进一步包括施用与所述式I的佛波醇酯的组合制剂或协同治疗方案可有效治疗或预防所述受试者的中风影响的至少一种次要或辅助治疗剂。
5.根据权利要求4所述的方法,其中在协同施用方案中,所述至少一种次要或辅助治疗剂是在所述佛波醇酯施用至所述受试者的同时、之前或之后施用至所述受试者。
6.根据权利要求4所述的方法,其中所述至少一种次要或辅助治疗剂是组织纤溶酶原激活物、抗凝血剂、抑制素、贝特类药物、血管紧张素II受体阻断剂、血管紧张素-转化酶抑制剂、β-阻断剂、抗血小板剂、钙通道阻断剂或利尿剂。
7.根据权利要求1所述的方法,其进一步包括手术干预与式I的佛波醇酯联合治疗或预防所述受试者的中风影响。
8.根据权利要求7所述的方法,其中所述手术干预是颈动脉内膜切除术、血管成形术、支架置入术、开颅术、起搏器***术、除颤器植入术、瓣膜置换术、冠状动脉分流术、心脏移植术、血管内弹簧圈栓塞术或卵圆孔未闭封堵术。
9.根据权利要求1所述的方法,其中所述一或多种中风影响是麻痹、空间障碍、判断力受损、左侧忽视、记忆丧失、失语、协调与平衡问题、恶心、呕吐、认知障碍、知觉障碍、定向力障碍、同侧偏盲或冲动。
10.一种预防或治疗哺乳动物受试者的一或多种中风影响的组合物,其包含有效量的式I的佛波醇酯或其药学上可接受的盐、异构体或对映异构体
其中R1和R2是选自由氢、羟基、 和其经取代的衍生物组成的组;且R3是氢、和其经取代的衍生物。
11.根据权利要求10所述的组合物,其中R1或R2为其余R1或R2为且R3为氢。
12.根据权利要求10所述的组合物,其中所述佛波醇酯是佛波醇13-丁酸酯、佛波醇12-癸酸酯、佛波醇13-癸酸酯、佛波醇12,13-二乙酸酯、佛波醇13,20-二乙酸酯、佛波醇12,13-二苯甲酸酯、佛波醇12,13-二丁酸酯、佛波醇12,13-二癸酸酯、佛波醇12,13-二己酸酯、佛波醇12,13-二丙酸酯、佛波醇12-肉豆蔻酸酯、佛波醇13-肉豆蔻酸酯、佛波醇12,13,20-三乙酸酯、12-脱氧佛波醇13-当归酸酯、12-脱氧佛波醇13-当归酸酯20-乙酸酯、12-脱氧佛波醇13-异丁酸酯、12-脱氧佛波醇13-异丁酸酯-20-乙酸酯、12-脱氧佛波醇13-苯乙酸酯、12-脱氧佛波醇13-苯乙酸酯20-乙酸酯、12-脱氧佛波醇13-十四烷酸酯、佛波醇12-顺芷酸酯13-癸酸酯、12-脱氧佛波醇13-乙酸酯、佛波醇12-乙酸酯或佛波醇13-乙酸酯。
13.根据权利要求10所述的组合物,其进一步包含与所述式I的佛波醇酯的组合制剂可有效治疗或预防所述受试者的中风影响的至少一种次要或辅助治疗剂。
14.根据权利要求13所述的组合物,其中所述至少一种次要或辅助治疗剂是组织纤溶酶原激活物、抗凝血剂、抑制素、贝特类药物、抗血小板剂、血管紧张素II受体阻断剂、血管紧张素-转化酶抑制剂、β-阻断剂、钙通道阻断剂或利尿剂。
15.根据权利要求10所述的组合物,其中所述一或多种中风影响是麻痹、空间障碍、判断力受损、左侧忽视、记忆丧失、失语、协调与平衡问题、恶心、呕吐、认知障碍、知觉障碍、定向力障碍、同侧偏盲或冲动。
16.一种预防处于中风风险中的哺乳动物受试者中风的方法,其包括向所述受试者施用有效量的式I的佛波醇酯或其药学上可接受的盐、异构体或对映异构体
其中R1和R2是选自由氢、羟基、 和其经取代的衍生物组成的组;且R3是氢、和其经取代的衍生物。
17.根据权利要求16所述的方法,其中R1或R2为其余R1或R2为且R3为氢。
18.根据权利要求16所述的方法,其中所述佛波醇酯是佛波醇13-丁酸酯、佛波醇12-癸酸酯、佛波醇13-癸酸酯、佛波醇12,13-二乙酸酯、佛波醇13,20-二乙酸酯、佛波醇12,13-二苯甲酸酯、佛波醇12,13-二丁酸酯、佛波醇12,13-二癸酸酯、佛波醇12,13-二己酸酯、佛波醇12,13-二丙酸酯、佛波醇12-肉豆蔻酸酯、佛波醇13-肉豆蔻酸酯、佛波醇12,13,20-三乙酸酯、12-脱氧佛波醇13-当归酸酯、12-脱氧佛波醇13-当归酸酯20-乙酸酯、12-脱氧佛波醇13-异丁酸酯、12-脱氧佛波醇13-异丁酸酯-20-乙酸酯、12-脱氧佛波醇13-苯乙酸酯、12-脱氧佛波醇13-苯乙酸酯20-乙酸酯、12-脱氧佛波醇13-十四烷酸酯、佛波醇12-顺芷酸酯13-癸酸酯、12-脱氧佛波醇13-乙酸酯、佛波醇12-乙酸酯或佛波醇13-乙酸酯。
19.根据权利要求16所述的方法,其进一步包括施用与所述式I的佛波醇酯的组合制剂或协同治疗方案可有效治疗或预防所述受试者的中风影响的至少一种次要或辅助治疗剂,其中所述次要或辅助治疗剂是在所述式I的佛波醇酯施用的同时、之前或之后施用。
20.根据权利要求19所述的方法,其中所述至少一种次要或辅助治疗剂是抗凝血剂、抑制素、贝特类药物、血管紧张素II受体阻断剂、抗血小板剂、血管紧张素-转化酶抑制剂、β-阻断剂、钙通道阻断剂或利尿剂。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108689851A (zh) * | 2018-05-28 | 2018-10-23 | 中山大学 | 一类惕各烷型二萜化合物及其制备方法和应用 |
CN108689851B (zh) * | 2018-05-28 | 2020-04-17 | 中山大学 | 一类惕各烷型二萜化合物及其制备方法和应用 |
CN112715542A (zh) * | 2021-01-20 | 2021-04-30 | 沈阳农业大学 | 巴豆烷二萜类化合物的制备方法及其在制备杀线虫的杀虫剂中的应用 |
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