CN102858155B - 使用双醋瑞因作为糖尿病的辅助治疗的方法 - Google Patents
使用双醋瑞因作为糖尿病的辅助治疗的方法 Download PDFInfo
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- CN102858155B CN102858155B CN201180018154.8A CN201180018154A CN102858155B CN 102858155 B CN102858155 B CN 102858155B CN 201180018154 A CN201180018154 A CN 201180018154A CN 102858155 B CN102858155 B CN 102858155B
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Abstract
本发明提供使用双醋瑞因或其衍生物与其他抗糖尿病剂的组合治疗II型糖尿病的方法。所述方法还可允许改善II性糖尿病患者的血糖控制和/或减少抗糖尿病剂的副作用和/或心血管风险。
Description
背景技术
双醋瑞因，[4，5-二(乙酰氧基)-9，10-二氧-2-蒽羧酸])是高度纯化的蒽醌衍生物。其在几个国家已经被批准为骨关节炎的缓解症状性药物(SYSADOA)。大黄酸是双醋瑞因的主要活性代谢物。大黄酸已经显示在2型(或II型)糖尿病啮齿动物模型中控制血糖浓度。然而，没有研究显示双醋瑞因可在患有2型糖尿病的人类中控制血糖。没有文献报道双醋瑞因可作为用于治疗对现有的抗糖尿病药治疗具有不充分的药物响应的II型糖尿病患者的辅助治疗。
糖尿病的患病率在全世界都已经增长。大约七个百分点的45-64岁人群患有糖尿病并且在超过65岁的人群中这一数目显著增加。有两种类型的糖尿病。在已知为II型的，非胰岛素依赖性糖尿病(NIDDM)或者成人发作的(与青少年糖尿病或I型相反)的糖尿病的类型中，其是在糖尿病耐受和相对胰岛素缺乏的背景下由高血糖所表征的病症。II型胰岛素患者中的胰腺经常持续分泌胰岛素。然而，这一胰岛素不足以预防糖尿病的症状，其包括心血管危险度因子的升高，所述心血管危险度因子例如高血糖、高血压、高三酸甘油酯血症、高血清低密度脂蛋白(LDL)胆固醇浓度、低血清高密度脂蛋白胆固醇浓度、受损的碳水化合物代谢、糖尿、降低的糖尿病敏感性和中心性肥胖。这些心血管风险因子中的许多已知早于糖尿病发作十年。II型糖尿病的症状已经导致严重的并发症，包括大血管并发症(冠心病、外周动脉疾病和中风)和微血管并发症(视网膜病、肾病和神经病)。现在已经认识到血糖控制和将糖化血红蛋白A1C(HbA1c)维持在7.0％以下在预防糖尿病并发症上的重要性。
已经在过去的几年中介绍了许多抗高血糖剂类型，每种具有其独特地作用机制：磺酰脲类、双胍类(bisguanide)、α-葡萄糖苷酶抑制剂、噻唑烷二酮类(TZD)、二肽基肽酶-4抑制剂(DPP-4抑制剂)、非磺酰脲胰岛素促泌素、胰高血糖素样肽-1类似物和胰岛素。根据临床守则，II型糖尿病的一线血糖降低治疗是二甲双胍或磺酰脲单一治疗。然而使用二甲双胍或磺酰脲的单一治疗具有有限的好处。仅约44％的患者在接受治疗三年之后维持HbA1c在7％以下，而仅约13％的患者在九年后维持所述水平。如果第一线治疗不满意，患者继续第二线组合治疗，例如二甲双胍和磺酰脲一起。在单独使用任何一种剂的单一治疗失败的患者中，仅约30％的用二甲双胍和磺酰脲的组合或第二线治疗治疗的患者在两年的治疗后获得低于7％的HbA1c。如果这种类型的治疗对于患者来说仍不足以控制血糖，那么DDP-4抑制剂、噻唑烷二酮类、胰高血糖素样肽-1类似物、氯茴苯酸类、α-葡萄糖苷酶抑制剂和/或胰岛素被加至第二线治疗。
尽管存在抗糖尿病药物，但是某些患者不能达到治疗目标。因此，还有对有效改善II型糖尿病的血糖控制的新药剂的需要。
发明内容
本发明涉及治疗II型糖尿病患者的治疗方法。本发明的方法特别适用于使用现有抗糖尿病治疗的具有不充分血糖控制的II型糖尿病患者。
更详细地，本发明提供使用双醋瑞因或其衍生物的用于II型糖尿病的治疗的方法。
在一个实施方案中，本发明提供用于II型糖尿病的辅助治疗的方法，其包括向对于抗糖尿病剂具有不充分响应的患有II型糖尿病的受治疗者施用治疗有效量的双醋瑞因或其药学上可接受的盐、类似物、前药或活性代谢物。
在还有一个实施方案中，本发明提供在接受至少一种抗糖尿病剂的受治疗者中改善血糖控制的方法，其包括向所述受治疗者施用：a)治疗有效量的双醋瑞因或其或其药学上可接受的盐、类似物、前药或活性代谢物，和b)所述抗糖尿病剂。
在另一个实施方案中，本发明提供对II型糖尿病的组合治疗的方法，其包括向需要其的受治疗者施用：a)至少一种抗糖尿病剂，和b)治疗有效量的双醋瑞因或其或其药学上可接受的盐、类似物、前药或活性代谢物。
在还有一个实施方案中，本发明提供减少向糖尿病患者所施用的抗糖尿病剂的副作用的方法，其包括向所述患者施用：a)治疗有效量的双醋瑞因或其或其药学上可接受的盐、类似物、前药或活性代谢物，和b)所述抗糖尿病剂。
在还有一个实施方案中，本发明提供减少向糖尿病患者所施用的糖尿病剂的心血管风险的方法，其包括向所述患者施用：a)治疗有效量的双醋瑞因或其或其药学上可接受的盐、类似物、前药或活性代谢物，和b)所述抗糖尿病剂。
附图说明
图1是表示用双醋瑞因或安慰剂治疗的整个过程中患者的糖基化血红蛋白(HbA1c)水平上的平均变化的曲线图。
图2是表示用双醋瑞因或安慰剂治疗的整个过程中患者的空腹血糖水平上的平均变化的曲线图。
图3是表示用双醋瑞因或安慰剂治疗的整个过程中患者的稳态模型评估(HOMA)β-细胞功能水平上的平均值化的曲线图。
图4是表示用双醋瑞因或安慰剂治疗的整个过程中患者的体重水平上的平均变化的曲线图。
具体实施方式
根据本发明，双醋瑞因可单独或与常规抗糖尿病药物组合用于II型糖尿病的治疗。优选地，双醋瑞因可被加至现有的抗糖尿病剂以增强患者已经对其显示不充分响应的现有的药剂的活性或协同作用。
如本文所用的，双醋瑞因[4，5-二(乙酰氧基)-9，10-二氧-2-蒽羧酸]是指具有下列结构式的化合物：
同样预期双醋瑞因的药学上可接受的盐、前药和活性代谢物用于本发明中的用途。药学上可接受的盐包括酸性或碱性基团的盐。大黄酸(9，10-二氢-4，5-二羟基-9，10-二氧-2-蒽羧酸)和单乙酰大黄酸是双醋瑞因的已知的活性代谢物，前药是设计以通过体内生理作用例如水解、代谢以及类似作用转化为活性药物的活性药物的药学上无活性的衍生物。
在一个实施方案中，本发明提供对II型糖尿病的辅助治疗方法，其包括向对于抗糖尿病剂具有不充分响应的患有II型糖尿病的患者施用治疗有效量的双醋瑞因或其或其药学上可接受的盐、类似物、前药或活性代谢物。
如本文所用的，术语“治疗(treat)”或“治疗(treatment)”意指逆转、缓解、抑制或减缓这些术语应用的疾病、病症或病况的进行或者这些疾病、病症或病况的一种或多种症状。
如本文所用的，术语“辅助治疗”或“附加治疗”意指对已经接受至少一种其他的抗糖尿病治疗的患者的另外的治疗。作为辅助治疗使用的药物被施用于受治疗者以使得初步治疗进行得更好。
如本文所用的，术语“抗糖尿病剂”是指用于通过降低血液中的葡萄糖水平来治疗糖尿病的药物。目前可获得的抗糖尿病药物的实例包括但不限于磺酰脲类、双胍类、α-葡萄糖苷酶抑制剂、噻唑烷二酮类(TZD)、二肽基肽酶-4抑制剂(DPP-4抑制剂)、非磺酰脲胰岛素促泌素、胰高血糖素样肽-1类似物(GLP-1类似物)和胰岛素。更具体地，抗糖尿病药物包括，但不限于，二甲双胍、格列本脲、格列美脲、glipyride、格列吡嗪、氯磺丙脲、格列齐特、阿卡波糖、米格列醇、吡格列酮、曲格列酮、罗格列酮、伊沙列酮、莫格列扎(muraglitizar)、培利格列扎、西他列汀、沙格列汀、维格列汀、阿格列汀、利拉利汀、度格列汀、度格列汀、瑞格列奈、那格列奈、米格列奈、艾塞那肽、利拉鲁肽、阿必鲁肽和胰岛素。这些药可单独或组合给予。
如本文所用的，术语“受治疗者”包括人类和动物。
因此，诊断患有II型糖尿病的受治疗者通常被给予一种或多种口服抗糖尿病剂以控制它们的血糖、血压和脂质以将并发症的风险最小化。
在一个实施方案中，本发明提供用于II型糖尿病的辅助治疗的方法，其包括向对于抗糖尿病剂具有不充分响应的患有II型糖尿病的受治疗者施用治疗有效量的双醋瑞因或其或其药学上可接受的盐、类似物、前药或活性代谢物。
根据本发明的辅助治疗的一个实施方案，双醋瑞因被加至患者目前所采用的抗糖尿病剂中。更具体地，可使用本发明的辅助治疗以降低血糖，降低胰岛素抵抗、降低糖化血红蛋白A1C(HbA1c)，增加餐后胰岛素水平或降低餐后葡萄糖波动。
在一个实施方案中，没有通过单独或与其他抗糖尿病剂组合使用抗糖尿病剂的抗糖尿病治疗受到充分控制的患有胰岛素抵抗、葡萄糖不耐受、高血糖症或高胰岛素血症的II型糖尿病患者适于本发明的辅助治疗。
在优选的实施方案中，对于抗糖尿病药物具有不充分响应的患有II型糖尿病的受治疗者(即，其胰岛素抵抗、葡萄糖不耐受、高血糖症或高胰岛素血症没有通过抗糖尿病治疗受到充分控制的患者)是其尽管接受一种或多种抗糖尿病剂但血红蛋白A1c(HbA1c)值仍在7％以上的患者。HbA1c值是具有所连接的葡萄糖的百分比血红蛋白并且是长期血糖控制的指示。优选地，其HbA1c值在8％至10％之间同时接受至少一种抗糖尿病药物的患者非常适于本发明的辅助治疗。
治疗有效量的双醋瑞因可随患者的年龄、体重、糖尿病程度以及病况上的个体差异而变化并且可由本领域技术人员确定。在本发明的优选的实施方案中，双醋瑞因的治疗有效量是在每天25至200mg的范围内。在一个实施方案中，双醋瑞因或其衍生物(包括但不限于双醋瑞因的药学上可接受的盐、前药、类似物和活性代谢物)可每天施用一次或两次。治疗有效量的双醋瑞因的药学上可接受的盐、前药、类似物和活性代谢物优选地相当于每天25至200mg的双醋瑞因基体(diacerein base)。
诊断为患有II型糖尿病的受治疗者可接受与一种或多种抗糖尿病药物一起的双醋瑞因，其药学上可接受的盐、前药、类似物或活性代谢物以达到治疗目标。
治疗目标可以是降低血糖、降低胰岛素抵抗、降低糖基化血红蛋白A1C(HbA1c)、增加餐后胰岛素水平或降低餐后葡萄糖波动。更具体地，治疗目标包括但不限于：(a)6％至7.0％的HbA1c；(b)餐前血糖：4.0至6.0mmol/L(72至108mg/dl)和(c)2小时餐后血糖：5.0至8.0mmol/L(90至144mg/dl)。
在一个实施方案中，用于II型糖尿病的辅助治疗的方法改善了受治疗者的肾功能。肾功能的改善可通过受治疗者中肌酸酐清除率的减少来证明。
在另一个实施方案中，用于II型糖尿病的辅助治疗的方法降低了受治疗者中的胰岛素抵抗。降低的胰岛素抵抗可通过受治疗者中降低的糖基化血红蛋白水平来证明。
在还有一个实施方案中，用于II型糖尿病的辅助治疗的方法导致受治疗者中炎性细胞因子(包括但不限于白介素和肿瘤坏死因子)的减少。白介素包括但不限于白介素IL-6和IL-12。肿瘤坏死因子包括但不限于TNF-α。
在还有一个实施方案中，本发明提供改善接受至少一种抗糖尿病剂的受治疗者中的血糖控制的方法，所述方法包括向所述受治疗者施用：a)治疗有效量的双醋瑞因或其或其药学上可接受的盐、类似物、前药或活性代谢物，和b)所述抗糖尿病剂。
在一个实施方案中，改善血糖控制的方法改善了受治疗者的肝功能。肝功能的改善可通过受治疗者中肌酸酐清除率的减少来证明。
在另一个实施方案中，改善血糖控制的方法减少了受治疗者中的胰岛素抵抗。减少的胰岛素抵抗可通过受治疗者中降低的糖基化血红蛋白水平来证明。
在还有一个实施方案中，改善血糖控制的方法导致受治疗者中炎性细胞因子(包括但不限于白介素和肿瘤坏死因子)的减少。白介素包括但不限于白介素IL-6和IL-12。肿瘤坏死因子包括但不限于TNF-α。
在一个实施方案中，没有通过使用至少一种抗糖尿病剂或其组合的抗糖尿病治疗受到控制的患有胰岛素抵抗、葡萄糖不耐受、高血糖症或高胰岛素血症的患者适于本发明的改善血糖控制的方法。优选地，对于抗糖尿病剂具有不充分响应的患有II型糖尿病的患者适于本发明的改善血糖控制的方法。
在另一个实施方案中，本发明提供用于II型糖尿病的组合治疗的方法，其包括向有需要的受治疗者施用：a)至少一种抗糖尿病剂，和b)治疗有效量的双醋瑞因或其药学上可接受的盐、类似物、前药或活性代谢物。
在还有一个实施方案中，本发明提供用于减少向糖尿病患者施用的抗糖尿病剂的副作用的方法，其包括向所述受治疗者施用a)治疗有效量的双醋瑞因或其药学上可接受的盐、类似物、前药或活性代谢物，和b)所述抗糖尿病剂。
在还有一个实施方案中，本发明提供减少向糖尿病患者施用的糖尿病剂的心血管风险的方法，其包括向所述患者施用：a)治疗有效量的双醋瑞因或其药学上可接受的盐、类似物、前药或活性代谢物，和b)所述抗糖尿病剂。
当向有需要的受治疗者施用时，双醋瑞因，其药学上可接受的盐、类似物、前药或活性代谢物可被制备为药物组合物。预期用于本发明的目的的药物组合物可以是固体、溶液、乳液、分散液、胶束、脂质体以及类似的形式。可以使用本领域已知的任何方式施用组合物，例如口服的、经鼻的、胃肠道外的、局部的、经皮的或者经直肠的。优选地，使组合物适于口服施用。例如，药物可与适合的赋形剂混合用于片剂、胶囊、丸剂、含片、锭剂、溶液、粉末或粒料、悬浮液、硬的或软的胶囊以及适于使用的任何其他形式的制备。用于制备药物组合物的方法和对适合的赋形剂的选择是本领域的技术人员容易理解的。
下列实施例证明本发明的某些方面，实施例不意味着以任何形式限制本发明。
实施例1
在患有未控制的2型糖尿病的患者中双醋瑞因的随机的、双盲的、安慰剂对照
的研究
目的：评估双醋瑞因治疗2型糖尿病(DM)的效力和安全性。
主要终末点：在通过之前的抗糖尿病治疗受到不充分控制的2型DM患者中在24周双盲治疗后比较追加双醋瑞因与没有追加治疗(安慰剂)对糖基化血红蛋白(HbA1c)的效力。
受治疗者：在筛选访视之前进行稳定的低血糖单一治疗至少3个月的男性或女性2型DM患者(BMI≤35kg/m2)。在筛选访视时获取的血红蛋白A1c(HbA1c)测量结果在7％和12％之间。加入研究中的患者接受一种或多种抗高血糖剂，包括磺酰脲、双胍类、α-葡萄糖苷酶抑制剂、噻唑烷二酮类(TZD)、二肽基肽酶-4抑制剂(DPP-4抑制剂)和非磺酰脲胰岛素促泌素。
程序：这是随机的、双盲的、平行对比的研究，在通过之前抗糖尿病治疗受到不充分控制的患有2型DM的患者中比较50mg双醋瑞因对比安慰剂。双醋瑞因的起始剂量是50mg每天早上一次进行4周并且如果患者已经开始适应药物则可以调整直到50mg每天两次(早上和晚上)。在以基线(0周)进入之前对患者进行四周的资格筛选(4周)。在这4周的筛选期期间，参与者继续他们之前的抗糖尿病治疗，饮食习惯和其他的生活周期习惯。为了在四周的筛选期后符合随机性，患者必须没有经历低血糖并且必须具有两次135至250mg/dL之间的空腹血糖(FPG)测量结果，在筛选期结束时，符合资格要求的患者被随机指定为接受每天两次50mg双醋瑞因或安慰剂进行24周观察。在治疗/观察期间，之前的抗糖尿病治疗包括类型和/或剂量没有变化。在实验期间，在8个时间请患者来到中心(筛选，基线，第4、8、12、16、20和24周)。整个研究持续时间包括对每个患者的筛选期是28周。治疗/观察结束后是两周的随访期。在这一随访期中，随访患者的不良事件。
用于效力/安全性评估的统计方法：两个治疗组之间的HbA1c减少的差异(双醋瑞因减去安慰剂)通过使用基线值作为协变量的协方差分析(ANCOVA)来分析。计算相应的95％的置信区间。同样分析组内变化，使用配对t检验以评估每个治疗组中从基线开始的差异。
对于效力参数，通过随访获得描述性统计。进行统计分析以估计从基线开始的平均变化。在浓度-时间曲线(AUC)下的面积被用来评估通过口服葡萄糖耐量试验测量的参数。
根据药事管理医学词典(MedDRA)不良事件词典概述不良事件。列表计算报告个体优选项不良事件的患者的数目和报告每个系统器官类型至少一个不良事件的患者的总数目。如果可以，使用费舍精确检验比较两个治疗组中的每一组的不良事件发生率。
结果：这一双盲的、平行组的研究包括通过现有口服抗糖尿病治疗受到不充分控制的患有2型糖尿病的76名患者。将患者随机指定为两个治疗组。一组接受双醋瑞因(38名患者)而另一组接受安慰剂(38名患者)。接受双醋瑞因的38名患者中的二十六名完成了研究，如同接受安慰剂的38名患者中的三十名一样。没有患者在24周的研究期间改变他们的抗糖尿病治疗。
表1
所有随机患者的抗糖尿病药物治疗
单药治疗：单独用二甲双胍或磺酰脲进行治疗
药物组合：用两种、三种或四种口服抗糖尿病剂(选自二甲双胍、磺酰脲、阿卡波糖、瑞格列奈、吡格列酮和西他列汀)进行治疗
主要终末点：基线和24周之间HbA1水平上的平均绝对差异是在双醋瑞因组中0.63个百分点的减少而安慰剂组中没有变化，产生0.63个百分点的组间差异(P＝0.0158)。参见图1，其证明HbA1水平上从基线开始的平均变化。
在24周在HbA1水平上具有任何变化的患者的数目是双醋瑞因组中的26名患者中的20名，相比较安慰剂组中30名患者中的15名。20周后双醋瑞因组中HbA1水平显著低于安慰剂组中(0.60％的绝对减少；P＝0.0223)参见图1。
第二终末点：
血糖过多
在24周双醋瑞因组中的空腹血糖水平比安慰剂组中更低。参见图2。
β细胞功能
在双醋瑞因组中观察到稳态模型评估(HOMA)β-细胞功能(HOMA-BETA)的持续改善但是在安慰剂组中没有观察到。如图3所证实的，在第24周，相同单位的葡萄糖在双醋瑞因患者中比在安慰剂患者中诱导更多的胰岛素分泌(双醋瑞因：56.26对比安慰剂：45.53)。在双醋瑞因组中HOMA-BETA中从基线开始的组内变化是明显的，但是在安慰剂组中不明显。
心血管安全性终末点
基线水平和第24周水平之间在体重(图4)、血压(表2和3)、脉搏率(表4)和脂质概况(表5至8)上在治疗组之间没有统计学上显著的差异。心血管安全性终末点的结果表明向现有抗糖尿病治疗加入双醋瑞因没有增加心脏病发作和心血管病症的风险。
表2
心血管(CV)安全性终末点-收缩压
表3
CV安全性终末点-舒张压e
表4
CV安全性终末点-脉搏率
表5
CV安全性终末点-总胆固醇
表6
CV安全性终末点-三酸甘油酯
表7
CV安全性终末点-HDL
表8
CV安全性终末点-LDL
不良作用：在研究期间，双醋瑞因组中的20名(54.1％)患者和安慰剂组中的18名(47.4％)患者报告了至少一种不良作用(AE)。抱怨不良作用的患者的发病率在两组之间没有检测到统计学上显著的差异。在两组中都常常报告的AE是上呼吸道感染和腹泻。特别地，没有观察到症状性低血糖，甚至是在HbA1c水平上具有显著提高的患者中。
Claims (4)
1.双醋瑞因或其药学上可接受的盐或活性代谢物在制备用于对于抗糖尿病剂具有不充分响应的患有II型糖尿病的受治疗者的II型糖尿病辅助治疗的药物中的用途，所述双醋瑞因的活性代谢物是大黄酸或单乙酰大黄酸。
2.根据权利要求1所述的用途，其中所述抗糖尿病剂是选自由磺酰脲、双胍、α-葡萄糖苷酶抑制剂、噻唑烷二酮、过氧化物酶体增殖激活受体拮抗剂、二肽基肽酶-4抑制剂、非磺酰脲胰岛素促泌素、胰高血糖素样肽-1类似物、二甲双胍、格列本脲、格列美脲、glipyride、格列吡嗪、氯磺丙脲、格列齐特、阿卡波糖、米格列醇、吡格列酮、曲格列酮、罗格列酮、伊沙列酮、莫格列扎、培利格列扎、西他列汀、沙格列汀、维格列汀、阿格列汀、利拉利汀、度格列汀、瑞格列奈、那格列奈、米格列奈、艾塞那肽、利拉鲁肽、阿必鲁肽和胰岛素所组成组中的至少一种药剂。
3.根据权利要求1所述的用途，其中所述受治疗者是患有选自由胰岛素抵抗、葡萄糖不耐受、高血糖症或高胰岛素血症所组成的组的病况的II型糖尿病患者。
4.根据权利要求1所述的用途，其中所述双醋瑞因的量是每天25至200mg。
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| PT (1) | PT2555618E (zh) |
| RU (1) | RU2563988C2 (zh) |
| TW (1) | TWI519297B (zh) |
| WO (1) | WO2011127240A1 (zh) |
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| RU2563988C2 (ru) * | 2010-04-08 | 2015-09-27 | ТиДаблЮАй БАЙОТЕКНОЛОДЖИ, ИНК. | Способы использования диацереина в дополнительном лечении диабета |
| CN101822660B (zh) * | 2010-05-13 | 2013-07-10 | 中国人民解放军肾脏病研究所 | 大黄酸类化合物或其盐在制备预防和治疗胰岛β细胞功能衰退药物中的应用 |
| CA2990948A1 (en) | 2015-07-01 | 2017-01-05 | Twi Biotechnology, Inc. | Diacerein or rhein topical formulations and uses thereof |
| CA2994987C (en) * | 2015-08-17 | 2023-09-26 | Twi Biotechnology, Inc. | Diacerein or its analogs for inhibiting expression of asc, nlrp3, and/or formation of nlrp3 inflammasome complex |
| TW201739448A (zh) * | 2016-05-06 | 2017-11-16 | 安成生物科技股份有限公司 | 用於治療及/或預防血液相關疾病之方法及配方 |
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| IT1276781B1 (it) * | 1995-06-23 | 1997-11-03 | Gentili Ist Spa | Derivati antrachinonmono- e disolfon- sostituiti e composizioni farmaceutiche che li contengono per il trattamento delle patologie |
| CN1086289C (zh) * | 1997-09-30 | 2002-06-19 | 中国人民解放军肾脏病研究所 | 大黄酸或大黄酸盐在制备治疗糖尿病肾病药中的用途 |
| AR026801A1 (es) * | 2000-01-12 | 2003-02-26 | Medidom Lab | Sustancias para uso en el tratamiento de la psoriasis |
| US20060252670A1 (en) | 2004-10-14 | 2006-11-09 | Intercept Pharmaceuticals Inc. | Method of reducing drug-induced adverse side effects in a patient |
| CN1748675A (zh) * | 2005-07-11 | 2006-03-22 | 丛晓东 | 大黄酸类化合物的复合物及制备方法与治疗糖尿病的应用 |
| TWI473610B (zh) * | 2008-10-28 | 2015-02-21 | Twi Biotechnology Inc | 包含雙醋瑞因（ｄｉａｃｅｒｅｉｎ）之醫藥組合物 |
| EP2467161A4 (en) * | 2009-08-20 | 2013-03-06 | Twi Biotechnology Inc | METHOD FOR DIAGNOSTICIZING DIABETES AND DETERMINING THE EFFECTIVENESS OF THERAPIES |
| RU2563988C2 (ru) * | 2010-04-08 | 2015-09-27 | ТиДаблЮАй БАЙОТЕКНОЛОДЖИ, ИНК. | Способы использования диацереина в дополнительном лечении диабета |
| JP6012639B2 (ja) * | 2011-03-11 | 2016-10-25 | ティダブリューアイ・バイオテクノロジー・インコーポレイテッドＴＷＩ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ， Ｉｎｃ． | 高尿酸血症および高尿酸血症関連代謝障害を治療するための方法および組成物 |
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Non-Patent Citations (1)
| Title |
|---|
| Diacerhein downregulate proinflammatory cytokines expression and decrese the autoimmune diabetes frequency in nonobese diabetic (NOD) mice;Malaguti,et al;《International Immunopharmacology》;20080630;第8卷(第6期);第782页摘要，第783页第6段，第786页第3段，第787页第4段 * |
Also Published As
| Publication number | Publication date |
|---|---|
| TWI519297B (zh) | 2016-02-01 |
| KR101567925B1 (ko) | 2015-11-10 |
| CA2794566C (en) | 2018-06-12 |
| US8536152B2 (en) | 2013-09-17 |
| CA2794566A1 (en) | 2011-10-13 |
| MX2012011517A (es) | 2012-11-29 |
| EP2555618A1 (en) | 2013-02-13 |
| RU2012147449A (ru) | 2014-05-20 |
| JP2016041739A (ja) | 2016-03-31 |
| CN102858155A (zh) | 2013-01-02 |
| JP2013523832A (ja) | 2013-06-17 |
| ES2560310T3 (es) | 2016-02-18 |
| AU2011237600A1 (en) | 2012-10-11 |
| JP6085552B2 (ja) | 2017-02-22 |
| PT2555618E (pt) | 2016-03-08 |
| NZ602583A (en) | 2014-10-31 |
| AU2011237600B2 (en) | 2016-06-23 |
| IL222133A (en) | 2017-01-31 |
| US20110251155A1 (en) | 2011-10-13 |
| BR112012024936A2 (pt) | 2015-09-15 |
| EP2555618B1 (en) | 2015-12-30 |
| TW201210586A (en) | 2012-03-16 |
| WO2011127240A1 (en) | 2011-10-13 |
| RU2563988C2 (ru) | 2015-09-27 |
| KR20130045266A (ko) | 2013-05-03 |
| EP2555618A4 (en) | 2013-11-13 |
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