CN102885800B - 一种姜黄素的用途 - Google Patents
一种姜黄素的用途 Download PDFInfo
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- CN102885800B CN102885800B CN201210325241.4A CN201210325241A CN102885800B CN 102885800 B CN102885800 B CN 102885800B CN 201210325241 A CN201210325241 A CN 201210325241A CN 102885800 B CN102885800 B CN 102885800B
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Abstract
本发明提供了姜黄素在预防或/和治疗一种抗肿瘤药物所导致的延迟性腹泻药物中的用途，其中，所述的抗肿瘤药物是指伊立替康或其活性代谢物7-乙基-10-羟基喜树碱(SN-38)，所述的延迟性腹泻是在伊立替康给药24h之后出现，并能持续7天的重度腹泻。本发明中，姜黄素药效作用明确，可有效缓解迟发性腹泻，保护肠粘膜。
Description
技术领域
本发明涉及一种姜黄素的新用途，具体是，在预防或/和治疗抗肿瘤药物伊立替康导致的延迟性腹泻中的用途。
背景技术
伊立替康(简称CPT-11)是临床广泛使用的抗肿瘤药物，选择性抑制拓扑异构酶I而发挥细胞毒作用，用于化疗后转移性结肠直肠癌复发和恶化的一线治疗。本品也可单独或者与其他药物联合治疗小细胞肺癌、非小细胞肺癌、恶性脑瘤、胃癌、胰腺癌、子宫颈癌、卵巢癌等。但是伊立替康导致的腹泻(特别是延迟性腹泻)严重影响其临床应用。
伊立替康导致的腹泻分为急性腹泻和延迟性腹泻。急性腹泻主要发生在给药24小时之内，持续时间短，腹泻程度轻，对伊立替康临床用药影响不大，且皮下注射阿托品能进行预防和治疗[Yumuk P F，etal.The absence of early diarrhea with atropine premedicationduring irinotecan therapy in metastatic colorectal patients.Int J Colorectal Dis，2004]。延迟性腹泻通常发生在给药24h之后发生，腹泻时间持续长(5～7天)，发病率高(在欧美临床试验中，延迟性腹泻发生率是60％～87％)，腹泻程度重(约40％的患者出现3～4度腹泻)，严重者常因脱水和电解质紊乱而死亡，导致药物化疗中止[Alimonti A.，et al.，New approaches to prevent intestinal toxicity of irinotecan-based regimens.Cancer treatment reviews，2004]，且延迟性腹泻的机制不完全清楚，与伊立替康剂量无关。总之延迟性腹泻是不可预知的重度腹泻，是严重限制伊立替康临床应用的主要限制因素，也是急需解决的问题。
目前，预防或治疗伊立替康所致延迟性腹泻的药物有：①洛哌丁胺(易蒙停)是人工合成的阿片类衍生物，在欧洲和美国，它是治疗CPT-11所致迟发型腹泻的标准疗法，其主要作用机制是有效抑制TNF-α诱导的肠分泌作用，但不影响SN-38、SN-38葡萄糖醛酸结合物(SBN-38G)的胆汁分泌。但有效率仅30％，且有麻痹性肠梗阻的不良反应。②口服抗生素(如链霉素和新霉素)可以有效地改善CPT-11所致的胃肠道毒性反应，机制是抗生素杀死肠道内细菌而减少β-葡萄糖苷酸酶的生成，降低肠道中SN-38G生物转化成SN-38，产生预防或治疗迟发型腹泻的作用。但是，长期使用抗生素有可能导致细菌耐药或者肠道菌群失调，从而导致药物口服吸收下降并且易引发二次腹泻。③环孢霉素A(简称CsA)是一种常见的免疫抑制剂，可以通过竞争性抑制多药耐药蛋白(MRP)和P糖蛋白(P-gp)降低CPT-11和SN-38的 胆汁排泄，同时CsA可减少伊立替康和SN-38自肠细胞中外排至肠道。但是CsA的器官毒性限制了它在这方面的应用。④通过口服碱性制剂(比如碳酸氢钠、氧化镁、碱水等)碱化肠液，使SN-38内酯型(活性型)向羧酸型(非活性型)方向移动，减少内酯型SN38肠浓度和降低肠道SN-38的吸收(内酯型SN-38肠吸收速率是羧酸型的10倍)，发挥延迟性腹泻治疗作用，但是长期服用有可能导致体内酸碱平衡被打破，带来不良后果。⑤近年来，大量研究发现沙利度胺能缓解伊立替康所致的腹泻毒性，一方面沙利度胺能显著减少CPT-11体内转化成SN-38，增加癌症患者体内CPT-11和SN-38G的AUC，并能显著减少CPT-11、SN-38和SN38G胆汁分泌；另一方面沙利度胺能抑制炎症因子肿瘤坏死因子(TNF-α)，白介素1和干扰素-□，并能抑制肠上皮细胞的凋亡，减少肠道内体液的分泌等等。同时沙利度胺通过抗新血管生成和免疫调节产生抗癌作用，本研究中以沙利度胺作为有效的阳性对照，不过沙利度胺具有一定毒副作用(如致畸等)。由于伊立替康导致的延迟性腹泻是多种复杂发病机制导致的，上述药物的疗效均有限，具有一定副作用等局限性，目前对伊立替康延迟性腹泻的预防和治疗没有很好的解决方案，极大地限制了伊立替康的临床应用，因此，研究高效低毒药物治疗或预防就显得至关重要。
广义的姜黄素通常称为姜黄色素，包括姜黄素、去甲氧基姜黄素、双去甲氧基姜黄素等，而姜黄素是其中最重要的活性成分。以下未作特殊声明时，指的是广义上的姜黄素。姜黄素的药理作用包括抗炎、抗氧化、清除自由基、抗菌、抗病毒、抗肿瘤和护肝作用等[鲍华英，陈荣华，国外医学儿科学分册，2003]，且毒性小，使用安全，具体特点有：
1.抗炎作用
肿瘤坏死因子(TNF-α)、白介素等炎症因子在炎症的发展过程中起到重要的作用。姜黄素能通过抑制TNF-α、白介素等改善肾炎炎症损害，并呈剂量依耐性[Anurag Kuhad，Sangeeta Pilkhwal，Sameer Sharma，Naveen Tirkey and Kanwaljit Chopra，Effect of Curcumin on Inflammation and Oxidative Stress in Cisplatin-Induced Experimental Nephrotoxicity，J.Agric.Food Chem.，2007]。在实验性胰腺炎中发现姜黄素可减轻组织中中性粒细胞浸润，改善其病变程度[Gukovsky I，Reyes CN，Vaquero EC，et al.Curcumin amdiorates ethanoland nonethanolexperimental pancreatitis.Am J Physiol Gastrointest Liver Physiol，2003]。
2.抗菌作用
姜黄素对金黄色葡萄球菌有较强的抗菌作用，抑制肠道细菌生长能减少细菌所产生的β-葡萄糖醛酸酶。
3.抗氧化作用
近年来，许多研究证实了姜黄素可以上调各种抗氧化因子、减少丙二醛(MDA)的产生而发挥抗氧化作用，从而保护细胞膜的结构和功能。
4.抗肿瘤作用
姜黄素的抗肿瘤作用主要通过一系列信号途径抑制肿瘤细胞增殖，诱导细胞凋亡，同时还具有抑制肿瘤转移、抗血管生成、提高免疫力等作用。美国的国家卫生局(NIH)已批准姜黄素开始实行临床实验，治疗乳腺癌，直肠癌和胰腺癌。
5、安全性好
研究证明姜黄素安全性好，毒性低。姜黄素急性毒性试验表明，大、小鼠经口最大耐受量均大于12.0g/kg，大鼠30d长毒试验结果显示各项指标与对照组比较均无显著性差异。
6、目前尚没有姜黄素用于预防或/和治疗伊立替康所致延迟性腹泻的报道。
发明内容
本发明的目的是提供一种姜黄素的新用途。
本发明所提供的新用途具体为：以姜黄素为活性成分预防或/和治疗抗肿瘤药物伊立替康所产生的延迟性腹泻。
姜黄素在制备预防或/和治疗抗肿瘤药物伊立替康所致延迟性腹泻药物的应用。
上述预防或/和治疗抗肿瘤药物伊立替康所致延迟性腹泻的药物可通过口服或注射的方式导入机体。
本发明药物用于预防或/和治疗抗肿瘤药物伊立替康所致延迟性腹泻是基于姜黄素可通过抗炎、抗氧化、清除自由基和抗菌作用等多种作用联合来缓解伊立替康导致的延迟性腹泻。并且姜黄素本身毒性低，安全性好。另外姜黄素的抗肿瘤作用可与伊立替康发挥协同抗肿瘤作用。
附图说明
图1为溶剂组回肠和结肠电镜照片
图2为伊立替康模型组回肠和结肠电镜照片
图3为姜黄素组回肠和结肠电镜照片
图4为沙利度胺阳性对照组回肠和结肠电镜照片
具体实施方式
以下通过实施例形式的具体实施方式对本发明的上述内容再作进一步的详细说明，但不应将此理解为本发明上述主题范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例姜黄素对伊立替康所致延迟性腹泻的治疗作用
1、实验方法
在预试验基础上，32只ICR雄性小鼠随机分为4组，每组8只，每只小鼠单笼饲养，自由饮食、进水。模型组每天腹腔注射伊立替康75mg/kg，连续四天；姜黄素组每天腹腔注射伊立替康75mg/kg，连续四天，同时每天灌胃姜黄素混悬液175mg/kg，连续7天；沙利度胺阳性对照组，每天腹腔注射伊立替康75mg/kg，连续四4天，同时每天灌胃沙利度胺混悬液350mg/kg，连续7天；空白对照组，每天注射溶解伊立替康的溶剂75mg/kg，连续四天。从第四日起每天两次观察腹泻情况并记录评分，第7天处死动物，取回肠、结肠组织，进行病理检查，并用髓过氧化酶(MPO)和超氧化物歧化酶(SOD)试剂盒测定，观察动物死亡率体重。
2、实验结果
(1)腹泻程度
腹泻程度按下述Kurita评分标准[Kurita A，et al，Modified irinotecan hydrochloride(CPT-11)administration schedule improves induction of delayed-onset diarrhea in rats.Cancer chemotherapy and pharmacol ogy，2000]进行评分。
0级：大便正常
1级：轻度腹泻；大便可见轻微湿软、成型
2级：中度腹泻；大便较湿且不成形，有轻微肛周着色
3级：重度腹泻；水样便，伴有重度肛周着色
4级：腹泻致死
小鼠腹泻程度结果见表1，结果表明，伊立替康给药组出现中度到重度腹泻，表明成功建立伊立替康腹泻模型。姜黄素组较伊立替康模型组腹泻程度明显减小(P＜0.05)，且腹泻下降程度优于沙利度胺组。
表1腹泻级数测定的结果(n＝8)
注：*表示与模型组相比P＜0.05。#表示与沙利度胺阳性组相比P＜0.05。
(2)肠组织病理学检查
小鼠肠组织进行常规石蜡包埋、HE染色、光镜检查及摄影，按表2评分标准对肠组织病理学情况进行评分。
表2肠组织病理学评分标准
各给药组给药7天后肠组织病理学评价结果见表3，病理损伤级数按每组以每只受试动物各项评分之和的均值±标准偏差表示，部分肠组织病理镜检照片见图1～4，表3结果表明姜黄素给药组肠组织病理损伤程度较伊立替康模型组显著下降(P＜0.01)，有显著性差异，并且降低结肠损伤程度比沙利度胺阳性组效果更显著。
表3肠组织病理学评价结果(n＝8)
注：*表示与伊立替康模型组相比P＜0.05，#表示与沙利度胺组相比P＜0.05。
(3)肠组织中髓过氧化酶MPO水平
取小鼠小肠，准确称重，以1∶9生理盐水稀释，组织匀浆，制备成10％组织匀浆。接着以缓冲液1∶1稀释，按髓过氧化酶(MPO)试剂盒说明书操作，测定MPO水平，结果见表4。结果表明伊立替康组较空白溶剂组显著提高肠组织中MPO水平，表明伊立替康可引起中性粒细胞的浸润程度，产生炎症。姜黄素组能显著下调肠组织MPO水平(P＜0.01)，优于比沙利度胺阳性对照组，表明姜黄素具有显著对抗伊立替康所致炎症的作用。
表4小肠组织髓过氧化酶(MPO)测定结果(n＝8)
注：*表示与模型组相比P＜0.05。
(4)肠组织超氧化物歧化酶(SOD)活力
小肠组织匀浆液，用超氧化物歧化酶(SOD)试剂盒测定SOD活力，结果见表5，结果表明姜黄素能大幅度提高组织SOD水平，大大高于模型组和阳性对照组有显著性差异(P＜0.05)，且比空白溶剂组的SOD水平高，表明姜黄素具有强大的清除自由基能力，保护肠粘膜免于自由基的氧化伤害。
表5肠组织中超氧化物歧化酶(SOD)的活力(n＝8)
注：*表示与伊立替康模型组相比P＜0.05。#表示与沙利度胺阳性组相比P＜0.05。
(5)小鼠死亡率与体重
各给药组小鼠死亡率和体重情况见表6，结果表明伊立替康的毒性也体现在死亡率增加和体重下降，姜黄素可大大增加受试动物的生存率，并能改善体重下降的程度。
表6小鼠死亡率和体重(n＝8)
Claims (2)
1.姜黄素在制备预防或/和治疗伊立替康或其活性代谢物7-乙基-10羟基喜树碱所致延迟性腹泻药物中的用途。
2.根据权利要求1所述的用途，其特征在于：所述姜黄素替换为去甲氧基姜黄素、双去甲氧基姜黄素、二氢姜黄素、六氢姜黄素，或者它们的组合物。
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| 化疗相关性腹泻的发生机制和治疗策略;方青芳;《中国临床药理学与治疗学》;20090331;第14卷(第3期);351-355 * |
| 周燕 等.姜黄素灌胃对顺铂所致的肠道损伤的保护效应.《中国现代医学杂志》.2012,第22卷(第3期),37-40. |
| 姜黄素灌胃对顺铂所致的肠道损伤的保护效应;周燕 等;《中国现代医学杂志》;20120131;第22卷(第3期);37-40 * |
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