CN115381820A - 盐酸去亚甲基四氢小檗碱在制备治疗溃疡性结肠炎药物中的应用 - Google Patents
盐酸去亚甲基四氢小檗碱在制备治疗溃疡性结肠炎药物中的应用 Download PDFInfo
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Abstract
本发明涉及生物医药领域，具体涉及盐酸去亚甲基四氢小檗碱在制备治疗溃疡性结肠炎药物中的应用。本发明通过体内外实验，惊奇的发现盐酸去亚甲基四氢小檗碱抗溃疡性结肠炎优于小檗碱和盐酸去亚甲基小檗碱，并且具有显著性差异。其活性更好，毒性更低，具有出人意料的技术效果。
Description
技术领域
本发明涉及生物医药领域，具体涉及盐酸去亚甲基四氢小檗碱在制备治疗溃疡性结肠炎药物中的应用。
背景技术
近二十年来，我国炎症性肠病(inflammatory bowel disease，IBD)患者人数呈逐年增多的趋势，该疾病已由少见病向“常见病”转化。溃疡性结肠炎(ulcerative colitis，UC)是炎症性肠病的一种亚型，是一种慢性非特异性肠道炎症疾病。UC主要累及结直肠的黏膜与黏膜下层，以肠粘膜连续、弥漫性的炎症损伤为主要特征，且病程较长。UC的临床表现包括严重腹泻、便血、进行性蠕动功能缺失等，严重影响人类健康。UC的发病机制尚不明确，可能是由于遗传因素、免疫应答、肠道微生物稳态和上皮屏障失衡所致。值得关注的是，UC易增加患结直肠癌的风险。目前临床上治疗UC的药物主要有以下4类：1.氨基水杨酸类药物，如柳氮磺胺吡啶和5-氨基水杨酸，2.糖皮质激素类药物，如泼尼松和氢化可的松，3.免疫抑制剂，如硫唑嘌呤或6-巯基嘌呤(6-MP)，4.生物制剂，如中和炎症因子TNF-α的英夫利昔和阿达木单抗，这类药物价格昂贵，并易引发继发感染，因此，临床上会非常谨慎地使用这类药物。上述治疗药物主要从抗炎、抑制免疫和中和炎症因子机制上治疗UC，治标不治本，使该病迁延难愈，无法根治。因此，UC患者迫切需要具有更有效治疗方法以及副作用弱的安全药物。
近年来，治疗类风湿关节炎的JAK(Janus激酶)抑制剂(如托法替尼)用于治疗UC。因此，激酶抑制剂用于治疗UC的新型药物研发的热点。在溃疡性结肠炎的发展过程中，被激活的免疫细胞分泌多种促炎介质，如活性氧(ROS)、中性粒细胞浸润、细胞因子等，刺激炎症级联反应，导致肠上皮屏障的破坏和细胞凋亡，使慢性肠道炎症持续存在。近年来有研究发现，在DSS(dextran sulfate sodium，DSS)结肠炎、肝螺杆菌结肠炎、T细胞转移性结肠炎等实验性结肠炎模型中IL-23水平升高，这与IL-23可能在结肠炎发病中发挥重要作用的观点一致。在发现IL-23之前，研究使用ustekinumab单抗中和IL-12的p40亚基，现在已知可以同时阻断IL-12和IL-23。p40阻滞剂被发现在各种小鼠模型中非常有效地抑制实验性结肠炎的活性。Guselkumab靶向IL-23的亚基p19，在治疗溃疡性结肠炎与克罗恩病的临床试验表现出优异效果。因此，特异性阻断UC发病过程中IL-23分泌可作为UC用药的有效靶点，现已成为治疗UC的关键靶点之一。
盐酸去亚甲基四氢小檗碱，如式(Ⅰ)所示。
盐酸去亚甲基四氢小檗碱(式Ⅰ)的英文名为Demethylenetetrahydroberberine。本发明专利将其简称为DMTHB。它的分子式：C19H21NO4，相对分子质量：327.2。CAS号为47346-21-4，学术名为6H-Dibenzo[a,g]quinolizine-2,3-diol,5,8,13,13a-tetrahydro-9,10-dimethoxy；6H-二苯并[a，g]喹嗪-2,3-二醇，5,8,13,13a-四氢-9,10-二甲氧基。盐酸去亚甲基四氢小檗碱可以与无机酸或者有机酸形成多种盐，如氯化盐、硫酸盐、磷酸盐、溴化盐、碘化盐、枸橼酸盐、延胡索酸盐、马来酸盐、苹果酸盐和琥珀酸盐等分子形式存在。尽管小檗碱和盐酸去亚甲基小檗碱有治疗溃疡性结肠炎的报道，但两个化合物存在溶解度不佳、给药剂量高、口服生物利用度低等问题，治疗效果不尽如意，有待进一步提高。为获得更好的治疗效果，本发明首次发现盐酸去亚甲基四氢小檗碱治疗溃疡性结肠炎作用。
发明内容
为了获得更好的治疗效果，本发明旨在于提供盐酸去亚甲基四氢小檗碱(DMTHB)作为一种新型防治溃疡性结肠炎药物的应用。
盐酸去亚甲基四氢小檗碱在制备治疗溃疡性结肠炎药物中的应用，其中盐酸去亚甲基四氢小檗碱的结构式如式Ⅰ所示
一种治疗溃疡性结肠炎的药物组合物，其特征在于，含有药物有效剂量的权利要求1所示的盐酸去亚甲基四氢小檗碱及药学可接受的辅料。
所述的药物组合物，其特征在于，所述药物组合物是片剂、胶囊、丸剂、注射剂、缓释剂及各种微粒给药系统。
本发明所用盐酸去亚甲基四氢小檗碱产品采用常规化学与分离纯化制得。本实验室采用高效液相色谱(HPLC)分析检测，其纯度达99％以上，并经液相色谱-质谱联用(LC-MS)和核磁共振法分析鉴定，表明本实验室所用的盐酸去亚甲基四氢小檗碱产品化学结构正确。此项研究表明盐酸去亚甲基四氢小檗碱其纯度和化学结构符合开展体内、体外水平的药理学活性研究要求。
根据本发明还涉及含有作为活性成份的盐酸去亚甲基四氢小檗碱和常规药物赋形剂或辅剂的药物组合物。通常本发明药物组合物含有0.1～95％重量％的盐酸去亚甲基四氢小檗碱。在单元剂型中本发明化合物一般含量为0.1～100mg。本发明化合物的药物组合物可根据本领域公知的方法制备。用于此目的时，如果需要，可将本发明化合物与一种或多种固体或液体药物赋形剂和/或辅剂结合，制成可作为人药或兽药使用的适当的施用形式或剂量形式。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等。本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射、皮内注射和穴位注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明化合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
例如为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸钠等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
例如为了将给药单元制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、单硬脂酸甘油脂、高岭土、滑石粉等；粘合剂，如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂如琼脂粉、干燥粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊，将有效成份本发明化合物盐酸去亚甲基小檗碱与上述的各种载体混合，并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂，混悬于水性介质中形成混悬剂，亦可装入硬胶囊中或制成注射剂应用。
例如，将本发明化合物盐酸去亚甲基小檗碱制成注射用制剂，如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂，这种制剂可以是含水或非水的，可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂、分散剂、渗透压调节剂、增溶剂和pH调节剂。如稀释可选用水、乙醇、聚乙二醇、1，3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂、脂肪酸酯等。渗透压调节剂可以是氯化钠、甘露醇、甘油、葡萄糖、磷酸盐、醋酸盐等；增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基β-环糊精等；pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等。如制备冻干粉针剂，还可以加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或香料等。这些辅料是本领域常用的。
本发明所用的无菌介质都可以通过本领域技术人员众所周知的标准技术制得。可将它们灭菌，例如通过经由细菌过虑器过滤、通过向组合物中加入灭菌剂、通过将组合物放射处理、或通过将组合物加热灭菌。还可以在临用前将它们制成无菌可注射介质。
为了达到用药目的，增加治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。当然用于实施本发明化合物的给药途径取决于疾病和需要治疗的部位。因为本发明化合物的药动学和药效学特征会有某种程度的不同，因此在组织中获得治疗浓度的最优选方法是逐渐增加剂量并监测临床效果。对于这样的逐渐增加治疗剂量，初始剂量将取决于给药途径。
对于任何特定患者，本发明化合物药物组合物的给药剂量取决于许多因素，例如所要预防或治疗疾病的性质和严重程度，患者或动物的性别、年龄、性格及个体反应，给药途径、给药次数、治疗目的，因此本发明的治疗剂量可以有较大范围的变化。根据所治疗患者的病症，可能必须对剂量作出某些改变，并且在任何情况下，都由医师决定个体患者的合适剂量。
给药剂量是指不包括载体重量在内(当使用载体时)的化合物的重量。一般来讲，本发明中药学成分的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量，加以适当的调整，以达到其治疗有效量的要求，完成本发明的预防或治疗目的。可以是单一剂量形式给药或分成几个，例如二、三或四个剂量形式给药；这受限于给药医生的临床经验以及包括运用其它治疗手段的给药方案。本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用并调整剂量。
有益效果
尽管小檗碱和盐酸去亚甲基小檗碱有治疗溃疡性结肠炎的报道，两个化合物存在溶解度不佳、给药剂量高、口服生物利用度低等问题，治疗效果不尽如意，故寻找更好的治疗效果药物成为本领域所要解决的技术问题。盐酸去亚甲基四氢小檗碱是盐酸去亚甲基小檗碱的还原产物，结构相似，分子缺少共轭基团，其化学性质也随着改变，极性变小，脂溶性增加，其抗溃疡性结肠炎活性是否保持成为未知。
本发明通过体内外实验，惊奇的发现盐酸去亚甲基四氢小檗碱抗溃疡性结肠炎优于小檗碱和盐酸去亚甲基小檗碱，并且具有显著性差异。其活性更好，毒性更低，具有出人意料的技术效果。具体如下：
在体外实验中，本发明通过CCK8法、ROS探针法，通过细胞培养、荧光显微镜分析盐酸去亚甲基四氢小檗碱对DSS刺激正常结肠上皮细胞产生ROS清除的作用。结果表明，盐酸去亚甲基四氢小檗碱在对细胞无毒性的情况下，可保护结肠上皮细胞减轻DSS刺激引起的细胞损伤，提高细胞活力。盐酸去亚甲基四氢小檗碱在细胞水平上对ROS有很强的清除作用。溃疡性结肠炎属于一种慢性特异性炎症疾病，本发明发现，盐酸去亚甲基四氢小檗碱具有体外的抗炎和抗氧化生物活性，这为开展DMTHB治疗溃疡性结肠炎的药物研究奠定了重要的理论基础。
在体内实验中，本发明以C57BL/6小鼠为动物试验模型，考察盐酸去亚甲基四氢小檗碱对DSS诱导的急性溃疡性结肠炎的治疗作用。治疗方案是：在DSS造模第3天开始，小鼠表现出稀便症状，通过口服灌胃小鼠DMTHB，每天1次，共7天，给药组分别设置50mg/kg(IG)和100mg/kg(IG)高低两个剂量。同时设置剂量为100mg/kg(IG)的小檗碱和100mg/kg(IG)的盐酸去亚甲基小檗碱对照组。自造模开始，每天观察小鼠的饮食和体重变化，同时记录小鼠状态，给药一周后解剖小鼠。实验结果分析表明，盐酸去亚甲基四氢小檗碱低剂量和高剂量组均能显著改善小鼠溃疡性结肠炎引起的体重下降、结肠萎缩肿胀、充血病症，显示出盐酸去亚甲基四氢小檗碱对DSS诱导的溃疡性结肠炎具有保护作用。此外，与DSS组相比，DMTHB低剂量与高剂量给药组的髓过氧化物酶水平显著降低，表明DMTHB可降低结肠组织中的中性粒细胞浸润，起到优于等剂量BBR组与DMB组的抗炎作用。结肠组织病理学研究结果表明，模型组小鼠结肠结构紊乱，隐窝及腺体缺失，发生严重炎症细胞浸润，而DMTHB给药组的结肠病变范围和程度较模型组明显减轻，同时治疗效果强于同剂量的BBR组和DMB组。这些实验结果充分说明盐酸去亚甲基四氢小檗碱能有效治疗DSS诱导的急性溃疡性结肠炎。
附图说明
图1 DMTHB作用NCM460细胞24h对其细胞活力的影响；
图2 DMTHB给药对DSS损伤的NCM460细胞的细胞活力影响；
图3 DMTHB给药对DSS损伤的NCM460细胞产生ROS的染色图；
图4 DSS诱导的UC小鼠体重变化图；
图5 DMTHB治疗DSS诱导的UC小鼠结肠组织形态图；
图6 DMTHB治疗DSS诱导的UC小鼠结肠长度/结肠重量分析图；
图7 DMTHB治疗DSS诱导的UC小鼠HE染色图(×400)；
图8 DMTHB对DSS诱导的小鼠结肠组织蛋白免疫印迹结果(A)及灰度分析图(B)。
具体实施方式
下面的实施例可以帮助本领域的技术人员更全面的理解本发明，但不以任何方式限制本发明。
术语
UC：溃疡性结肠炎
IBD：炎症性肠病
DMTHB:盐酸去亚甲基四氢小檗碱
DSS：葡聚糖硫酸钠
BBR：盐酸小檗碱
DMB：盐酸去亚甲基小檗碱
ROS：活性氧
MPO：髓过氧化物酶
IG：灌胃
实施例1.盐酸去亚甲基四氢小檗碱(DMTHB)对NCM460细胞的细胞毒性作用。
方法：采用CCK-8法检测细胞活力。提前将细胞96孔板边缘孔中填充无菌PBS,每孔100μL。对处于对数生长期的正常结肠上皮细胞NCM460进行收集，调整细胞数量为105个/ml，每孔100μL接种于细胞96孔板中。置37℃，5％C02的细胞培养箱中预培养24h后，保证细胞贴壁。对由DMSO溶解的浓度为200mM的DMTHB母液进行梯度稀释，稀释后的浓度分别为200μM、100μM、50μM、25μM、12。5μM、6.25μM、3.125μM，另设空白组、细胞培养液对照(Control)组和药物溶解介质(DMSO)组(稀释方法同药物浓度200μM)，每组重复6孔。继续培养24h后，向每孔加入10μLCCK-8溶液，注意不要生成气泡。将培养板在培养箱内孵育1-4h，用酶标仪测定各孔在450nm处的吸光度。细胞活力*(％)＝[A(加药)-A(空白)]/[A(0加药)-A(空白)]×100。
结果：低剂量DMTHB对正常结肠上皮细胞NCM460无明显毒性作用，与Control组的细胞活力无显著性差异，如图1所示，药物浓度高于50μM后，对细胞增殖产生显著性抑制作用，且呈剂量依赖，。
实施例2.盐酸去亚甲基四氢小檗碱对DSS诱导NCM460细胞损伤的保护作用。
方法：采用CCK-8实验评估DMTHB对DSS诱导的细胞损伤的保护作用。提前将细胞96孔板边缘孔中填充无菌PBS,每孔100μL。对处于对数生长期的正常结肠上皮细胞NCM460进行收集，调整细胞数量为105个/ml，每孔100μL接种于细胞96孔板中。置37℃，5％C02的细胞培养箱中预培养24h后，保证细胞贴壁。对由DMSO溶解的浓度为200mM的DMTHB母液进行稀释，稀释后的浓度分别为5μM、10μM、20μM，另设不加药的细胞培养液对照(Control)组和DSS组，每组重复6孔。预给药6h后，DSS组和给药组分别加入无菌PBS溶解后的DSS溶液，使培养液中DSS终浓度为80mg/ml，Control组加入等体积的PBS溶液。继续培养12h后，向每孔加入10μLCCK-8溶液，注意不要生成气泡。将培养板在培养箱内孵育1-4h，用酶标仪测定各孔在450nm处的吸光度。细胞活力*(％)＝[A(加药)-A(空白)]/[A(0加药)-A(空白)]×100。
结果：如图2所示，实验中DSS会诱导正常结肠上皮细胞损伤，抑制上皮细胞增殖。各浓度的DMTHB给药后可在不同程度上保护细胞，显著增加细胞活力，保护效果呈现剂量依赖性。
实施例3.盐酸去亚甲基四氢小檗碱清除DSS诱导结肠上皮细胞产生的ROS。
方法：本实验采用ROS荧光探针法，细胞水平检测DMTHB对DSS诱导结肠上皮细胞氧化损伤的作用。将NCM460细胞株分别按细胞数4×105个/ml接种于24孔板中，置于37℃，5％CO2的培养箱中，培养24h保证细胞处于生长旺盛期。给药组分别给药10μM、20μM的DMTHB以及20μM的BBR和20μM的DMB治疗，重复3个孔。药物孵育6h后，DSS组和各给药组都给予80mg/mlDSS溶液，Control组加入同等体积的PBS溶液。将培养板置于培养箱继续孵育12h，使其产生大量的ROS造成细胞氧化损伤。利用荧光探针DCFH-DA(10μM)与ROS结合产生荧光的原理，荧光显微镜下观察ROS的清除作用。
结果：荧光显微镜下显示各种浓度的DMTHB皆能显著性抑制过氧化物在NCM460细胞中产生的ROS，且效果优于同剂量的BBR和DMB,结果如图3所示。
实施例4.盐酸去亚甲基四氢小檗碱治疗可提高溃疡性结肠炎小鼠的生存率。
方法：本实验选用雌性C57BL/6小鼠，体重20-22g，适应环境1周后，随机分为6组，每组6只小鼠。各组分别为正常对照(Control)组、模型(DSS)组、盐酸去亚甲基四氢小檗碱低剂量(50mg/kg)组、盐酸去亚甲基四氢小檗碱高剂量(100mg/kg)组、盐酸小檗碱(100mg/kg)组、盐酸去亚甲基小檗碱(100mg/kg)组。第0天，模型组和给药组小鼠自由饮用4％DSS溶液，造模7天后，正常饮用蒸馏水5天。正常对照组自由饮用双蒸水12天。给药组小鼠在第3天开始灌胃各组对应药物，每天1次，持续7天，同时对照组和模型组小鼠给予同体积赋形剂。记录实验期间小鼠的死亡数目。在灌胃7天结束后，解剖小鼠。
结果：高剂量DMTHB给药后，溃疡性结肠炎小鼠的生存率得到显著提高。如表1所示，实验期间，模型组和DMTHB低剂量组分别死亡3只小鼠。BBR组与DMB组小鼠各死亡1只，对照组与DMTHB高剂量组无小鼠死亡。
表1 DMTHB治疗对UC小鼠死亡率的影响
实施例5.盐酸去亚甲基四氢小檗碱治疗可减缓溃疡性结肠炎小鼠的体重下降。
方法：本实验选用雌性C57BL/6小鼠，体重20-22g，适应环境1周后，随机分为6组，每组6只小鼠。各组分别为正常对照(Control)组、模型(DSS)组、盐酸去亚甲基四氢小檗碱低剂量(50mg/kg)组、盐酸去亚甲基四氢小檗碱高剂量(100mg/kg)组、盐酸小檗碱(100mg/kg)组、盐酸去亚甲基小檗碱(100mg/kg)组。第0天，模型组和给药组小鼠自由饮用4％DSS溶液，造模7天后，正常饮用蒸馏水5天。正常对照组自由饮用双蒸水12天。给药组小鼠在第3天开始灌胃各组对应药物，每天1次，持续7天，同时对照组和模型组小鼠给予同体积赋形剂。记录实验期间小鼠的体重变化。在灌胃7天结束后，解剖小鼠。
结果：如图4所示，对照组小鼠不受DSS影响，体重基本保持升高趋势。随着饮用DSS的各组小鼠发生不同程度的腹泻、便血等一系列结肠炎症状，进食量减少的同时消耗量增加，导致小鼠体重减轻，精神萎靡。与模型组相比，给药组小鼠的体重下降自第7天开始有明显改善，且DMTHB高剂量组与模型组有显著性差异。
实施例6.盐酸去亚甲基四氢小檗碱治疗可改善溃疡性结肠炎小鼠的结肠萎缩与肿胀。
方法：本实验选用雌性C57BL/6小鼠，体重20-22g，适应环境1周后，随机分为6组，每组6只小鼠。各组分别为正常对照(Control)组、模型(DSS)组、盐酸去亚甲基四氢小檗碱低剂量(50mg/kg)组、盐酸去亚甲基四氢小檗碱高剂量(100mg/kg)组、盐酸小檗碱(100mg/kg)组、盐酸去亚甲基小檗碱(100mg/kg)组。第0天，模型组和给药组小鼠自由饮用4％DSS溶液，造模7天后，正常饮用蒸馏水5天。正常对照组自由饮用双蒸水12天。给药组小鼠在第3天开始灌胃各组对应药物，每天1次，持续7天，同时对照组和模型组小鼠给予同体积赋形剂。在灌胃7天结束后，解剖小鼠取其结肠组织拍照、称重、测量长度。
结果：结肠肿胀程度可以通过单位长度的结肠重量表示，DSS造模使结肠出现肿胀、萎缩增厚、出血等症状，单位长度结肠重量增加。如图5、6所示，不同剂量的DMTHB给药可以缓解结肠肿胀，改善萎缩程度，治疗效果优于同剂量的BBR与DMB。
实施例7.盐酸去亚甲基四氢小檗碱治疗可降低溃疡性结肠炎小鼠产生过量MPO。
方法：髓过氧化物酶(myeloperoxidase，MPO)又称过氧化物酶，是血红素辅基的血红素蛋白酶，是血红素过氧化物酶超家族成员之一。它是中性粒细胞的功能标志和激活标志，其水平及活性变化对提示肠道中性粒细胞炎症浸润有重要意义。雌性C57BL/6小鼠，体重20-22g，适应环境1周后，随机分为6组，每组6只小鼠。各组分别为正常对照(Control)组、模型(DSS)组、盐酸去亚甲基四氢小檗碱低剂量(50mg/kg)组、盐酸去亚甲基四氢小檗碱高剂量(100mg/kg)组、盐酸小檗碱(100mg/kg)组、盐酸去亚甲基小檗碱(100mg/kg)组。第0天，模型组和给药组小鼠自由饮用4％DSS溶液，造模7天后，正常饮用蒸馏水5天。正常对照组自由饮用双蒸水12天。给药组小鼠在第3天开始灌胃各组对应药物，每天1次，持续7天，同时对照组和模型组小鼠给予同体积赋形剂。在灌胃7天结束后，解剖小鼠取同一部位结肠组织。取一定质量的结肠组织冰上剪碎，于生理盐水中匀浆制成10％的结肠匀浆液，4℃，8000rpm离心10min，取上清，对照MPO检测试剂盒说明书，测定结肠组织中MPO活性水平。
结果：如表3所示，与对照组相比，DSS组小鼠的MPO活性水平显著升高，DMTHB给药后较其他组可降低MPO活性，减轻结肠组织的中性粒细胞浸润，表现出优异的抗炎作用。
表3 UC小鼠结肠组织MPO表达水平
(n＝6,mean±variance，#p<0.05、##p<0.01、###p<0.001、####p<0.0001VSControl，*p<0.05、**p<0.01、***p<0.001、****p<0.0001VS DMTHB-100mg/kg)
实施例8.盐酸去亚甲基四氢小檗碱治疗可保护溃疡性结肠炎小鼠的组织病理损伤。
方法：雌性C57BL/6小鼠，体重20-22g，适应环境1周后，随机分为6组，每组6只小鼠。各组分别为正常对照(Control)组、模型(DSS)组、盐酸去亚甲基四氢小檗碱低剂量(50mg/kg)组、盐酸去亚甲基四氢小檗碱高剂量(100mg/kg)组、盐酸小檗碱(100mg/kg)组、盐酸去亚甲基小檗碱(100mg/kg)组。第0天，模型组和给药组小鼠自由饮用4％DSS溶液，造模7天后，正常饮用蒸馏水5天。正常对照组自由饮用双蒸水12天。给药组小鼠在第3天开始灌胃各组对应药物，每天1次，持续7天，同时对照组和模型组小鼠给予同体积赋形剂。在灌胃7天结束后，解剖小鼠取同一部位结肠组织。充分清洗后，采用多聚甲醛固定组织，HE染色进行病理学检查。
结果：结肠组织病理学HE染色结果可看到，空白对照组小鼠结肠组织形态正常，腺体排列有序，有完整的隐窝结构且未见炎症细胞浸润。模型组结肠组织的隐窝及腺体结构遭到破坏，无序且有大量炎症细胞浸润。DMTHB治疗后，腺体与隐窝结构得到一定得恢复，且炎症浸润减少，治疗效果优于DMB和BBR。同时，DMTHB(100mg/kg)给药组的治疗效果优于50mg/kg组，表现出一定的剂量依赖性，HE染色如图6所示。
实施例9.盐酸去亚甲基四氢小檗碱治疗可抑制溃疡性结肠炎小鼠分泌IL-23。
方法：雌性C57BL/6小鼠，体重20-22g，适应环境1周后，随机分为6组，每组6只小鼠。各组分别为正常对照(Control)组、模型(DSS)组、盐酸去亚甲基四氢小檗碱低剂量(50mg/kg)组、盐酸去亚甲基四氢小檗碱高剂量(100mg/kg)组、盐酸小檗碱(100mg/kg)组、盐酸去亚甲基小檗碱(100mg/kg)组。第0天，模型组和给药组小鼠自由饮用4％DSS溶液，造模7天后，正常饮用蒸馏水5天。正常对照组自由饮用双蒸水12天。给药组小鼠在第3天开始灌胃各组对应药物，每天1次，持续7天，同时对照组和模型组小鼠给予同体积赋形剂。在灌胃7天结束后，解剖小鼠取同一部位结肠组织。提取结肠组织蛋白后进行蛋白免疫印迹实验，检测组织中IL-23蛋白表达水平。
结果：如图7所示，DSS组较正常对照组小鼠而言，IL-23表达显著升高。DMTHB给药组的IL-23表达明显减少，且抑制IL-23分泌的效果优于BBR和DMB，表明DMTHB可通过IL-23这一关键靶点治疗急性溃疡性结肠炎。
Claims (3)
1.盐酸去亚甲基四氢小檗碱在制备治疗溃疡性结肠炎药物中的应用，其中盐酸去亚甲基四氢小檗碱的结构式如式Ⅰ所示
2.一种治疗溃疡性结肠炎的药物组合物，其特征在于，含有药物有效剂量的权利要求1所示的盐酸去亚甲基四氢小檗碱及药学可接受的辅料。
3.根据权利要求2所述的药物组合物，其特征在于，所述药物组合物是片剂、胶囊、丸剂、注射剂、缓释剂及各种微粒给药系统。
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