CN113057956B - 一种含藤黄科成份的药物及制备缓解自身免疫药物的用途 - Google Patents
一种含藤黄科成份的药物及制备缓解自身免疫药物的用途 Download PDFInfo
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Abstract
本发明属于生物医药领域，具体是关于一种含藤黄科植物活性成份的药物及其在制备缓解自身免疫性疾病药物的用途。本发明的药物活性成份为藤黄氧蒽酮E和伽升沃D中的一种或两种。实验显示，藤黄氧蒽酮E和伽升沃D对多种自身免疫疾病模型具有改善作用，且具有调控cAMP的活性，适用于改善多种自身免疫疾病。
Description
技术领域
本发明属于生物医药领域，特别涉及一种含藤黄科植物活性成份的药物及在制备缓解自身免疫疾病药物的用途。
背景技术
自身免疫性疾病是识别自身抗原的淋巴细胞增生活化，对内源性自身抗原的耐受性丧失，导致免疫系统对自身产生免疫反应而造成的疾病。此类疾病包括自身免疫性肝损伤（Autoimmune liver injury, AII）、系统性红斑狼疮( Systemic lupuserythematosus, SLE) 、银屑病( Psoriasis, PS)、多发性硬化（Multiple sclerosis，MS）、自身免疫性脑脊髓炎（Autoimmune encephalomyelitis, AE）等。由于自身抗原信息缺乏、疾病发病机制复杂等原因，目前对自身免疫性疾病缺乏治愈措施，药物治疗仅用于缓解症状和延缓病情发展而无法根治。
核转录因子κB是先天性和适应性免疫反应的关键调节剂，参与免疫功能调解的多个方面，包括淋巴细胞发育、先天免疫细胞分化等。核转录因子κB参与了许多自身免疫性疾病的发病，例如自身免疫性肝损伤、系统性性红斑狼疮、类风湿关节炎、I型糖尿病、多发性硬化症、自身免疫性脑脊髓炎等等。在正常免疫反应中核转录因子κB属于短暂激活状态，但在自身免疫性疾病中，受影响的组织中核转录因子κB处于长期激活状态，从而诱导细胞因子和趋化因子，介导免疫细胞的募集。此外，核转录因子κB还直接或间接促进自身免疫T细胞的活化。因此，核转录因子κB调节是自身免疫性疾病中的一个有吸引力的药物靶点，成为药物研发的热点之一。
磷酸二酯酶是负责环核苷酸水解和随后失活的酶家族，分布于大脑和具有免疫功能的细胞（例如嗜中性粒细胞、T淋巴细胞、巨噬细胞和嗜酸性粒细胞）内，具有水解细胞内第二信使环磷酸腺苷（cAMP）的作用。其中磷酸二酯酶4几乎仅在免疫相关细胞中表达。抑制磷酸二酯酶4会升高环磷酸腺苷水平，激活下游蛋白激酶A。该途径的激活可调节多种细胞因子的基因转录，并抑制肿瘤坏死因子α的产生。靶向磷酸二酯酶4可以绕过复杂的抗原受体特异性免疫调节机制，对自身免疫性疾病发挥缓解作用。因此， 磷酸二酯酶4抑制剂已引起广泛关注，可用于治疗多种自身免疫疾病，包括银屑病、自身免疫性肝损伤、系统性红斑狼疮和多发性硬化症等。其中Apremilast已经用于自身免疫性疾病如银屑病的治疗，并能改善肝功能相关酶指标和肝功能。Rolipram也对自身免疫性肝损伤、类风湿关节炎、多发性硬化症、自身免疫性脑脊髓炎有明显改善作用。以核转录因子κB和磷酸二酯酶为靶点进行治疗能够避免后续参与因素的复杂作用。
藤黄科存在大量药用植物，且本科植物的生物活性和治疗作用也很广泛，是筛选抗肿瘤、抗病毒、抗炎、免疫调节等药物的天然库。藤黄氧蒽酮 E（Garciniaxanthone E），CAS 173294-74-1是存在于藤黄科植物菲岛福木 Garcinia subelliptica、大叶藤黄Garcinia xanthochymus、大苞藤黄Garcinia bracteata等药用植物中的氧蒽酮成份之一，已发现该成份具有促进神经生长等作用。伽升沃D（ Garcinone D），CAS 107390-08-9是存在于藤黄科植物倒捻子Garcinia mangostana中的氧蒽酮成份之一，已发现该成份有激活核因子E2相关因子2、血红素加氧酶-1和抑制CDK4等药理作用。促进神经生长对于多发性硬化症、自身免疫性脑脊髓炎等神经损伤性自身免疫疾病具有保护作用；激活核因子E2相关因子2、血红素加氧酶-1等则对多发性硬化症、自身免疫性脑脊髓炎、系统性红斑狼疮、类风湿关节炎等自身免疫疾病的治疗有积极意义。但目前缺乏对藤黄氧蒽酮 E和伽升沃D的系统研究。
发明内容
针对上述问题，本发明通过对藤黄科植物中藤黄氧蒽酮 E、伽升沃D两个氧蒽酮的靶点筛选分析和研究，提供一种缓解自身免疫性疾病的药物。藤黄氧蒽酮 E、伽升沃D已知具有促进神经生长、激活核因子E2相关因子2及抑制CDK4等作用。这些活性可用于多种相关的自身免疫性疾病，包括系统性红斑狼疮、多发性硬化症、自身免疫性脑脊髓炎、类风湿关节炎等。本发明在研究中还发现，藤黄氧蒽酮 E、伽升沃D一定剂量范围内可提高血清cAMP水平。这一活性可用于多种相关的自身免疫性疾病，包括类风湿关节炎、银屑病、自身免疫性肝损伤、强直性脊柱炎、系统性红斑狼疮和多发性硬化症等。
因此，本发明首先提供一种含藤黄科植物活性成份的药物，具体是以藤黄氧蒽酮E、伽升沃D中的一种或两种作为活性成份的药物。
根据发明人研究中发现的剂量与活性的关系，以藤黄氧蒽酮 E、伽升沃D作为活性成份的药物中，藤黄氧蒽酮 E、伽升沃D的配比（w/w）优选为1:（1~3）。
上述含藤黄科植物活性成份的药物，优选通过口服或外用给药。
其中口服药物优选为干混悬剂或胶囊剂，辅料优选为羧甲基纤维素钠、羟丙基甲基纤维素、微晶纤维素。
本发明其次提供了藤黄氧蒽酮 E及伽升沃D在制备缓解自身免疫疾病药物中的用途。根据藤黄氧蒽酮 E及伽升沃D的活性和靶点，所述自身免疫疾病包括但不限于系统性红斑狼疮、自身免疫性脑脊髓炎、多发性硬化症、类风湿关节炎、银屑病、自身免疫性肝损伤、强直性脊柱炎、自身免疫性甲状腺炎。
申请人研究了藤黄氧蒽酮 E、伽升沃D对部分自身免疫疾病的改善作用以及对cAMP的调控作用。藤黄氧蒽酮 E、伽升沃D中、高剂量下灌胃给药对模型动物的症状具有改善作用，并可提高cAMP水平。
具体实施方式
以下是藤黄氧蒽酮 E、伽升沃D的部分制剂和研究举例。在本发明的基本框架下，制剂的辅料可以用相同功能的辅料替换和变化，辅料用量也可以调整，所以实施例的制剂不限制保护范围。
实施例1藤黄氧蒽酮 E的干混悬剂或胶囊剂和制备方法
用料：藤黄氧蒽酮 E 650mg、羧甲基纤维素钠40mg、羟丙基甲基纤维素31 mg、微晶纤维素79 mg（淀粉浆制备软材湿法制粒）。
干混悬剂或胶囊剂制备：将藤黄氧蒽酮 E、羧甲基纤维素钠、羟丙基甲基纤维素、微晶纤维素粉碎过100目筛混合均匀，加10%淀粉浆制备软材，软材以18目筛制粒，60℃干燥，以16目筛整粒，分装入铝箔袋做成袋装口服干混悬剂或分装入胶囊壳做成口服胶囊。
实施例2 藤黄氧蒽酮 E的注射剂和制备方法
用料：藤黄氧蒽酮 E 120mg、泊洛沙姆188 0.3g、乙醇0.7g、注射用水定容至100ml。
注射剂的制备：向50 ml注射用水中加入乙醇，向水醇溶液中加入泊洛沙姆188使溶解，向含泊洛沙姆188的水醇溶液中加入藤黄氧蒽酮 E搅拌使溶解，加余量注射用水定容至100ml。
实施例3 藤黄氧蒽酮 E、伽升沃D复方干混悬剂或胶囊剂和制备方法
用料：藤黄氧蒽酮 E 325mg、伽升沃D325mg、羧甲基纤维素钠40mg、羟丙基甲基纤维素31 mg、微晶纤维素79 mg（淀粉浆制备软材湿法制粒）。
干混悬剂或胶囊剂制备：将藤黄氧蒽酮 E、伽升沃D、羧甲基纤维素钠、羟丙基甲基纤维素、微晶纤维素粉碎过100目筛混合均匀，加10%淀粉浆制备软材，软材以18目筛制粒，60℃干燥，以16目筛整粒，分装入铝箔袋做成袋装口服干混悬剂或分装入胶囊壳做成口服胶囊。
实施例4 藤黄氧蒽酮 E、伽升沃D复方注射剂和制备方法
用料：藤黄氧蒽酮 E 40mg、伽升沃D 80 mg、泊洛沙姆188 0.5g、乙醇 0.7g、注射用水定容至100ml。
注射剂的制备：向60 ml注射用水中加入乙醇，向水醇溶液中加入泊洛沙姆188使溶解，向含泊洛沙姆188的水醇溶液中加入藤黄氧蒽酮 E、伽升沃D搅拌使溶解，加余量注射用水定容至100ml。
实施例5 藤黄氧蒽酮 E、伽升沃D复方外用洗剂和制备方法
用料：藤黄氧蒽酮 E 400mg、伽升沃D 400mg、70%乙醇水溶液100 ml。
外用洗剂的制备：取70%乙醇水溶液（V/V）100 ml，加入藤黄氧蒽酮 E、伽升沃D搅拌均匀，用于皮肤局部擦洗。本外用洗剂也可不含伽升沃D或藤黄氧蒽酮 E作为单方使用。
实施例6 藤黄氧蒽酮 E对系统性红斑狼疮模型的抑制作用研究
选用180～200g的雌性SD大鼠，以Freund 's完全及不完全佐剂和卵清白蛋白，参照我单位造模方法诱导大鼠Arthus反应（张凤山, 黄长军. 免疫调节胶囊对系统性红斑狼疮治疗作用及机制的实验研究[C].首届国际中西医结合风湿病学术会议论文汇编104-106.）。卵清白蛋白-Freund 's完全佐剂及卵清白蛋白-Freund 's不完全佐剂中卵清白蛋白浓度为0.5g/L。完全佐剂卡介苗浓度12mg/mL。肌注体积0.5ml/只/次。
最后1次注射卵清白蛋白-Freund 's不完全佐剂后，取造模大鼠32只，随机分为4组，8只/组：即0.9%NaCl组（NS组，1.5ml/天）、藤黄氧蒽酮 E 2.8mg/只/天组（GEL组，1.5ml/天）、藤黄氧蒽酮 E 5.6mg/只/天组（GEM组，1.5ml/天）、藤黄氧蒽酮 E 11.2mg/只/天组（GEH组，1.5ml/天）。其中藤黄氧蒽酮 E加入0.9%NaCl中灌胃。各组连续给药14天。最后1天给药后以1%卵清白蛋白NaCl溶液0.2ml单点背部皮下注射进行抗原攻击。抗原攻击后3小时，测定皮肤红斑直径(cm)。组间单因素方差分析比较显示，结果表明，GEM、GEH组皮肤红斑直径与NS组相比有显著减小（表1）。
表1 各组大鼠抗原攻击后3小时皮肤红斑直径(cm, n=8)
*：p<0.01, vs NS 组。
实施例7 藤黄氧蒽酮 E、伽升沃D对自身免疫性脑脊髓炎模型的抑制作用研究
选用180～200g的雌性SD大鼠，采用同种脑脊髓匀浆法建立自身免疫性脑脊髓炎模型。此模型也是多发性硬化症常用的动物模型。
取8只SD大鼠处死后剥离脊髓和脑组织，加入等质量0.9%NaCl溶液搅拌制备脑脊髓匀浆。向脑脊髓匀浆中加入等体积Freund 's完全佐剂（卡介苗浓度25mg/mL），制备成抗原乳剂。另取60只SD大鼠后足足底皮下注射抗原乳剂0.2mL/只，后足足背皮下注射百日咳疫苗0.2 mL/只（2×1010菌体/mL）。第12天各组大鼠再次注射，剂量同上。造模第14天，取出现症状的大鼠42只，随机分为7组，6只/组：即0.9%NaCl组（NS组，1.5ml/天）、藤黄氧蒽酮 E4.5mg/只/天组（GEL组，1.5ml/天）、藤黄氧蒽酮 E 9.0mg/只/天组（GEM组，1.5ml/天）、藤黄氧蒽酮 E 18.0mg/只/天组（GEH组，1.5ml/天）、伽升沃D 6.4 mg/只/天组（GDL组，1.5ml/天）、伽升沃D 12.8 mg/只/天组（GDM组，1.5ml/天）、伽升沃D 25.6 mg/只/天组（GDH组，1.5ml/天）。其中藤黄氧蒽酮 E及伽升沃D加入0.9%NaCl中灌胃。各组连续给药7天。最后1天给药完成后3小时，按照以下标准评估各组大鼠伸进功能评分：
0分：无异常；1分：尾巴无力或尾巴麻痹；2分：后腿轻瘫，被动翻身后可恢复体位；3分：后腿瘫痪，被动翻身后不能恢复体位，刺激后身体仍可挪动；4分：后腿瘫痪，前腿肌力减弱，或伴尿便失禁；5分：死亡或濒死状态。
实验结果表明，造模首日至造模第20天，各组大鼠无死亡现象。组间单因素方差分析比较显示，给药组中 GEH、GDH组症状评分与NS组相比显著降低（表2）。
表2 各组大鼠给药结束后症状评分及死亡率
*：p<0.05, vs NS 组。
实施例8藤黄氧蒽酮 E、伽升沃D对类风湿关节炎模型的抑制作用研究
选用180～200g的雄性SD大鼠，按照我单位造模方法以Freund 's完全佐剂建立大鼠类风湿关节炎模型（张凤山, 黄长军. 免疫调节胶囊对系统性红斑狼疮治疗作用及机制的实验研究[C].首届国际中西医结合风湿病学术会议论文汇编104-106.）。完全佐剂卡介苗浓度10mg/mL。
Freund 's完全佐剂注射当日起第9天，取42只大鼠，随机分为7组，6只/组：即0.9%NaCl组（NS组，1.5ml/天）、藤黄氧蒽酮 E 2.8mg/只/天组（GEL组，1.5ml/天）、藤黄氧蒽酮 E5.6mg/只/天组（GEM组，1.5ml/天）、藤黄氧蒽酮 E 11.2mg/只/天组（GEH组，1.5ml/天）、伽升沃D 6.4 mg/只/天组（GDL组，1.5ml/天）、伽升沃D 12.8 mg/只/天组（GDM组，1.5ml/天）、伽升沃D 25.6 mg/只/天组（GDH组，1.5ml/天）。其中藤黄氧蒽酮 E及伽升沃D加入0.9%NaCl中灌胃。各组连续给药12天。
最后1天给药完成后3小时，按照文献报道的方法评价各组大鼠关节炎指数（李培培, 等. 大鼠佐剂性关节炎模型表现特征及评价指标[J]. 国免疫学杂志2012年第28卷）。评分完毕眼球采血、分离血清，加入磷酸盐缓冲液稀释后采用ELISA试剂盒测定血清cAMP浓度(pmol/mL)。组间单因素方差分析比较显示，GEH、GDH组关节炎指数与NS组相比显著降低（表3），组间非参数检验显示，GEH、GDH组血清cAMP浓度与NS组相比显著升高。
表3 各组大鼠关节炎指数和血清cAMP浓度
*：p<0.01, vs NS 组。
以上制剂和动物研究虽然是少数实施例，但不影响本领域人员在实施例基础上进行简单变换，如辅料和用量变换。基于cAMP调控作用也可用于其他多种自身免疫性疾病。在本发明的基本技术下，上述变换应视为本发明的保护范围。
Claims (1)
1.一种氧蒽酮类物质在制备缓解自身免疫性疾病的药物中的用途，其特征在于，所述氧蒽酮类物质为藤黄氧蒽酮 E，所述自身免疫性疾病选自系统性红斑狼疮、自身免疫性脑脊髓炎、类风湿关节炎中的一种。
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