CN109999021A - 去乙酰佛司可林在制备预防和治疗哮喘药物中的应用 - Google Patents
去乙酰佛司可林在制备预防和治疗哮喘药物中的应用 Download PDFInfo
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Abstract
本发明属于医药技术领域，具体公开了去乙酰佛司可林(DFSK)在制备预防和治疗哮喘的药物或保健品中的用途。DFSK是从药用植物毛喉鞘蕊花中分离到的二萜类化合物，具有较好的成药性质。本发明采用卵清白蛋白(OVA)诱导建立哮喘大鼠模型，DFSK灌胃给药后可明显改善哮喘大鼠肺组织的病理损伤，显著延长大鼠引喘潜伏期，明显改善哮喘大鼠的肺功能。实验结果证明DFSK具有作为预防和治疗哮喘的药物新用途。
Description
技术领域
本发明属于肺部疾病的治疗药物领域，尤其涉及一种二萜类化合物--去乙酰佛司可林在制备预防和治疗哮喘的药物或保健品中的应用。
背景技术
哮喘(asthma)是由多种细胞和细胞组分参与的气道慢性炎症性疾病。这种慢性炎症导致气道高反应性的产生，通常出现广泛多变的可逆性气流受限，并引起反复发作的喘息、气急、胸闷或咳嗽等症状。哮喘的发病机制较为复杂，辅助性T细胞的应答、气道炎症细胞因子的分泌、各种触发因素、遗传因素、氧化应激等都有参与其中。哮喘患者的发病率在逐渐增加，全球患者的数量已超过3亿。气道炎症和气道重塑是哮喘的两个重要特征。目前治疗哮喘的临床用药主要有吸入型糖皮质激素、β2受体激动剂、白三烯调节剂等。这些药物仅改善哮喘症状，不能治愈，而且长期服用还会出现副作用。
去乙酰佛司可林(deacetylforskolin，DFSK)是从药用植物毛喉鞘蕊花(Coleusforskolin)中提取分离得到的二萜类化合物，其结构式如下式所示：
DFSK为佛司可林(FSK)的衍生物，体外实验研究证明其具有激动腺苷酸环化酶(AC)的作用(Yang WM,et al.Chin Ophthal Res.2001,19(1):1-4.)。目前，尚未见文献报道DFSK具有预防和治疗哮喘的功效及其在治疗哮喘药物中的应用。
发明内容
本发明的目的在于提供一种二萜类化合物去乙酰佛司可林(DFSK)在制备预防和治疗哮喘的药物或保健品中的应用。所述药物包括去乙酰佛司可林以及药学上可接受的载体。可以为口服剂、注射剂或吸入剂。
本发明在卵清白蛋白(OVA)诱导大鼠哮喘模型上，通过口服灌胃给药DFSK进行实验研究，证明DFSK对具有制备预防和治疗哮喘药物的用途。
在过敏性哮喘大鼠模型上，与模型组比较，DFSK(1、2mg/kg)组气管管腔内的黏液分泌明显减少，炎性细胞较少，明显改善了过敏性哮喘大鼠肺组织的病理状况。用1％OVA末次雾化激发引喘后，DFSK(1、2mg/kg)组与模型组比较，其引喘潜伏期显著增加(P<0.05)。清醒动物肺功能检测结果显示，与模型组比较，DFSK(1、2mg/kg)组的50％呼气流速(EF50)、呼吸频率(F)均显著升高(P<0.05)。麻醉动物肺功能检测结果显示，DFSK(2mg/kg)组的0.3秒用力呼气量(FEV0.3)与模型组比较显著升高(P<0.05)。结果表明DFSK可明显减轻OVA诱导的大鼠哮喘模型的肺组织病理损伤、增加引喘潜伏期、改善大鼠的肺功能。
本发明通过OVA诱导建立大鼠哮喘模型，口服灌胃给药DFSK证明其对大鼠哮喘模型具有很好的干预作用，可用于制备预防和治疗哮喘的药物及保健品。
附图说明
图1：本发明实施例2中DFSK对OVA诱导的大鼠哮喘模型肺组织形态结构的影响(HE染色,×200)。A：正常组(control)、B：模型组(model)、C：STL 2mg/kg组、D：DFSK 1mg/kg组、E：DFSK 2mg/kg组。
图2：本发明实施例2中DFSK对OVA诱导哮喘大鼠引喘潜伏期的影响。组间比较采用单因素方差分析(One Way Analysis of Variance)，P<0.05差异有统计学意义。与正常对照组比较，###P<0.001；与模型组比较，*P<0.05。
图3：本发明实施例2中DFSK对OVA诱导的大鼠哮喘模型清醒动物肺功能指标(EF50、F)的影响。组间比较采用双因素方差分析(Two Way Analysis of Variance)，P<0.05差异有统计学意义。与正常对照组比较，##P<0.01；与模型组比较，**P<0.01。
图4：本发明实施例2中DFSK对OVA诱导的大鼠哮喘模型麻醉动物肺功能指标FEV0.3的影响。组间比较采用单因素方差分析(One Way Analysis of Variance)，P<0.05差异有统计学意义。与正常对照组比较，#P<0.05；与模型组比较，*P<0.05。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明作进一步详细的说明。但本发明的保护范围不受具体实施例的任何限制，而是由权利要求加以限定。
实施例1DFSK的制备
DFSK的制备参考文献中毛喉鞘蕊花化学成分的提取分离方法进行(汪亚勤.毛喉鞘蕊花的化学成分及其提取物的含量测定[D].复旦大学，2009.)。
(1)取10kg滇产毛喉鞘蕊花(Coleus forskohlii)干品，在室温下用50升95％乙醇(ethanol)提取3次，提取液经减压浓缩得到乙醇提取物，提取物加入少量水拌匀后，依次用乙酸乙酯、正丁醇萃取，减压浓缩后，得到各自的提取物。
(2)取乙酸乙酯提取物上硅胶柱，用递增比例的石油醚-乙酸乙酯梯度洗脱，以薄层层析TLC监测洗脱结果，得到有效部位CF-E。有效部位CF-E再经过反复硅胶柱层析、RP-C18柱层析、凝胶柱层析、重结晶纯化，可以获得毛喉鞘蕊花的纯粹的单体成分DFSK。
(3)将DFSK加入淀粉或相应的辅料，混匀后制粒，压制成片剂或胶囊等口服制剂，或者加入其他辅料制成口服液、喷雾气雾剂、贴膏剂等，或者加入注射溶媒及其他辅料等制成注射剂。
实施例2在OVA诱导大鼠哮喘模型上，DFSK对哮喘防治作用的实验研究
1、实验方法
(1)大鼠哮喘模型的建立
SD雄性大鼠按体重分为正常组，模型组，沙丁胺醇(STL，2mg/kg)阳性对照组、DFSK1mg/kg剂量组、DFSK 2mg/kg剂量组。于实验开始的第1天和第8天，除正常组外，其余各组大鼠按1mL/只腹腔注射抗原液(含10mg OVA，100mg Al(OH)3)以初次致敏，正常组大鼠注射等量生理盐水。在OVA初次致敏第11天后，各受试药处理组按照10mL/kg灌胃给药。在初次致敏第14天后，采用1％OVA对大鼠进行雾化激发引喘，每天一次，每次20min，连续激发5周。
(2)清醒动物肺功能评价
在OVA激发引喘的5周中，每周测定大鼠清醒状态肺功能。采用Emka清醒式肺功能检测系统新建检测四只大鼠肺功能的模式，然后加载命名之后校正腔体，再对应动物编号分别放入动物，待动物在腔体内平静5-10min后，检测大鼠的呼吸频率(F)、50％的呼气流速(EF50)等肺功能指标，数据由软件自动导出用于分析处理。
(3)麻醉动物肺功能测定
在OVA激发引喘5周后，末次测定动物引喘潜伏期后，用10％水合氯醛(3.5mL/kg)腹腔注射麻醉大鼠，并在麻醉状态下暴露出大鼠的气管，用不锈钢气管针插管，腹腔注射肌松剂维库溴铵(6mg/kg)，使用FlexiVent FX4震荡式肺功能仪测定大鼠的0.3秒用力呼气量(FEV0.3)等肺功能指标，由flexiWare软件自动导出数据用于分析处理。
(4)大鼠引喘潜伏期测定
大鼠OVA雾化激发引喘5周后，测定大鼠的引喘潜伏期。除正常组采用生理盐水雾化激发外，其余各组采用1％OVA雾化激发引喘。观察大鼠的引喘反应，包括皮肤瘙痒、烦躁不安、呼吸急促、腹式呼吸明显等症状，记录从雾化开始到动物出现引喘反应的时间为引喘潜伏期。
(5)肺病理组织学分析
肺功能检测结束后处死大鼠，取大鼠左肺组织放入4％多聚甲醛溶液中固定24小时以上；脱水透明：用由低浓度到高浓度的酒精作脱水剂，逐渐脱去组织块中的水分。再将组织块置于透明剂二甲苯中透明，以二甲苯替换出组织块的中酒精；浸蜡包埋：将已透明的组织块放入已溶化的石蜡中，放入溶蜡箱保温。待石蜡完全浸入组织块后进行包埋，包埋后方可进行切片、烤片操作。HE染色制片：切片经环保脱蜡液脱蜡，酒精100％-95％-75％洗净环保脱蜡液至流水冲洗，然后过苏木素3-5分钟，流水冲洗后入1％的盐酸酒精分化后水洗(洗掉多余未与细胞核结合的苏木素)，1％氨水返蓝后水洗，放入伊红染色10-20秒，流水冲洗后放入75％-95％-100％酒精浓度低到高脱水，吹干后放入环保脱蜡液中透明，最后用中性树脂封片。显微镜下观察病理组织学变化。
2、实验结果
(1)DFSK对OVA诱导哮喘大鼠肺组织病理形态学的影响
结果如图1所示。正常组支气管腔内无异物，管腔结构无明显病理改变；模型组支气管黏膜上皮杯状细胞增多，支气管腔中有大量脱落崩解的上皮细胞和黏液成分，黏液中见—夏科莱登结晶(嗜酸性粒细胞崩解产物)，黏液腺增生及平滑肌肥大，基底膜增厚，黏膜水肿，黏膜下层及基层见嗜酸性粒细胞，单核细胞等炎性细胞浸润；与模型组比较，DFSK1mg/kg组可见支气管腔内有大量脱落崩解的上皮细胞和黏液，炎性细胞较少，DFSK 2mg/kg组支气管腔内无异物，结构无明显病理改变；STL 2mg/kg组支气管管腔内有大量脱落崩解的上皮细胞和黏液成分，黏膜下层及基层见嗜酸性粒细胞，单核细胞及炎性细胞，支气管管壁黏膜腺增生，平滑肌肥大，基底膜增厚。提示DFSK抑制大鼠支气管管腔中黏液成分和炎性细胞分泌，改善哮喘大鼠的病理状况，对哮喘有一定的拮抗作用。
(2)DFSK对OVA诱导哮喘大鼠引喘潜伏期的影响
结果如表1和图2所示。用1％OVA末次雾化激发引喘后，与正常组比较，模型组大鼠引喘潜伏期显著降低(P<0.001)；与Model组比较，DFSK(1、2mg/kg)以及STL(2mg/kg)组引喘潜伏期显著延长(P<0.05)。
表1.DFSK对OVA诱导哮喘大鼠引喘潜伏期的影响(Mean±SEM)
组间比较采用单因素方差分析(One Way Analysis of Variance)，P<0.05差异有统计学意义。与正常对照组比较，###P<0.001；与模型组比较，*P<0.05。
(3)DFSK对OVA诱导哮喘大鼠清醒动物肺功能的影响
如图3所示，与正常组比较，模型组大鼠的50％呼气流速(EF50)和呼吸频率(F)均显著降低(P<0.01)。与模型组比较，STL 2mg/kg组的EF50和F显著升高(P<0.01)，DFSK 1mg/kg组的EF50显著升高(P<0.01)，DFSK 2mg/kg组的EF50和F均显著升高(P<0.01)。结果表明DFSK能提高哮喘大鼠的EF50和F，对OVA诱导的哮喘大鼠肺功能有一定的保护作用。
(4)DFSK对OVA诱导哮喘大鼠麻醉动物肺功能的影响
结果如图4所示。与正常组比较，OVA诱导的哮喘大鼠0.3秒用力呼气量(FEV0.3)显著降低(P<0.05)。与模型组比较，STL 2mg/kg组和DFSK 1mg/kg组的FEV0.3有升高趋势，DFSK2mg/kg组的FEV0.3显著升高(P<0.05)。结果表明一定剂量的DFSK能提高哮喘大鼠的肺通气功能。
Claims (3)
1.去乙酰佛司可林在制备预防和治疗哮喘的药物或保健品中的应用，所述去乙酰佛司可林的结构如下所示：
2.如权利要求1所述的应用，其特征在于所述药物包括去乙酰佛司可林以及药学上可接受的载体。
3.如权利要求1所述的应用，其特征在于所述药物为口服剂、注射剂或吸入剂。
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