CN107865840A - Apigenin在制备治疗慢性阻塞性肺疾病药物中的应用 - Google Patents
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Abstract
本发明公开了Apigenin在制备预防和治疗慢性阻塞性肺疾病的药物中的新的应用。本发明涉及的Apigenin在制备抗慢性阻塞性肺疾病药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于慢性阻塞性肺疾病抑制活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于抗慢性阻塞性肺疾病显然具有显著的进步。
Description
技术领域
本发明涉及化合物Apigenin的新用途，尤其涉及Apigenin在制备治疗慢性阻塞性肺疾病药物中的应用。
背景技术
慢性阻塞性肺疾病(chronic obstructive pulmonary disease，COPD)是一种全球范围内常见的慢性病，目前在全球死亡原因中排名第四，据世界卫生组织预测，到2020年，COPD将在全球疾病发病中排名第五，死亡原因中排名第三。
COPD是一种不完全可逆的气流受限特征的疾病，与肺部对有害气体或有毒颗粒的异常炎症反应有关，其慢性炎症反应遍及气道、肺实质和肺血管。参与COPD的细胞有中性粒细胞、T淋巴细胞和巨噬细胞等炎性细胞，当细胞被激活后释放多种炎性介质，如白三烯B4(LTB4)、白细胞介素8(IL-8)、RANTES、Eotaxin、肿瘤坏死因子α(TNFα)、基质金属蛋白酶9(MMP-9)等，参与肺实质破坏、肺血管等炎症反应。病理变化特征表现为肺泡腔炎性细胞(如巨噬细胞)浸润、小支气管和细支气管周围灶性炎性细胞浸润，肺组织边缘肺泡腔扩张、破坏，肺泡壁变宽，其上皮细胞肿胀、变圆、部分脱落。COPD与慢性支气管炎和肺气肿密切相关，但定义上有所不同，支气管哮喘与特应性变态反应有关，其气流受限具可逆性(与慢性气管炎合并时会出现气流受限不完全可逆)。现在尚无药物能遏制COPD病情的进行性发展，其药物治疗的研究进展相当缓慢，目前临床常常将治疗哮喘的药物用于治疗COPD，由于COPD的发病机制不同于哮喘，难以取得满意的疗效。
本发明涉及的化合物Apigenin是一个2014年发表(Ebenezer de Mello Cruz，etal.,Leishmanicidal activity of Cecropia pachystachya flavonoids:Arginaseinhibition and altered mitochondrial DNA arrangement.Phytochemistry,89(2013)71–77.)的新化合物，该化合物拥有全新的骨架类型(Ebenezer de Mello Cruz，et al.,Leishmanicidal activity of Cecropia pachystachya flavonoids:Arginaseinhibition and altered mitochondrial DNA arrangement.Phytochemistry,89(2013)71–77.)，对于本发明涉及的Apigenin在制备治疗慢性阻塞性肺疾病药物中的用途属于首次公开，由于属于全新的结构类型，而且其对于治疗慢性阻塞性肺疾病活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于慢性阻塞性肺疾病的防治显然具有显著的进步。
发明内容
长期吸烟是最常见的人类COPD致病因素，我们实验室用香烟诱导模拟小鼠COPD模型，拟研究Apigenin对香烟诱导的小鼠COPD的缓解作用。
本发明目的在于提供化合物Apigenin在制备抗COPD疾病药物中的应用。Apigenin在剂量50、100、200mg/kg下灌胃给药，对香烟诱导的COPD小鼠BALF中炎性细胞因子TNFα的生成有抑制作用；对趋化因子RANTES的分泌由抑制作用；对BALF中的炎性细胞(中性粒细胞和巨噬细胞)的募集有抑制作用；对小鼠肺部病理变化有逆转作用。
所述化合物Apigenin结构如式(Ⅰ)所示：
所述Apigenin在制备治疗慢性阻塞性肺疾病药物中的应用，Apigenin对COPD小鼠BALF中TNFα生成有抑制作用。
一种治疗慢性阻塞性肺疾病药物，由Apigenin为活性成分添加辅料制备而成，制备方法为取5克化合物Apigenin,加入糊精195克，混匀，常规压片制成1000片。
一种治疗慢性阻塞性肺疾病药物，由Apigenin为活性成分添加辅料制备而成，制备方法为取5克化合物Apigenin，加入淀粉195克，混匀，装胶囊制成1000粒。
本发明涉及的Apigenin在制备抗慢性阻塞性肺疾病药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于慢性阻塞性肺疾病抑制活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于抗慢性阻塞性肺疾病显然具有显著的进步。
具体实施方式
本发明所涉及化合物Apigenin的制备方法参见文献(Lu Wang，et al.,Asymmetric Synthesis of the Tricyclic Core of Calyciphyll ine A-TypeAlkaloids via Intramolecular[3+2]Cycloaddition.Organic Letters，2014,16,1076-1079.)
以下通过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1：本发明所涉及化合物Apigenin片剂的制备：
取5克化合物Apigenin，加入糊精195克，混匀，常规压片机制成1000片。
实施例2：本发明所涉及化合物Apigenin胶囊剂的制备：
取5克化合物Apigenin，加入淀粉195克，混匀，装胶囊制成1000粒。
下面通过药效学实验来进一步说明其药物活性。
方法：SPF级雌性BALB/c小鼠，18-20g，随机分为正常对照组、模型对照组、阳性对照组(特布他林，10mg/kg，灌胃给药)、药物处理组(Apigenin 5、10、20mg/kg，灌胃给药)，每组10只。将小鼠置于4L容器内，每日烟熏(金健牌香烟，焦油含量小于16mg)，一周五次，连续四周，每日烟熏前1小时灌胃给药.小鼠在末次烟熏后1小时，以苯巴比妥钠麻醉，用0.6mL预冷的PBS缓冲液(pH7.0)肺部灌流，冲洗3次，吸出支气管肺泡灌洗液(BALF)，250×g离心10min，上清用于分析TNFα、RANTES的含量。细胞用PBS缓冲液重悬，计数，细胞涂片后用瑞氏-吉姆萨染色，分析BALF中炎性细胞总数及中性粒细胞、巨噬细胞数量的变化。
实验例1：Apigenin对COPD小鼠支气管肺泡灌洗液(BALF)中炎症介质生成抑制作用(1)Apigenin对COPD小鼠BALF中TNFα生成抑制作用
前炎性细胞因子TNFα是COPD的发病过程中的启动因子。COPD患者的TNFα水平高于正常人，培养的支气管上皮细胞与香烟的烟雾接触可分泌TNFα。TNFα可促使中性粒细胞脱颗粒，诱导起到粘膜细胞增生和高分泌，增加上皮细胞IL-8生成，增加巨噬细胞基质金属蛋白酶生成，促进气道高反应性。本实验目的在于考察Apigenin对COPD小鼠BALF中TNFα生成的影响，结果见表1.
表1Apigenin对COPD小鼠BALF中TNFα生成的影响(n＝10)
与模型对照组比较，**P<0.01*P<0.05，与正常对照组比较，##P<0.01#P<0.05
结果：Apigenin在剂量5、10、20mg/kg下对COPD模型小鼠灌胃给药，可降低小鼠BALF中TNFα的生成。
(2)Apigenin对COPD小鼠BALF中RANTES分泌抑制作用
炎症细胞的迁移受到趋化因子的调节，各种结构细胞核炎性细胞均可分泌这些小分子蛋白，COPD发病过程中RANTES分泌增加，趋化单核/巨噬细胞，T淋巴细胞，嗜酸性细胞。本实验目的在于考察Apigenin对COPD小鼠BALF中RANTES分泌的影响，结果见表2。
表2Apigenin对COPD小鼠BALF中RANTES分泌的影响(n＝10)
与模型对照组比较，**P<0.01*P<0.05，与正常对照组比较，##P<0.01#P<0.05
结果：Apigenin在剂量5、10、20mg/kg下对COPD模型小鼠灌胃给药，可降低小鼠BALF中RANTES的分泌。
实验例2Apigenin对COPD小鼠BALF中炎性细胞募集的抑制作用
(1)Apigenin对COPD小鼠BALF中总炎性细胞募集的抑制作用
COPD以遍及气道、肺实质和肺血管的慢性炎症为特征，这种炎症表现为中性粒细胞、T淋巴细胞和巨噬细胞在肺内增多。激活的炎症细胞释放一系列炎性介质，包括LTB4、IL-8、TNFa和其他能破坏肺结构或维持中性粒细胞炎症的介质。本实验目的在于考察Apigenin对COPD小鼠BALF中总炎性细胞募集的影响，结果见表3。
表3Apigenin对COPD小鼠BALF中总炎性细胞募集的影响(n＝10)
与模型对照组比较，**P<0.01*P<0.05，与正常对照组比较，##P<0.01#P<0.05
结果：Apigenin在剂量5、10、20mg/kg下对COPD模型小鼠灌胃给药，可降低小鼠BALF中总炎性细胞的募集。
(2)Apigenin对COPD小鼠BALF中中性粒细胞募集的抑制作用
中性粒细胞在COPD发病中具有重要作用，它可以释放两种丝氨酸蛋白酶，弹性蛋白酶和半胱氨酰蛋白酶-3，诱导动物产生人类肺气肿样的病理变化。中性粒细胞生命短暂，它循环招募到气道以及穿越间隙腔的过程十分迅速。病理研究证明有些COPD患者支气管组织内中性粒细胞数目增加与气流阻塞的程度有关。吸烟的COPD患者气道内中性粒细胞数目增加，特别是那些伴有慢性支气管炎的患者。影响COPD患者肺内中性粒细胞募集的主要因素为IL-8趋化活性增强。本实验目的在于考察Apigenin对COPD小鼠BALF中中性粒细胞募集的影响，结果见表4。
表4Apigenin对COPD小鼠BALF中中性粒细胞募集的影响(n＝10)
与模型对照组比较，**P<0.01*P<0.05，与正常对照组比较，##P<0.01#P<0.05
结果：Apigenin在剂量5、10、20mg/kg下对COPD模型小鼠灌胃给药，可降低小鼠BALF中中性粒细胞的募集。
(3)Apigenin对COPD小鼠BALF中巨噬细胞募集的抑制作用
吸烟者和COPD患者肺内巨噬细胞较正常人群水平增加，多聚集在肺泡、细支气管和小气道。肺泡壁巨噬细胞数目和轻中度肺气肿以及COPD患者的小气道疾病程度呈正相关。组织病变和损伤部位可见到COPD缓慢进展和慢性病变与巨噬细胞长期增加平行。巨噬细胞可能通过释放基质金属蛋白酶导致弹性组织降解能力异常增高，诱发肺气肿的发生。
本实验目的在于考察Apigenin对COPD小鼠BALF中巨噬细胞募集的影响，结果见表5。
表5Apigenin对COPD小鼠BALF中巨噬细胞募集的影响(n＝10)
与模型对照组比较，**P<0.01*P<0.05，与正常对照组比较，##P<0.01#P<0.05
结果：Apigenin在剂量5、10、20mg/kg下对COPD模型小鼠灌胃给药，可降低小鼠BALF中巨噬细胞的募集。
实验例3Apigenin对COPD小鼠肺部病理变化的逆转作用
对小鼠肺部病理观察可见，模型组肺泡壁变宽，肺泡壁上皮细胞肿胀，变圆，部分脱落，肺泡腔可见巨噬细胞，小支气管和细支气管周围灶性炎性细胞浸润，肺组织边缘肺泡腔扩张。Apigenin组肺泡壁上皮细胞肿胀，肺泡腔可见少量巨噬细胞和粒细胞浸润，未见淋巴细胞浸润，小鼠肺组织未见出血。
结论：Apigenin在剂量5、10、20mg/kg下灌胃给药，对香烟诱导的小鼠慢性阻塞性肺淤血、炎性细胞浸润等有一定的治疗作用。
Claims (4)
1.Apigenin在治疗慢性阻塞性肺疾病药物中的应用，所述化合物Apigenin结构如式(Ⅰ)所示：
2.如权利要求1所述Apigenin在治疗慢性阻塞性肺疾病药物中的应用，其特征在于Apigenin对COPD小鼠BALF中TNFα生成有抑制作用。
3.一种治疗慢性阻塞性肺疾病药物，其特征在于由权利要求1所述Apigenin为活性成分添加辅料制备而成，制备方法为取5克化合物Apigenin,加入糊精195克，混匀，常规压片制成1000片。
4.一种治疗慢性阻塞性肺疾病药物，其特征在于由权利要求1所述Apigenin为活性成分添加辅料制备而成，制备方法为取5克化合物Apigenin，加入淀粉195克，混匀，装胶囊制成1000粒。
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| CN112843044A (zh) * | 2021-01-19 | 2021-05-28 | 天津中医药大学 | 山姜素在制备用于治疗气流受限性肺疾病药物中的应用 |
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| CN108785309A (zh) * | 2018-04-23 | 2018-11-13 | 周静 | 化合物在制备治疗慢性肺病的药物中的用途 |
| CN112843044A (zh) * | 2021-01-19 | 2021-05-28 | 天津中医药大学 | 山姜素在制备用于治疗气流受限性肺疾病药物中的应用 |
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