CN114917212A - 胡黄连素硝酮在制备防治哮喘药物中的用途 - Google Patents
胡黄连素硝酮在制备防治哮喘药物中的用途 Download PDFInfo
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Abstract
本发明属于医药技术领域,具体公开了胡黄连素硝酮在制备防治哮喘药物中的用途。本发明建立OVA诱导的小鼠哮喘动物模型,通过整体动物实验与离体气管实验等研究方法对胡黄连素硝酮的抗炎、抗氧化与舒张气管作用进行研究。试验结果证实,胡黄连素硝酮能明显改善哮喘模型小鼠的肺组织炎症及其所致肺组织损伤、抑制炎症细胞因子的产生,降低肺湿/干重比值与肺通透指数。提高肺组织匀浆中超氧化物歧化酶与谷胱甘肽的水平,降低脂质过氧化产物丙二醛的水平,改善肺部氧化应激状态。降低离体气管平滑肌张力,改善气管痉挛。本发明的胡黄连素硝酮可作为活性成分,与药物学上可接受的载体或赋形剂制备防治哮喘的药物组合物。
Description
本申请为2015年12月16日申请的第201510955782.9号发明专利申请的分案申请。
技术领域
本发明属于医药技术领域,具体涉及胡黄连素硝酮在制备防治哮喘药物中的用途。
背景技术
哮喘(asthma)是一种以多种细胞和细胞因素起作用的慢性气道炎症,是一种由外源蛋白致敏和激发产生过敏性炎症的疾病,常见症状主要有气喘、气短、胸闷、咳嗽等,主要的临床特征包括可逆性的气流阻塞、肺和支气管的高反应性、气道炎症。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。哮喘症状一般在夜间或凌晨发作和加重,患者可在几分钟内发病,发作时严重影响患者的生活质量。患者在哮喘发作时,会出现呼吸急促,严重时还会出现呼吸困难、低血氧症等。哮喘患者的发病率在逐渐增加,全球的数量已超过3亿。
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。如吸入型糖皮质激素虽然具有抗炎和免疫抑制作用,但只能以小剂量进行长期治疗,长期使用会出现水钠潴留,一旦停药后极易出现停药反应。β2受体激动剂可以松弛平滑肌、降低血管通透性、减轻气道粘膜下水肿,缓解哮喘症状,但本类药物没有抑制气道内炎症的作用,而且长期、单一应用β2受体激动剂可造成细胞膜β2受体的下调,出现耐药现象。白三烯调节剂作用不及糖皮质激素,临床上多与糖皮质激素进行联合用药。
近年来,从中药胡黄连提取的活性成分胡黄连素逐渐成为呼吸疾病治疗药物研究的一个热点。胡黄连素(Apocynin),化学名为3-甲氧基-4-羟基-苯乙酮,分子式为C9H10O3,结构如下
胡黄连素是一个非常有效的抗氧化剂和抗炎剂,能选择性抑制人类中性粒细胞活性氧(ROS)释放。胡黄连素可从中药胡黄连的根部分离得到,它也广泛存在于多种植物中。研究发现,胡黄连素在许多涉及氧化应激损伤和炎症反应的疾病中发挥治疗作用,如哮喘、急性肺损伤、关节炎、缺血性脑中风等。
中草药胡黄连早年已用于哮喘与肺损伤的治疗,研究发现其有效成分胡黄连素可抑制TNF-α诱导的人呼吸道上皮细胞产生的多种炎症因子,从而起到抗炎作用(Houser KR,Johnson DK,Ishmael FT.Anti-inflammatory effects of methoxyphenolic compoundson human airway cells[J].Journal of inflammation.2012,9:6.)。对臭氧暴露的轻度哮喘患者,吸入给予胡黄连素可明显缓解气道对乙酰甲胆碱的高反应性及其导致的气道狭窄(Peters EA,Hiltermann JT,Stolk J.Effect of apocynin on ozone-induced airwayhyperresponsiveness to methacholine in asthmatics[J].Free radical biology&medicine.2001,31(11):1442-1447.)。在人II型肺泡上皮细胞(A549)中,胡黄连素可通过增加谷氨酰半胱氨酸合成酶的活性而增加细胞内谷胱甘肽的合成,这一作用部分地与转录因子AP-1的激活有关(Lapperre TS,Jimenez LA,Antonicelli F,Drost EM,Hiemstra PS,Stolk J,MacNee W,Rahman I.Apocynin increases glutathione synthesis andactivates AP-1in alveolar epithelial cells[J].FEBS letters.1999,443(2):235-239.)。胡黄连素还可减轻大鼠在体肺灌流模型中脂多糖诱导的肺损伤,及其所致炎症反应、凋亡和核因子NF-κB的上调与活化(Chian CF,Chiang CH,Yuan-Jung C,Chuang CH,LiuSL,Yi-Han J,Zhang HB,Ryu JH.Apocynin attenuates lipopolysaccharide-inducedlung injury in an isolated and perfused rat lung model[J].Shock.2012,38(2):196-202.)。
研究还发现,胡黄连素可剂量依赖性地减轻BALB/c小鼠的关节炎症状,起到改善浮肿,抑制TNF-α、IL-1β等致炎因子的产生、T细胞介导的免疫反应以及降低血管通透性等作用(Pandey A,Kour K,Bani S,Suri KA,Satti NK,Sharma P,Qazi GN.Amelioration ofadjuvant induced arthritis by apocynin.Phytotherapy Research,2009,23(10):1462-1468.)。腹腔注射胡黄连素能有效降低线栓法造成的SD大鼠脑缺血后的梗死率(TangLL,Ye K,Yang XF,Zheng JS.Apocynin attenuates cerebral infarction aftertransient focal ischaemia in rats.Journal of International MedicalResearch.2007,35(4):517-522.)。
胡黄连素可以通过阻断NADPH氧化酶的亚基,特异性抑制NADPH氧化酶活性,进而抑制其产生超氧阴离子,从而起到清除氧自由基,抑制机体ROS产生的作用。这可改善相关疾病的氧化应激状态与炎症反应等,显示出一定的治疗作用,但胡黄连素的治疗效果通常具有一定的局限性。
本领域技术人员一直致力于胡黄连素的结构修饰与活性研究,设计合成了若干胡黄连素衍生物,专利号为ZL200610037302.1(胡黄连素的衍生物及其制备方法和应用)和专利号为201010185981.3(胡黄连素衍生物及其制备与应用)的专利中设计合成了若干胡黄连素衍生物。
N-叔丁基-α-苯基硝酮(N-tert-Butyl-α-Phenylnitrone,PBN)为一个有效的自由基清除剂和抗氧化剂,常被用来修饰其他化合物以增强其抗氧化性能,所获得的衍生化产物一般可以保持母体的原有效果,又可以增强母体的抗氧化活性。
综上,现有哮喘治疗药物尚有不足之处有待改进,哮喘以慢性炎症为主要治疗目标之一,炎症与氧化应激密切相关,不少研究从抗氧化角度寻找哮喘治疗药物。中药胡黄连的有效成分胡黄连素不但具有抗氧化活性同时具有抗炎作用,但其药效有待提高。
发明内容
本发明的目的是针对现有治疗哮喘药物存在的不足之处,提供一种胡黄连素硝酮在制备防治哮喘药物中的用途。胡黄连素原料易得、来源丰富,与硝酮偶联得到的胡黄连素硝酮显示出抗氧化与抗炎双重作用,具有显著的哮喘防治作用。
本发明目的通过以下技术方案实现:
式(I)所示结构的胡黄连素硝酮在制备防治哮喘药物中的用途,
所述药物是以胡黄连素硝酮为活性成分,加上药学上可接受的载体或赋形剂制备而成的药剂。
本课题组设计合成的化合物经过活性筛选,证明胡黄连素硝酮衍生物的生物活性优于母体化合物胡黄连素。因此,本发明重点研究胡黄连素硝酮衍生物对哮喘的治疗作用。通过研究发现,胡黄连素硝酮减少肺泡灌洗液中炎细胞的数量,抑制肺泡灌洗液中炎症细胞因子的增高,改善肺组织炎症;可降低肺通透指数,减少肺组织湿/干重比值;可减少肺组织中炎细胞的浸润,使肺泡结构有所恢复,水肿情况减轻,可改善哮喘所致肺组织损伤的病理学变化;可提高肺组织匀浆中超氧化物歧化酶活性与谷胱甘肽含量,并减少丙二醛含量,改善肺组织氧化应激状态;还可降低气管平滑肌张力,对气管平滑肌有明显的舒张作用,可缓解气管痉挛。
本发明通过建立卵清蛋白(OVA)诱导的BALB/c小鼠哮喘模型,观察胡黄连素硝酮对哮喘小鼠肺泡灌洗液(BALF)中的炎细胞、细胞因子,肺通透指数(LPI),肺湿/干重比值,肺组织超氧化物歧化酶(SOD)活性,谷胱甘肽(GSH)与丙二醛(MDA)水平的影响;采用HE染色观察胡黄连素硝酮对哮喘小鼠肺组织结构及病理学评分的影响;并考察胡黄连素硝酮对OVA诱导的BALB/c哮喘模型小鼠气管平滑肌张力的影响。从抗炎、抗氧化与改善气道张力等方面共同论证胡黄连素硝酮在制备防治哮喘药物中的用途。
实验结果表明,胡黄连素硝酮能减少肺泡灌洗液中炎细胞数量及细胞因子水平,降低肺通透性,减少肺湿/干重比值,显著改善哮喘小鼠的病理状态。胡黄连素硝酮可提高肺组织匀浆中超氧化物歧化酶活性与谷胱甘肽含量,并减少丙二醛含量,改善肺组织的氧化应激状态。离体气管平滑肌张力实验结果显示,胡黄连素硝酮对OVA诱导的哮喘小鼠的离体气管平滑肌有明显的舒张作用,可缓解气管痉挛。对各组小鼠肺组织切片HE染色后,观察发现胡黄连素硝酮对OVA诱导的哮喘小鼠肺组织炎症细胞浸润与结构损伤具有明显的改善作用。以上结果表明,胡黄连素硝酮对哮喘具有较好的治疗作用,在抗氧化与抗炎方面达到了与阳性对照药地塞米松(2mg/kg)接近甚至更优的效果,对离体气管具有明显的舒张作用,可达到阳性对照药异丙肾上腺素(2mg/kg)作用的62%。
与现有技术相比,本发明具有以下优点及有益效果:
鉴于已有哮喘治疗药物存在的不足之处,以及胡黄连素与硝酮在抗炎、抗氧化与哮喘治疗方面的活性,本发明公开将硝酮修饰到胡黄连素上所得到的衍生物——胡黄连素硝酮在制备防治哮喘药物中的用途。通过将硝酮与胡黄连素结构结合起来,使所公开的胡黄连素硝酮同时具有胡黄连素和硝酮基的结构,从而能同时发挥胡黄连素的抗炎、抗氧化作用,并通过硝酮基结合进一步增强抗氧化作用。所公开的胡黄连素硝酮在制备防治哮喘药物中的用途,从哮喘的根本症状——长期慢性炎症的治疗入手,有望获得更具优势的哮喘治疗药物,弥补现有治疗药物的不足。
本发明通过公开胡黄连素硝酮对哮喘的药效评价,公开了胡黄连素硝酮在制备防治哮喘药物中的用途,发现其同时具有抗炎、抗氧化作用,可减轻气管痉挛状态,且疗效优于母体化合物胡黄连素,在一些抗氧化与抗炎指标上,接近甚至超过阳性对照药物地塞米松。
附图说明
图1胡黄连素硝酮对OVA诱导的哮喘模型小鼠肺泡灌洗液中炎细胞数量的影响(n=11;###P<0.001,模型组与对照组相比;**P<0.01,***P<0.001,治疗组与模型组相比)。
图2胡黄连素硝酮对OVA诱导的哮喘模型小鼠肺泡灌洗液中肿瘤坏死因子α、白介素4、白介素13含量的影响(n=11;###P<0.001,模型组与对照组相比;***P<0.001,治疗组与模型组相比)。
图3胡黄连素硝酮对OVA诱导的哮喘模型小鼠肺湿/干重比值、肺通透指数的影响(n=11;###P<0.001,模型组与对照组相比;**P<0.01,***P<0.001,治疗组与模型组相比)。
图4胡黄连素硝酮对OVA诱导的哮喘模型小鼠肺组织病理学变化及病理学评分的影响(HE,×20倍;n=5;##P<0.01,模型组与对照组相比;*P<0.05,**P<0.01,治疗组与模型组相比)。
图5胡黄连素硝酮对OVA诱导的哮喘模型小鼠肺组织匀浆中谷胱甘肽、超氧化物歧化酶、丙二醛水平的影响(n=11;###P<0.001,模型组与对照组相比;**P<0.01,***P<0.001,治疗组与模型组相比)。
图6胡黄连素硝酮对OVA诱导的哮喘模型小鼠离体气管的舒张作用(n=11;###P<0.001,模型组与对照组相比;***P<0.001,治疗组与模型组相比)。
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例1
雌性BALB/c小鼠,体重20-25g,6-8周龄,随机分为正常对照组,OVA模型组,胡黄连素(Apo)组,胡黄连素硝酮(AN-1)低、中、高剂量组,阳性药物地塞米松(Dex)组,每组11只。置于23±2℃,照明时间为12h/天环境中,动物适应环境一周后开始实验。实验第一天开始,除正常对照组外,各组动物均腹腔注射含有卵清蛋白(OVA)10μg、氢氧化铝1mg的磷酸盐缓冲液(PBS)200μl,间隔7天一次,持续3周,正常对照组以等体积PBS代替。第21天开始,除正常对照组外,将各组小鼠置于透明密闭容器内,予激发液(含有20g/L OVA的PBS)雾化激发,一天一次,一次30min,持续3天,正常对照组以PBS代替激发液。在每次激发步骤前1小时,各组均以腹腔注射方式给药。阳性药物组给予地塞米松(2mg/kg),胡黄连素组给予胡黄连素27mg/kg,胡黄连素硝酮低、中、高剂量组分别给予胡黄连素硝酮21.5mg/kg、43mg/kg、86mg/kg,正常对照组和模型组给予同等体积的PBS,持续3天。对各组小鼠肺泡灌洗液(BALF)中炎细胞进行计数,采用ELISA法检测BALF中炎症细胞因子的含量,测定肺组织湿/干重比值、肺通透指数(LPI),将肺组织切片进行组织病理学检查,以评价胡黄连素硝酮对哮喘所致小鼠肺组织炎症的治疗作用。
胡黄连素硝酮可以显著改善肺组织炎症,具体实验结果如下:
(1)以正常对照组小鼠为基准,模型组哮喘小鼠BALF中的嗜酸性粒细胞、中性粒细胞与淋巴细胞这三种炎细胞数量均剧增。所述的胡黄连素硝酮对哮喘小鼠BALF的炎细胞数量增加具有明显的抑制作用,结果如图1所示。与模型组相比,阳性药物组小鼠炎细胞数量显著减少,经胡黄连素硝酮治疗的哮喘小鼠BALF中炎细胞数量随剂量变化呈不同程度的下降,效果均具有极显著性差异(P<0.001)。胡黄连素硝酮组的效果优于母体化合物胡黄连素组。
(2)与正常对照组小鼠相比,模型组哮喘小鼠BALF中的肿瘤坏死因子α(TNF-α)、白介素4(IL-4)、白介素13(IL-13)的含量均明显增加。阳性药物组与胡黄连素硝酮治疗组哮喘小鼠BALF中的TNF-α、IL-4、IL-13水平值均较模型组明显下降,有极显著性差异(P<0.001)。胡黄连素硝酮减少小鼠肺组织炎症因子的作用显著优于胡黄连素(P<0.01或0.001)),且中、高剂量组的作用与阳性药物地塞米松效果无显著性差异,结果如图2所示。
(3)胡黄连素硝酮各组小鼠肺湿/干重比值测定结果显示,模型组小鼠的湿/干重比值较正常对照组显著增大。经胡黄连素硝酮治疗后,小鼠肺湿/干重比值较模型组明显减小,说明肺组织含水量减小,水肿程度减轻,结果如图3所示。胡黄连素硝酮效果与母体化合物无显著性差异,且三个剂量组的效果与阳性药物组也无显著性差异。
(4)模型组肺通透指数大大增加,为正常对照组的4.9倍。与模型组相比,阳性药物组肺通透指数减少43%,胡黄连素硝酮治疗组LPI减少17%-33%。所述的胡黄连素硝酮在高剂量下可以很好地减小肺通透指数,降低OVA所致血管的通透性增高,结果如图3所示。胡黄连素硝酮高剂量组与模型组相比有极显著性差异(P<0.01),与阳性药物组无显著性差异。
(5)组织病理学检查结果显示,正常对照组的肺组织未见炎细胞、肺泡结构正常,模型组小鼠肺组织出现大量炎细胞浸润,肺泡出血、肺泡壁增厚、结构被破坏,支气管粘膜水肿。经胡黄连素、胡黄连素硝酮和地塞米松干预后,炎症情况均有所改善,肺泡结构有所恢复,水肿情况减轻,而且减轻程度按照胡黄连素组<胡黄连素硝酮低剂量组<胡黄连素硝酮中剂量组<胡黄连素硝酮高剂量组<阳性药物地塞米松组的顺序递增,病理学评分也呈递减趋势,结果见图4。与模型组相比,胡黄连素硝酮的中、高剂量组的病理学评分显著降低(P<0.01或0.001)。胡黄连素硝酮组的病理学评分明显低于母体化合物组(P<0.05),其高剂量组改善肺组织病理变化的作用与阳性药物组无显著性差异。
实施例2
雌性BALB/c小鼠,体重20-25g,6-8周龄,随机分为正常对照组,OVA模型组,胡黄连素(Apo)组,胡黄连素硝酮(AN-1)低、中、高剂量组,阳性药物地塞米松(Dex)组,每组11只。置于23±2℃,照明时间为12h/天环境中,动物适应环境一周后开始实验。实验第一天开始,除正常对照组外,各组动物均腹腔注射含有卵清蛋白(OVA)10μg、氢氧化铝1mg的磷酸盐缓冲液(PBS)200μl,间隔7天一次,持续3周,正常对照组以等体积PBS代替。第21天开始,除正常对照组外,将各组小鼠置于透明密闭容器内,予激发液(含有20g/L OVA的PBS)雾化激发,一天一次,一次30min,持续3天,正常对照组以PBS代替激发液。在每次激发步骤前1小时,各组均以腹腔注射方式给药。阳性药物组给予地塞米松(2mg/kg),胡黄连素组给予胡黄连素27mg/kg,胡黄连素硝酮低、中、高剂量组分别给予胡黄连素硝酮21.5mg/kg、43mg/kg、86mg/kg,正常对照组和模型组给予同等体积的PBS,持续3天。采用试剂盒检测肺组织中超氧化物歧化酶(SOD)、谷胱甘肽(GSH)和丙二醛(MDA)的水平,以评价胡黄连素硝酮对哮喘引起的氧化损伤的治疗作用。
与正常对照组比较,哮喘模型组小鼠肺组织匀浆中SOD、GSH活性显著下降,MDA水平增加。与模型组相比,阳性药物组小鼠SOD与GSH水平上升,MDA水平下降,经胡黄连素硝酮治疗的哮喘小鼠SOD活性和GSH水平提高,MDA水平降低,均有极显著性差异(P<0.001)。结果提示,胡黄连素硝酮能逆转哮喘模型小鼠肺组织内GSH、SOD水平的下降和MDA水平的升高,有效改善小鼠肺内氧化应激效应,以增加对哮喘的疗效,结果如图5所示。胡黄连素硝酮增加GSH和SOD的作用明显优于母体化合物(P<0.01);且各剂量组的作用均显著优于阳性对照药物(P<0.001)。胡黄连素硝酮降低MDA的能力与母体化合物无显著性差异;低、中剂量组的作用弱于阳性对照药物,高剂量时与阳性对照药物无显著性差异。
实施例3
雌性BALB/c小鼠,体重20-25g,6-8周龄,随机分为正常对照组,OVA模型组,胡黄连素(Apo)组,胡黄连素硝酮(AN-1)低、中、高剂量组,阳性药物异丙肾上腺素组,每组11只。置于23±2℃,照明时间为12h/天环境中,动物适应环境一周后开始实验。实验第一天开始,除正常对照组外,各组动物均腹腔注射含有卵清蛋白(OVA)10μg、氢氧化铝1mg的磷酸盐缓冲液(PBS)200μl,间隔7天一次,持续3周,正常对照组以等体积PBS代替。第21天开始,除正常对照组外,将各组小鼠置于透明密闭容器内,予激发液(含有20g/L OVA的PBS)雾化激发,一天一次,一次30min,持续3天,正常对照组以PBS代替激发液。在每次激发步骤前1小时,各组均以腹腔注射方式给药。阳性药物组给予异丙肾上腺素(2mg/kg),胡黄连素组给予胡黄连素27mg/kg,胡黄连素硝酮低、中、高剂量组分别给予胡黄连素硝酮21.5mg/kg、43mg/kg、86mg/kg,正常对照组和模型组给予同等体积的PBS,持续3天。剥离气管测定离体气管平滑肌的张力,考察各种药物治疗对哮喘小鼠离体气管平滑肌收缩的影响。
将离体气管条置于通有95%O2、5%CO2的克-亨氏营养液中,固定于浴槽与肌张力换能器之间,待离体气管条平衡后,加入OVA刺激,模型组小鼠的离体气管平滑肌张力平均值为3.401±0.096g,与正常对照组(3.176±0.072g)相比显著升高(P<0.001)。与模型组相比,胡黄连素硝酮低、中、高剂量组离体气管的平滑肌张力明显降低,张力平均值均低于2.5g,高剂量组张力最低至2.312±0.096g。所述的胡黄连素硝酮可以明显减小离体气管张力,减轻气管痉挛,缓解哮喘症状,结果见图6。胡黄连素硝酮的作用与母体化合物无显著性差异,三个剂量的效果均低于阳性药物异丙肾上腺素(1.659±0.032g)。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
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