CN109999015A - 紫草素在制备预防或治疗房颤药物中的用途 - Google Patents
紫草素在制备预防或治疗房颤药物中的用途 Download PDFInfo
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- CN109999015A CN109999015A CN201910333383.7A CN201910333383A CN109999015A CN 109999015 A CN109999015 A CN 109999015A CN 201910333383 A CN201910333383 A CN 201910333383A CN 109999015 A CN109999015 A CN 109999015A
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- alkannin
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Abstract
本发明属于生物医药领域，具体涉及紫草素在制备预防或治疗房颤药物或保健品中的用途；具体表现为紫草素能浓度依赖地抑制心房特异表达的Ikur/hKv1.5钾离子通道，可作为Ikur/hKv1.5钾通道阻滞剂；对Ach‑Cacl2诱导的房颤大鼠起到保护作用。本发明为目前紫草素的应用提供了一种全新的选择，具有新的临床应用前景。
Description
技术领域
本发明属于生物医药领域，具体涉及紫草素在制备预防或治疗房颤药物中的用途。
背景技术
心房颤动(Atrial Fibrillation，AF)简称房颤，是临床常见的一种以心房不能规律收缩，代之以一连串快速而不规则的肌纤维蠕动样运动的房性心律失常。房颤发生时，患者心率增加，心输出量减少，表现为心慌、气短、胸闷、胸痛、运动耐力减低等症状。严重时，甚至诱发心房内血栓脱落，心功能衰竭，具有很高的致死率和致残风险。最新的流行病学调查指出，全球房颤患者人数已超过3.35亿，占世界总人口的0.5％，患者数量还逐年增加约5％。房颤患病率及发病率随年龄增高而上升，我国年龄低于60岁的人群中男性患病率0.43％，女性患病率0.44％；而在年龄大于60岁的人群中，男女患病率分别猛增至1.83％和1.92％。可以预见，随着我国人口老龄化，房颤患者将越来越多，这不仅给有限的医疗资源带来极大的消耗，也给患者和家庭带来沉重的负担。目前，房颤的临床治疗不理想，研发新型高效的房颤治疗药物是当前世界医学界的迫切需求。
抗心律失常药物是房颤治疗的最重要方法。目前用于转复房颤的药物多以选择或非选择性阻滞Ikr/HERG钾通道为主的III类抗心律失常药物。然而，由于Ikr/HERG在心房心室的分布无差异，造成这类药物在延长心房有效不应期的同时还明显延长了心室肌的有效不应期和Q-T间期，有促进恶心室性心律失常的不良作用。这也使得钾通道HERG已成为筛选可能引起长Q-T综合症副作用的关键膜通道靶标。一些临床常见的HERG通道抑制剂类药物如索他洛尔曾被报道会增加冠心病患者的死亡率；多非利特有3.3％的概率导致严重的尖端扭转性室速。胺碘酮是临床上房颤患者普遍使用的药物，能有效转复心房颤动，降低患者死亡率，但长期使用会导致患者Q-T间期延长的不良反应风险。因此，开发具有心房选择性的新型房颤药物是当前房颤治疗领域的研究热点。
Ikur是人心房肌细胞的主要外向电流之一，在心房肌细胞的复极化过程中起着重要作用。hKv1.5或称KCNA5基因所编码的钾离子通道蛋白是构成人心房肌Ikur电流的编码基因。人类心脏中，hKv1.5通道蛋白丰富，不均匀表达在心房肌细胞表面，高密度表达于润盘区，而未在心室肌细胞发现。Ikur人心房特异性表达使其成为研究心房颤动治疗药物的新型靶点。研究指出，Ikur的减弱会引起APD和ERP的延长，拮抗心房颤动。最新报道指出新近合成的小分子药物AVE0118，S9947和S20951对Ikur具有高度特异性阻滞作用，在犬、猪、羊等载体动物实验中静脉注射这些Ikur选择性阻滞剂均可有选择性延长心房有效不应期，降低房颤诱发率，并对心室的电生理活动无显著影响。跨国制药公司也积极合成并筛选这类药物。维纳卡兰(Vernakalant)于2010年开始作为心房颤动治疗药物，是目前临床上唯一使用的Ikur/hKv1.5通道特异性阻滞剂，治疗心房颤动效果优于胺碘酮，能有效终止心脏手术后新发的心房颤动，其对Ikur/hKv1.5钾通道的半效抑制浓度约13μM。
中药紫草始载于《神农本草经》，为紫草科植物软紫草、紫草、黄华软紫草的根，是药典记载的临床常用中药。紫草素(英文名称：Shikonin)是传统中药紫草中提取的一种有效的萘醌类化合物，其分子式为C16H16O5。证实具有抗炎、抗肿瘤、促进伤口愈合、抗病毒、抗血栓、抗氧化、降血糖等多种生物学活性。目前，紫草素对心血管系统疾病保护作用已被关注，报道指出紫草素可以通过抑制纤维化、抗凋亡、抗炎等分子机制削弱心肌损伤。但是目前，紫草素在房颤中的作用及机制尚无研究报道。
发明内容
本发明的目的在于提供紫草素在生物医药领域的新用途。
本发明公开了紫草素在制备Ikur/hKv1.5钾通道阻滞剂中用途。
本发明公开了紫草素在制备预防或治疗房颤的药物或保健品中用途。
其中，所述药物或保健品可包含紫草素及药学上可接受的载体(辅料)混合制成的各种剂型，用于制备预防或/和治疗房颤的药物。
其中，所述紫草素可为人工合成。
其中，所述药学上可接受的载体(辅料)可包括离子交换材料、氧化铝、硬脂酸铝、卵磷脂、自乳化药物传递系统(SEDDS)如d-维生素E聚乙二醇1000琥珀酸酯、吐温或其他类似聚合介质等药物制剂用的表面活性剂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、氨基乙酸、山梨酸、山梨酸钾、饱和植物脂肪酸部分甘油酯混合、水、盐、电解质如硫酸盐精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、硅酸镁等。聚乙烯吡咯酮、纤维素物质、聚乙烯醇、羧甲基纤维素钠、聚丙烯酸酯、乙烯-聚氧乙烯-嵌段聚合物和羊毛脂、环糊精如α-，β-，γ-环糊精或其经化学修饰的衍生物如2-和3-羟丙基-β-环糊精等羟烷基环糊精及其可溶性衍生物。
其中，所述药物或保健品可进一步包含药用辅料，包括填充剂(如无水乳糖、淀粉、乳糖珠粒和葡萄糖)、粘合剂(如微晶纤维素)、崩解剂(如交联羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素和交联PVP)、润滑剂(如硬脂酸镁)、吸收促进剂、香味剂、甜味剂、稀释剂、赋形剂、润湿剂、溶剂、增溶剂和着色剂等。
其中，所述药物或保健品的给药制剂可包括溶剂、栓剂、片剂、注射剂、霜剂、软膏剂、贴剂、喷雾剂等。
其中，所述药物或保健品的给药途径可包括皮下、皮内、动脉内、静脉内、肌内、关节内、滑液内、胸骨内、鞘内、病灶内、颅内注射或输注，口服、局部、直肠、经鼻、经颊、阴道、舌下、皮内、粘膜、气管、尿道给药，通过吸入气雾、植入蓄积及针刺方式，优选依据个体情况给药。
其中，所述紫草素可与其它药物联合给药。
其中，所述紫草素可作用于预防或治疗房颤。
本发明的实施例
(1)对Ikur/hKv1.5通道抑制活性的鉴定：将稳定表达hKv1.5钾通道的CHO细胞株培养于F12培养基，添加10％胎牛血清及400μg/ml的G418。待细胞生长覆盖瓶壁70％～80％时，0.25％胰蛋白酶消化轻柔吹打收集单细胞悬液。全细胞模式下记录灌流不同浓度紫草素后的Ikur电流，统计分析药物对Ikur电流的抑制效果。我们发现，紫草素对hKv1.5/Ikur电流有显著抑制作用且呈剂量依赖性。
(2)对房颤大鼠的疗效鉴定：对本发明中建立的房颤大鼠施用紫草素预处理，经实验验证发现本发明涉及的紫草素能够显著对房颤动物的电重构、结构重构水平起到显著改善作用，起预防或/和治疗房颤的作用。
对比现有技术，本发明涉及的紫草素有如下有益效果：本发明涉及的紫草素能够有效抑制心房特异表达的Ikur/hKv1.5钾通道活性，起到预防或/和治疗房颤的作用。可以拓展、开发紫草素的临床新应用，亦可为当前治疗心房颤动提供更多选择。
附图说明
图1采用全细胞膜片钳技术灌流Control和50μM紫草素作用稳定表达hKv1.5基因的CHO细胞3分钟后记录获得的原始电流代表图以及外液洗脱后的电流代表图。
图2为Clamfit软件统计不同浓度紫草素作用Ikur/hKv1.5通道的药物阻断百分比，其计算公式为：E＝1-Idrug/Icon。其中，Icon是对照条件下的峰电流，Idrug是给药条件下的峰电流。Hill方程拟合药物的正态化的剂量-效应关系曲线。
数值结果用means±SEM表示。采用Sigmaplot(SPSS，Chicago)软件进行非线性曲线拟合。
图3房颤大鼠尾静脉给予生理盐水或联合4mg/kg紫草素腹腔注射预处理后给予Ach-Cacl2同时记录得到的典型心电图。
图4为各组大鼠尾静脉给予Ach-Cacl2或生理盐水后诱发出房颤所需的时间统计图。
图5为各组大鼠尾静脉给予Ach-Cacl2或生理盐水后房颤持续时间统计图。
图6为实验末各组大鼠心房组织透射电镜代表图。
图7为实验末各组大鼠血清炎症因子IL-6水平。
数值结果用means±SEM表示。统计比较使用Student’s t test分析。其中，“*”相比对照组具有显著性差异，0.01<P<0.05；“**”相比对照组具有显著性差异，P<0.01；“#”相比模型组具有显著性差异，0.01<P<0.05；“##”相比模型组具有显著性差异，P<0.01。
具体实施方式
下面结合实施例对本发明作进一步说明。所举实施例是为了更好地对本发明的内容进行说明，但并不是本发明的内容仅限于所举实施例。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。
为了使本领域的技术人员更好的理解本发明的技术方案，下面结合具体实施例对本发明作进一步的详细说明。
实施例紫草素对稳定表达于CHO细胞的Ikur/hKv1.5通道影响。
紫草素的准备：紫草素是商品药，采用化学纯度98％或以上的紫草素粉末溶解于DMSO，配置成贮存浓度为10mM的母液。使用前用电生理细胞外液稀释成所需的工作浓度。DMSO终浓度不超过0.1％。
细胞外液成分(mM)：NaCl 140，KCl 4.7，CaCl2 2，MgCl2 1.1，HEPES 10，用NaOH调PH至7.4。
电极内液成分(mM)：NaCl 10，KCl 120，EGTA 1，HEPES 10，MgCl2 1.1，用KOH调节PH至7.2。
将消化后获得的hKv1.5细胞悬液滴入细胞灌流槽，静置10分钟后用细胞外液进行灌流。倒置显微镜下选择形态规则的细胞作为实验对象，使用以下刺激程序：细胞钳制在-80mV，hKv1.5电流由从-80mV至60mV，阶跃10mV，时程为1500ms，采样刺激频率为10000Hz。待记录到的峰电流幅值电流稳定后，灌流给予含不同浓度(0、12.5μM、25μM和50μM)的紫草素3min，在灌流末同时记录电流。Clamfit软件统计药物阻断百分比，Hill方程拟合正态化的剂量-效应曲线，计算药物半效抑制浓度IC50。
实验动物选择雄性SD大鼠，平均体重220g。首先将大鼠随机分成对照组和造模组。其中造模组大鼠尾静脉注射Ach-Cacl2混合液0.1ml/100g(内含CaCl2 5-10mg/mL，Ach 33-66μg/ml)，对照组大鼠同样方法注射等体积生理盐水。第3天，给药同时记录大鼠心电图，剔除造模组中对药物不敏感大鼠。之后将造模组大鼠随机分为模型组和紫草素组。
第4天起，向其中紫草素组大鼠首先腹腔注射相同体积浓度为4mg/kg的紫草素，30min后，对紫草素组和模型组大鼠尾静脉注射Ach-Cacl2。空白组大鼠同等方法注射等体积生理盐水。至第14天，给药同时记录大鼠心电图。实验末大鼠眼眶采血后，3500r/min离心吸取上清，酶联免疫吸附试验法检测大鼠血清IL-6表达变化；之后麻醉取大鼠心脏标本，沿长轴切取心房肌组织浸泡于电镜固定液，制片负染后进行电镜拍照。
实验结果
如图1-b所示，50μM紫草素对hKv1.5电流有明显的抑制作用，可使峰电流幅值减少约51.40％±2.55％(n＝5)，继续灌流细胞外液，hKv1.5电流可洗回(图1-c)。此结果证明紫草素是Ikur/hKv1.5通道的有效抑制剂。
如图2所示，Hill方程拟合不同浓度(0、12.5μM、25μM和50μM)紫草素作用hKv1.5钾通道的抑制百分比，发现紫草素对hKv1.5钾通道的抑制作用呈现浓度依赖性。经计算，紫草素抑制Ikur/hKv1.5钾通道的半数抑制浓度IC50为48.95μM。
如图3所示，各组大鼠尾静脉注射Ach-CaCl2混合液或生理盐水同时记录大鼠心电图发现，空白组给予生理盐水不会造成房颤心电图，模型组注射Ach-Cacl2后，p波消失、代之出现小f波等房颤典型心电图。紫草素预处理同样出现典型房颤心电图，但房颤特征波持续时间均较模型组短。
图4为各组大鼠房颤诱发时间的统计。经统计，紫草素组较模型组延长0.4s诱发出房颤特征心电图，说明紫草素预处理能够降低大鼠诱导房颤发生的敏感程度(p＜0.05)。
图5为各组大鼠房颤持续时间的统计。较模型组相比，紫草素显著缩短了大鼠房颤持续时间(p＜0.01)。
图6为各组大鼠心房组织透射电镜拍摄结果。可见模型组大鼠心房组织肌丝结构紊乱，肌小节结构消失，线粒体排列紊乱，肿胀，基质消失甚至出现空泡样改变。较模型组相比，紫草素预处理组大鼠心房肌肌丝排列整齐、线粒体结构基本正常，具有明显地改善现象。
图7为各组大鼠血清IL-6水平变化。与正常对照组相比，模型组大鼠血清IL-6水平显著增高。与模型组相比，紫草素预处理组对血清IL-6水平改善明显(p＜0.05)。
上述实验结果说明(1)紫草素能够对心房特异表达的Ikur/hKv1.5钾通道具有显著抑制活性，是Ikur/hKv1.5钾通道的有效抑制剂；(2)紫草素对房颤大鼠具有显著保护作用，具体表现为紫草素能够对房颤大鼠心房电重构和结构重构水平起改善作用。包括降低诱发房颤的敏感程度、缩短房颤持续时间、改善心房肌组织超微结构和降低血清炎症因子IL-6的水平。表明紫草素具有预防或/和治疗心房颤动疾病的潜力，可用于进一步制备预防/或治疗房颤的药物或保健品。
以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，在不脱离本发明的精神和范围内，可以对本发明的技术方案进行修改或者等同替换，而脱离本发明技术方案的宗旨和范围，其均应涵盖在本发明的权利要求范围当中。
Claims (2)
1.紫草素在制备预防或治疗房颤的药物或保健品中的用途。
2.紫草素在制备Ikur/hKv1.5钾通道阻滞剂中的用途。
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