CN109288835A - 化合物在制备治疗急性肺栓塞的药物中的应用 - Google Patents
化合物在制备治疗急性肺栓塞的药物中的应用 Download PDFInfo
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- CN109288835A CN109288835A CN201810898901.5A CN201810898901A CN109288835A CN 109288835 A CN109288835 A CN 109288835A CN 201810898901 A CN201810898901 A CN 201810898901A CN 109288835 A CN109288835 A CN 109288835A
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Classifications
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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Abstract
本发明发现原苏木素A和/或原苏木素B在制备预防和/或治疗急性肺栓塞的组合物中的应用前景。本发明还提供原苏木素A和/或原苏木素B在制备预防和/或治疗由急性肺栓塞导致的急慢性并发症的药物中的应用。
Description
技术领域
本发明涉及原苏木素A和/或原苏木素B在制备预防和/或治疗急性肺栓塞的组合物中的应用。
背景技术
肺栓塞是内源性或外源性栓子堵塞肺动脉及其分支引起急性肺循环障碍的临床和病理生理综合征,以肺循环和呼吸功能障碍为主要临床和病理特征。该病具有起病急骤,临床表现多样,易误诊和漏诊,死亡率高的特点。目前,对急性肺栓塞治疗主要集中在抗凝、溶栓、介入和手术治疗等手段。因此,开发具有治疗急性肺栓塞的新型药物,特别是口服制剂具有十分重大的意义。
原苏木素A和原苏木素B,是源于苏木(Sappan Lignum)的天然化合物,具体是从豆科植物苏木(Caesalpinia Sappan L.)的干燥心材中提取的,具体结构参加下述通式(I),当Q为羰基时为原苏木素A,当Q为图示的特定二羟基取代乙基时为原苏木素B。迄今尚未见到原苏木素A和/或原苏木素B对肺栓塞的作用报道。
发明内容
本发明的发明人经过系统的药理试验,表明原苏木素A和/或原苏木素B能够显著缓解血栓引起的大鼠急性肺栓塞,降低大鼠呼吸频率,降低肺脏器指数,同时改善栓塞所致的肺部组织损伤,且活性作用呈剂量依赖性关系,从而发现原苏木素A和/或原苏木素B在预防和/或治疗急性肺栓塞方面具有很好的生物活性,有望用于制备相应的药物或者保健品,从而完成了本发明。
具体而言,本发明提供了如下的技术方案:
本发明的原苏木素A和/或原苏木素B在制备预防和/或治疗急性肺栓塞的药物或保健品中的应用,优选将原苏木素A和/或原苏木素B为主要活性成分来制备。具体而言,所述主要活性成分是指原苏木素A和/或原苏木素B在药物活性成分中的重量比例大于50%,优选大于70%,进一步优选大于90%。
本发明中的,预防和/或治疗急性肺栓塞,很重要的作用是指,在肺栓塞后减少呼吸频率的增加和/或改善肺功能损伤,在针对这些症状的药物或保健品中可以应用原苏木素A和/或原苏木素B。
一般而言治疗急性肺栓塞的药物或保健品,还可以和选自巴西苏木素、苏木酮A、阿司匹林、华法林、氯吡格雷、噻氯匹定、双嘧达莫中的一种或多种合用。
原苏木素A和/或原苏木素B还可以在制备预防和/或治疗由急性肺栓塞导致的急慢性并发症的药物或保健品中进行应用。原苏木素A和/或原苏木素B同样可以作为这类药物的主要活性成分发挥作用。
急性肺栓塞导致的急慢性并发症主要有肺动脉高压、肺梗死、心肌缺血、心衰竭、休克等。优选的,所述预防和/或治疗由急性肺栓塞导致的急慢性并发症的药物或保健品,这样的药物或保健品还可以和选自巴西苏木素、苏木酮A、阿司匹林、华法林、氯吡格雷、噻氯匹定、双嘧达莫中的一种或多种合用,这样的药物或保健品,还可以包括一种或多种药学上可接受的辅料。
一般而言,本发明中所述的药物或保健品还可以包括一种或多种药学上可接受的辅料。所述治疗急性肺栓塞的药物或保健品可以是口服制剂,也可以是非口服制剂,从患者适应性上考虑优选是口服制剂。
所述口服制剂包括但不限于片剂、胶囊剂、滴丸剂、颗粒剂、粉剂、口腔膜剂和口服液中的类型。所述非口服制剂可以选自注射剂、膏剂、霜剂和栓剂中的一种或多种。
本发明所述药学上可以接受的辅料,包括药学领域常规的溶剂(如水、乙醇、丙二醇、注射用油等)、稀释剂(如淀粉、糖粉、糊精、乳糖、预胶化淀粉、微晶纤维、无机钙盐(如硫酸钙、磷酸氢钙、药用碳酸钙等)、甘露醇等、植物油、聚乙二醇等)、粘合剂(如水、乙醇、淀粉浆、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素和乙基纤维素、羟丙甲纤维素等)、崩解剂(如干淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠等)、润滑剂(如硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇类、月桂醇硫酸镁等)、吸收促进剂(如表面活性剂、Azone(月桂氮卓酮)、EDTA、水杨酸、氨基酸乙胺衍生物、乙酰醋酸酯类、β-二羧酸酯、芳香族酸性化合物、脂肪族酸等)、防腐剂(如苯甲酸、羟丙丁酯、羟丙甲酯、苯酚、间甲酚等)、矫味剂(如蔗糖、甜菊素等)等。
在用于预防和/或治疗急性肺栓塞、在急性肺栓塞后减少呼吸频率的增加和/或改善肺功能损伤、或者预防和/或治疗由急性肺栓塞导致的急慢性并发症时,本发明所述的药物的施用对象为人或哺乳动物。出于此目的,本发明所述药物的摄入的质量或给予的质量,以原苏木素A和/或原苏木素B计,按照成人体重60~70kg计算,通常每人每天摄入120~700mg,更优选的每人每天摄入300~400mg。
附图说明
以下结合附图,对本发明做进一步说明。
图1示出了实施例4中各组受试动物的肺脏HE染色图,其中“sham”组为正常对照组,“model”组为肺栓塞模型组,“PTA(20mg/kg)”组为原苏木素A低剂量组,“PTA(50mg/kg)”组为原苏木素A高剂量组。
图2示出了实施例7中各组受试动物的肺脏HE染色图,其中“sham”组为正常对照组,“model”组为肺栓塞模型组,“PTB(20mg/kg)”组为原苏木素B低剂量组,“PTB(50mg/kg)”组为原苏木素B高剂量组。
具体实施方式
以下参照具体的实施例来说明本发明。本领域技术人员能够理解,这些实施例仅用于说明本发明,其不以任何方式限制本发明的范围。
下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的原料、试剂材料等,如无特殊说明,均为市售购买产品。其中,部分原料、试剂购买情况如下:
苏木药材购自北京同仁堂科技发展股份有限公司;
原苏木素B购自宝鸡辰光生物科技有限公司;试剂纯度为98%。
乙醇、石油醚、乙酸乙酯、正丁醇均为分析纯,购自北京化工厂。
实施例1原苏木素A的分离和鉴定
苏木干燥心材(21kg),切成小细条,依次用8倍、6倍、6倍量95%乙醇回流提取3次,每次1h;提取液减压回收溶剂得95%乙醇提取物,待挥尽溶剂至无醇味后,混悬于水中,依次用石油醚、乙酸乙酯、正丁醇萃取,分别回收溶剂后得石油醚萃取物60g,乙酸乙酯萃取物1400g,正丁醇萃取物360g。
取乙酸乙酯萃取物800g,经硅胶(100~200目)柱色谱,氯仿-甲醇=30:1、20:1、10:1、5:1、1:1梯度洗脱,TLC比对合并后得到Fr.A-Fr.N共14个流份。流份Fr.E经硅胶(200~300目)柱色谱,石油醚-乙酸乙酯(3:1、2:1、1:1),得流份Fr.E-B、Fr.E-C、Fr.E-E、Fr.E-F。流份Fr.E-F经硅胶(200~300目)柱色谱,氯仿-甲醇(25:1、20:1、15:1、10:1、5:1、1:1)梯度洗脱,合并含有原苏木素A的馏分,经重结晶后得原苏木素A(20mg)。
原苏木素A:无色针晶(甲醇),硫酸乙醇显灰褐色。
ESI-MS:m/z 271[M-H]-,273[M+H]+,295[M+Na]+,分子式为C15H12O5。
1H-NMR(500MHz,DMSO-d6)δ:3.31(2H,s,8-H),4.47(2H,s,6-H),6.63(1H,s,12-H),6.64(1H,s,9-H),6.65(IH,d,J=2.5Hz,4-H),6.68(IH,dd,J=2.5,8.0Hz,2-H),7.07(1H,d,J=8.0Hz,1-H)。
13C-NMR(125MHz,DMSO-d6)δ:47.9(C-8),77.5(C-6),107.9(C-4),112.2(C-2),116.5(C-12),116.7(C-9),122.8(C-8a),125.0(C-12b),129.5(C-1),129.5(C-12a),144.2(C-11),144.4(C-10),157.3(C-4a),158.2(C-3),205.3(C-7)。
以上波谱数据与文献报道一致,因此鉴定化合物为原苏木素A。
HPLC色谱条件:
色谱柱:Agilent ZORBAX SB-Aq,5μm,4.6×250mm;
流动相:乙腈-水系统,按下表进行梯度洗脱;
流速:1.0mL/min;
检测波长:210nm;
测定:取上述制备得到的原苏木素A适量,用甲醇溶解,配制成每1mL含有0.2mg的供试品溶液。精密吸取所述供试品溶液10μL,注入色谱仪,梯度洗脱,记录色谱图,经面积归一化法计算,纯度95.0%。
以下的实施例2-4所用的原苏木素A均是按照上述方法制备得到。
实施例2原苏木素A对肺梗塞大鼠肺脏指数的改善作用
2.1受试动物:SD大鼠,8周,雄性,北京维通利华实验动物技术有限公司。
2.2受试药物:
原苏木素A(PTA),溶解于0.5%的CMCNa溶液里配制成5mg/mL的药物溶液。
2.3动物分组及处理:
SD大鼠40只,适应性喂养1周后,每组8只,随机分为5组:sham组(正常对照组)、model组(肺梗塞模型组)、PTA低剂量组(20mg/kg)、PTA高剂量组(50mg/kg)。给药方式为灌胃给药。
除正常对照组外,各组动物均行下述操作:
手术前一天和40分钟前分别按设计灌胃一次,正常对照组和模型组灌胃等量生理盐水。实验期间,均自由饮水和进食。
实验前取大鼠静脉血,凝固后修剪为2mm3血栓块,然后与生理盐水混合备用。将大鼠水合氯醛腹腔注射麻醉后,分离其右颈总静脉,从该颈总静脉注射0.5毫升血栓混悬液。正常对照组从颈总静脉注射生理盐水0.5毫升。各组大鼠分别在栓塞后6h,水合氯醛麻醉,分取肺组织,称重,多聚甲醛固定,并进行后续石蜡包埋和组织病理学分析。
2.4试验结果
表1示出了实施例2中各组受试动物的肺脏指数,其中“sham”组为正常对照组,“model”组为肺栓塞模型组,“PTA(20mg/kg)”组为原苏木素A低剂量组,“PTA(50mg/kg)”组为原苏木素A高剂量组。
具体地,表1示出肺栓塞模型组的肺脏指数相较正常对照组的大鼠均有显著提高,显示造模成功。PTA(原苏木素A)低剂量组(20mg/kg)和高剂量组(50mg/kg)的肺脏指数相较模型组有所降低;PTA(原苏木素A)高剂量组(50mg/kg)的作用效果更佳明显。
各组大鼠的肺脏指数(%),见表1。
表1各组大鼠肺脏指数(平均值±标准差)
注:*表示与肺栓塞模型组比较,P<0.05;#表示与对照组比较,P<0.05。
表1的数据示出:与正常对照组相比,肺栓塞模型组的肺脏指数显著升高(*P<0.05);与肺栓塞模型组比较,PTA低剂量组(20mg/kg)和PTA高剂量组(50mg/kg)组的肺脏指数都显著减少(*P<0.05)。
本实施例的结果说明:
经原苏木素A施与后大鼠能够有效地减少肺栓塞后肺脏指数的增加。证明原苏木素A能够很好地预防或改善肺栓塞引起的肺损伤。
实施例3原苏木素A对肺梗塞大鼠呼吸频率的改善作用
3.1受试动物:SD大鼠,8周,雄性,北京维通利华实验动物技术有限公司。
3.2受试药物:
原苏木素A(PTA),溶解于0.5%的CMCNa溶液里配制成5mg/mL的药物溶液。
3.3动物分组及处理:
SD大鼠40只,适应性喂养1周后,每组8只,随机分为5组:sham组(正常对照组)、model组(肺梗塞模型组)、PTA低剂量组(20mg/kg)、PTA高剂量组(50mg/kg)。给药方式为灌胃给药。
除正常对照组外,各组动物均行下述操作:
手术前一天和40分钟前分别按设计灌胃一次,正常对照组和模型组灌胃等量生理盐水。实验期间,均自由饮水和进食。
实验前取大鼠静脉血,凝固后修剪为2mm3血栓块,然后与生理盐水混合备用。将大鼠水合氯醛腹腔注射麻醉后,分离其右颈总静脉,从该颈总静脉注射0.5毫升血栓混悬液。正常对照组从颈总静脉注射生理盐水0.5毫升。各组大鼠分别在栓塞后6h,测定呼吸频率并分析数据。
3.4试验结果
表2示出了实施例3中各组受试动物的呼吸频率,其中“sham”组为正常对照组,“model”组为肺栓塞模型组,“PTA(20mg/kg)”组为原苏木素A低剂量组,“PTA(50mg/kg)”组为原苏木素A高剂量组。
具体地,表2示出肺栓塞模型组的呼吸频率相较正常对照组的大鼠均有显著提高,显示造模成功。PTA(原苏木素A)低剂量组(20mg/kg)和高剂量组(50mg/kg)的呼吸频率相较模型组有所降低;PTA(原苏木素A)高剂量组(50mg/kg)的作用效果更佳明显。
各组大鼠的呼吸频率,见表2。
表2各组大鼠的呼吸频率(平均值±标准差)
注:*表示与肺栓塞模型组比较,P<0.05;#表示与对照组比较,P<0.05。
表2的数据示出:与正常对照组相比,肺栓塞模型组的呼吸频率显著升高(*P<0.05);与肺栓塞模型组比较,PTA低剂量组(20mg/kg)和PTA高剂量组(50mg/kg)组的呼吸频率都显著降低(*P<0.05)。
本实施例的结果说明:
经原苏木素A施与的大鼠能够有效地减少肺栓塞后呼吸频率的增加。证明原苏木素A能够很好地预防和/或改善肺栓塞引起的肺功能损伤。
实施例4原苏木素A对肺梗塞大鼠肺组织损伤的保护作用
图1的数据示出:正常组肺泡结构完整、无水肿出血坏死;肺栓塞模型组造模后大部分区域结构不清,支气管上皮结构紊乱,梗死区见局部肺泡壁坏死、肺泡腔消失,肺泡出血;PTA低剂量组(20mg/kg)和PTA高剂量组(50mg/kg)组肺泡壁充血减轻,少部分肺泡腔内有红细胞,支气管可见,肺泡腔轮廓尚可见。
本实施例的结果说明:
原苏木素A能够有效地减少肺栓塞后肺组织的充血及结构破坏。证明原苏木素A能够很好地改善肺栓塞引起的肺组织结构完整性。
实施例5原苏木素B对肺梗塞大鼠肺脏指数的改善作用
5.1受试动物:SD大鼠,8周,雄性,北京维通利华实验动物技术有限公司。
5.2受试药物:
原苏木素B(PTB),溶解于0.5%的CMCNa溶液里配制成5mg/mL的药物溶液。
5.3动物分组及处理:
SD大鼠40只,适应性喂养1周后,每组8只,随机分为5组:sham组(正常对照组)、model组(肺梗塞模型组)、PTB低剂量组(20mg/kg)、PTB高剂量组(50mg/kg)。给药方式为灌胃给药。
除正常对照组外,各组动物均行下述操作:
手术前一天和40分钟前分别按设计灌胃一次,正常对照组和模型组灌胃等量生理盐水。实验期间,均自由饮水和进食。
实验前取大鼠静脉血,凝固后修剪为2mm3血栓块,然后与生理盐水混合备用。将大鼠水合氯醛腹腔注射麻醉后,分离其右颈总静脉,从该颈总静脉注射0.5毫升血栓混悬液。正常对照组从颈总静脉注射生理盐水0.5毫升。各组大鼠分别在栓塞后6h,水合氯醛麻醉,分取肺组织,称重,多聚甲醛固定,并进行后续石蜡包埋和组织病理学分析。
5.4试验结果
表3示出了实施例5中各组受试动物的肺脏指数,其中“sham”组为正常对照组,“model”组为肺栓塞模型组,“PTB(20mg/kg)”组为原苏木素B低剂量组,“PTB(50mg/kg)”组为原苏木素B高剂量组。
具体地,表3示出肺栓塞模型组的肺脏指数相较正常对照组的大鼠均有显著提高,显示造模成功。PTB(原苏木素B)低剂量组(20mg/kg)和高剂量组(50mg/kg)的肺脏指数相较模型组有所降低;PTB(原苏木素B)高剂量组(50mg/kg)的作用效果更佳明显。
各组大鼠的肺脏指数(%),见表3。
表3各组大鼠肺脏指数(平均值±标准差)
注:*表示与肺栓塞模型组比较,P<0.05;#表示与对照组比较,P<0.05。
表3的数据示出:与正常对照组相比,肺栓塞模型组的肺脏指数显著升高(*P<0.05);与肺栓塞模型组比较,PTB低剂量组(20mg/kg)和PTB高剂量组(50mg/kg)组的肺脏指数都显著减少(*P<0.05)。
本实施例的结果说明:
经原苏木素B施与的大鼠能够有效地减少肺栓塞后肺脏指数的增加。证明原苏木素B能够很好地预防和/或改善肺栓塞引起的肺损伤。
实施例6原苏木素B对肺梗塞大鼠呼吸频率的改善作用
6.1受试动物:SD大鼠,8周,雄性,北京维通利华实验动物技术有限公司。
6.2受试药物:
原苏木素B(PTB),溶解于0.5%的CMCNa溶液里配制成5mg/mL的药物溶液。
6.3动物分组及处理:
SD大鼠40只,适应性喂养1周后,每组8只,随机分为5组:sham组(正常对照组)、model组(肺梗塞模型组)、PTB低剂量组(20mg/kg)、PTB高剂量组(50mg/kg)。给药方式为灌胃给药。
除正常对照组外,各组动物均行下述操作:
手术前一天和40分钟前分别按设计灌胃一次,正常对照组和模型组灌胃等量生理盐水。实验期间,均自由饮水和进食。
实验前取大鼠静脉血,凝固后修剪为2mm3血栓块,然后与生理盐水混合备用。将大鼠水合氯醛腹腔注射麻醉后,分离其右颈总静脉,从该颈总静脉注射0.5毫升血栓混悬液。正常对照组从颈总静脉注射生理盐水0.5毫升。各组大鼠分别在栓塞后6h,测定呼吸频率并分析数据。
6.4试验结果
表4示出了实施例6中各组受试动物的呼吸频率,其中“sham”组为正常对照组,“model”组为肺栓塞模型组,“PTB(20mg/kg)”组为原苏木素B低剂量组,“PTB(50mg/kg)”组为原苏木素B高剂量组。
具体地,表4示出肺栓塞模型组的呼吸频率相较正常对照组的大鼠均有显著提高,显示造模成功。PTB(原苏木素B)低剂量组(20mg/kg)和高剂量组(50mg/kg)的呼吸频率相较模型组有所降低;PTB(原苏木素B)高剂量组(50mg/kg)的作用效果更佳明显。
各组大鼠的呼吸频率,见表4。
表4各组大鼠的呼吸频率(平均值±标准差)
注:*表示与肺栓塞模型组比较,P<0.05;#表示与对照组比较,P<0.05。
表4的数据示出:与正常对照组相比,肺栓塞模型组的呼吸频率显著升高(*P<0.05);与肺栓塞模型组比较,PTB低剂量组(20mg/kg)和PTB高剂量组(50mg/kg)组的呼吸频率都显著降低(*P<0.05)。
本实施例的结果说明:
经原苏木素B施与的大鼠能够有效地减少肺栓塞后呼吸频率的增加。证明原苏木素B能够很好地预防和/或改善肺栓塞引起的肺功能损伤。
实施例7原苏木素B对肺梗塞大鼠肺组织损伤的保护作用
图2的数据示出:正常组肺泡结构完整、无水肿出血坏死;肺栓塞模型组造模后大部分区域结构不清,支气管上皮结构紊乱,梗死区见局部肺泡壁坏死、肺泡腔消失,肺泡出血;PTB低剂量组(20mg/kg)和PTB高剂量组(50mg/kg)组肺泡壁充血减轻,少部分肺泡腔内有红细胞,支气管可见,肺泡腔轮廓尚可见。
本实施例的结果说明:
经原苏木素B施与的大鼠能够有效地减少肺栓塞后肺组织的充血及结构破坏。证明原苏木素B能够很好地预防和/或改善肺栓塞引起的肺组织结构完整性。
综上实施例说明,原苏木素A和/或原苏木素B在预防和/或临床治疗肺栓塞、以及预防和/或治疗由肺栓塞导致的急慢性并发症、以及在急性肺栓塞后减少呼吸频率的增加和/或改善肺功能损伤等方面,有着非常明确的生物活性,可以用于与预防和/或临床治疗肺栓塞相关的药品或保健品的制造中。
Claims (11)
1.通式(I)所示化合物在制备预防和/或治疗急性肺栓塞的药物或保健品中的应用,
2.根据权利要求1所述的应用,其特征在于,所述药物或保健品还包含选自巴西苏木素、苏木酮A、阿司匹林、华法林、氯吡格雷、噻氯匹定、双嘧达莫中的一种以上物质。
3.根据权利要求1所述的应用,其特征在于,所述药物或保健品还包括一种或多种药学上可接受的辅料。
4.根据权利要求1所述的应用,其特征在于,所述药物或保健品是口服制剂或非口服制剂;
优选的,所述口服制剂选自片剂、胶囊剂、滴丸剂、颗粒剂、粉剂、口腔膜剂和口服液中的一种或多种;
还优选的,所述非口服制剂选自注射剂、膏剂、霜剂和栓剂中的一种或多种。
5.根据权利要求1所述的应用,所述治疗急性肺栓塞的药物用于急性肺栓塞后减少呼吸频率的增加和/或改善肺功能损伤。
6.通式(I)所示化合物在制备预防和/或治疗由急性肺栓塞导致的急慢性并发症的药物或保健品中的应用,
7.根据权利要求6所述的应用,其特征在于,所述急性肺栓塞导致的急慢性并发症为选自肺动脉高压、肺梗死、心肌缺血、心衰竭、休克中的一种或多种。
8.根据权利要求6所述的应用,其特征在于,所述预防和/或治疗由急性肺栓塞导致的急慢性并发症的药物或保健品,还包含选自巴西苏木素、苏木酮A、阿司匹林、华法林、氯吡格雷、噻氯匹定、双嘧达莫中的一种或多种。
9.根据权利要求6所述的应用,其特征在于,所述预防和/或治疗由急性肺栓塞导致的急慢性并发症的药物还包括一种或多种药学上可接受的辅料。
10.根据权利要求6所述的应用,其特征在于,所述预防和/或治疗由急性肺栓塞导致的急慢性并发症的组合物是口服制剂或非口服制剂;
优选的,所述口服制剂可以选自片剂、胶囊剂、滴丸剂、颗粒剂、粉剂、口腔膜剂和口服液中的一种或多种;
还优选的,所述非口服制剂可以选自注射剂、膏剂、霜剂和栓剂中的一种或多种。
11.一种用于治疗急性肺栓塞的药物或保健品,其包含通式(I)所示化合物,
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