CN116392462A - 毛兰素在制备治疗肺动脉高压的药物中的应用 - Google Patents
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Abstract
本发明涉及生物医药技术领域，具体涉及毛兰素在制备治疗肺动脉高压的药物中的应用。经毛兰素治疗后，低氧及低氧联合Sugen5416小鼠的RVSP、RV/BW、RV/(S+LV)、WA％、WT％、PAVTI、PAT明显改善，由此得出毛兰素可以治疗低氧及低氧联合Sugen5416诱导的肺动脉高压。本发明开发了毛兰素新的用途，使毛兰素得到了更好的应用；并为肺动脉高压治疗提供新的药物研究方向，具有很好的应用前景。
Description
技术领域
本发明涉及生物医药技术领域，具体涉及毛兰素在制备治疗肺动脉高压的药物中的应用。
背景技术
肺动脉高压(pulmonary hypertension，PH)是一种进展性疾病，其可导致肺血管阻力和肺血管压力的进行性升高，从而发展为右心室肥厚，心力衰
竭甚至死亡。PH的诊断标准为海平面、静息状态下，经右心导管检查法测定的肺动脉平均压(mean pulmonary artery pressure，mPAP)≥25mmHg，正常成年人静息状态下mPAP为其上限不超过20mmHg。低氧性肺动脉高压（hypoxia pulmonary hypertension，HPH）属于PH中的第3类，即慢性缺氧/肺部疾病引起的肺动脉高压。HPH的形成包括低氧性肺血管收缩反应和肺血管重塑两个主要发病环节。基本病理特征涉及内皮细胞、平滑肌细胞和细胞外基质的改变，表现为血管平滑肌细胞增殖肥大、内皮细胞功能紊乱和细胞外基质沉积等。现肺动脉高压（PH）在临床上尚无根治的治疗方法，一些肺血管扩张剂，如内皮素受体拮抗剂、磷酸二酯酶5抑制剂等，虽然短期能够降低肺动脉高压，长期应用不但不会改善通气血流比值，甚至会加重右心室阻力，增加死亡率。
毛兰素(2-甲氧基-5-[2-(3，4，5-三甲氧基-苯基)-乙基]-苯酚)是一种低分子量的天然产物，主要分离提取自铁皮石斛和鼓槌石斛。此外毛兰素还存在于金钗石斛、球花石斛、流苏石斛中。除了天然来源，目前毛兰素也可通过化学合成获得。毛兰素分子式为C18H22O5，分子量为318.36，属于联苄衍生物。目前毛兰素研究范围不广，主要集中在肿瘤性疾病，炎性疾病和内分泌疾病中的糖尿病相关疾病，其更多的治疗作用和治疗机制有待进一步研究。
发明内容
本发明的目的是为了克服现有技术存在的缺点和不足，而提供一种毛兰素在制备治疗肺动脉高压的药物中的应用。
为实现上述目的，本发明的第一个方面是提供毛兰素在制备治疗肺动脉高压的药物中的应用。
优选的，所述肺动脉高压为低氧及低氧联合Sugen5416诱导形成的肺动脉高压。
优选的，所述药物用于改善肺动脉压力。
优选的，所述药物用于改善血管重塑。
本发明的第二个方面是提供一种用于治疗肺动脉高压的药物组合物，其含有如上所述的毛兰素或其药学上可接受的盐。
如本文所用，“药学上可接受的”的成分是适用于人和/或哺乳动物而无过度不良副反应(如毒性)的，即具有合理的效益/风险比的物质。合适的盐是本领域普通技术人员所熟知的。
优选的，所述毛兰素或其药学上可接受的盐作为其中一种药用活性成分。
优选的，药物的给药形式包括胶囊剂、片剂、粉剂、粒剂、糖浆或类似剂型形式的口服给药，或通过注射、软膏、栓剂或类似剂型的非口服给药。这些药物制剂可通过使用本领域熟知的辅助剂，如粘合剂，赋形剂，稳定剂，崩解剂，矫味剂，润滑剂等等以普通方法生成，也可以制备为控释给药剂型、缓释给药剂型、各种微粒给药系统。
优选的，药物的给药形式为胶囊剂、片剂、粉剂、粒剂、糖浆或类似剂型形式的口服给药，所述药物中毛兰素或其药学上可接受的盐正常给药为每天总剂量1-1000mg。虽然剂量随症状和病人的年龄，疾病或失调的性质及严重性和给药的途径和方式而变，但对成年病人口服给药的情况来说，毛兰素或其药学上可接受的盐正常给药为每天总剂量1至1000mg，可以为单剂量或者为分剂量形式给药；例如每日一次、二次或三次。
优选的，所述药物中毛兰素或其药学上可接受的盐正常给药为每天总剂量20-800mg。
优选的，所述药物中毛兰素或其药学上可接受的盐正常给药为每天总剂量50-600mg。
本发明的有益效果如下：本发明开发了毛兰素新的用途，使毛兰素得到了更好的应用；并为肺动脉高压治疗提供新的药物研究方向，具有很好的应用前景。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前提下，根据这些附图获得其他的附图仍属于本发明的范畴。
图1为毛兰素的天然来源-铁皮石斛和毛兰素的化学结构式；
图2为本发明实施例中六组小鼠右心室收缩压、富尔顿指数及右心体重比的变化图；
图3为本发明实施例中六组小鼠右心室超声心动图及结果分析图；
图4为本发明实施例中六组小鼠HE染色及统计图；
图5为本发明实施例中六组小鼠α-SM-actin免疫组化结果图；
图2-4中，*：P<0.05； ** ：P<0.01；*** ：P<0.001； **** ：P<0.0001。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将结合附图对本发明作进一步地详细描述。
如图1所示为毛兰素的天然来源-铁皮石斛和毛兰素的化学结构式。
本实施例通过体外实验对毛兰素在制备治疗肺动脉高压的药物中应用的可行性进行验证。
实施例1、低氧肺动脉高压（HPH）小鼠模型的建立
取成年健康C57BL/6小鼠72只，每组12只，分组如下：常氧组1、低氧组、低氧+毛兰素（10mg/kg）给药组、常氧组2、低氧+Sugen5416组、低氧+Sugen5416+毛兰素（10 mg/kg）给药组。除常氧对照组外，其余各组均放置于低氧氧舱中进行造模，通过调控系统调整氮气和空气的进气量，制造稳定的低氧环境（舱内氧气浓度9%-11%，湿度50%-70%，温度20℃-26℃）。常氧组和低氧组小鼠接受相同的光照条件和饮食供给。对于毛兰素给药组老鼠，每天早上入舱前根据体重腹腔注射相应量毛兰素（10mg/kg），对照组腹腔注射对应量的生理盐水。每天 24 小时持续低氧，共持续3周。3周后，将所有小鼠麻醉并进行有创血流动力学测量，然后收集小鼠肺等组织进行进一步研究。
实施例2、毛兰素对HPH高压模型小鼠肺动脉压力的影响
低氧肺动脉高压模型小鼠造模3周后，通过血流动力学及右心室重构评估发现，毛兰素可明显降低低氧肺动脉高压小鼠模型的右心室收缩压（RVSP）（图2A）,同时发现毛兰素可降低低氧肺动脉高压模型小鼠RV/WT和RV/（S+LV）比率（图2B）。同时我们通过小动物心超发现毛兰素可以逆转低氧肺动脉高压模型小鼠PAVTI、PAT、PAT/PET等右心功能指标的降低（图3AB）。上述结果证明了毛兰素可以缓解低氧肺动脉高压模型小鼠的肺动脉压力。
实施例3、毛兰素对HPH模型小鼠肺血管组织形态学的变化的影响
低氧肺动脉高压模型小鼠造模3周后，通过对肺组织切片进行H&E 染色、免疫组化染色等病理研究发现，毛兰素显著减弱了低氧肺动脉高压模型小鼠的肺动脉肌化（图4），降低了低氧肺动脉高压模型小鼠的肺动脉管壁骨架蛋白α-SM-actin 表达量（图5）。上述结果证明了毛兰素可以缓解肺动脉高压模型大小鼠的血管重塑。
综合上述结果，经毛兰素治疗后，低氧及低氧联合Sugen5416小鼠的RVSP、RV/BW、RV/(S+LV)、WA％、WT％、PAVTI、PAT明显改善，由此得出毛兰素可以治疗低氧及低氧联合Sugen5416诱导的肺动脉高压。
Claims (10)
1.毛兰素在制备治疗肺动脉高压的药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述肺动脉高压为低氧及低氧联合Sugen5416诱导形成的肺动脉高压。
3.根据权利要求1或2所述的应用，其特征在于：所述药物用于改善肺动脉压力。
4.根据权利要求1或2所述的应用，其特征在于：所述药物用于改善血管重塑。
5.一种用于治疗肺动脉高压的药物组合物，其含有如权利要求1所述的毛兰素或其药学上可接受的盐。
6.根据权利要求5所述的药物组合物，其特征在于：所述毛兰素或其药学上可接受的盐作为其中一种药用活性成分。
7.根据权利要求5或6所述的药物组合物，其特征在于：药物的给药形式包括胶囊剂、片剂、粉剂、粒剂、糖浆或类似剂型形式的口服给药，或通过注射、软膏、栓剂或类似剂型的非口服给药。
8.根据权利要求7所述的药物组合物，其特征在于：药物的给药形式为胶囊剂、片剂、粉剂、粒剂、糖浆或类似剂型形式的口服给药，所述药物中毛兰素或其药学上可接受的盐正常给药为每天总剂量1-1000mg。
9.根据权利要求8所述的药物组合物，其特征在于：所述药物中毛兰素或其药学上可接受的盐正常给药为每天总剂量20-800mg。
10.根据权利要求8所述的药物组合物，其特征在于：所述药物中毛兰素或其药学上可接受的盐正常给药为每天总剂量50-600mg。
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