WO2022206250A1 - 生物碱化合物在制备预防和/或治疗心脏损伤的产品中的用途 - Google Patents
生物碱化合物在制备预防和/或治疗心脏损伤的产品中的用途 Download PDFInfo
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- WO2022206250A1 WO2022206250A1 PCT/CN2022/078277 CN2022078277W WO2022206250A1 WO 2022206250 A1 WO2022206250 A1 WO 2022206250A1 CN 2022078277 W CN2022078277 W CN 2022078277W WO 2022206250 A1 WO2022206250 A1 WO 2022206250A1
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- alkaloid compound
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to the field of medical use of alkaloid compounds, in particular to the use of an alkaloid compound in the preparation of products for preventing and/or treating heart damage.
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- Health & Medical Sciences (AREA)
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- Cardiology (AREA)
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Abstract
本发明公开了一种生物碱化合物在制备预防和/或治疗心脏损伤的产品中的用途，对该生物碱化合物进行了活性研究，验证了本发明提供的生物碱化合物能够抑制心肌毒性作用诱导的细胞凋亡，通过下调p-JNK和/或Cleaved-Caspase-3的表达水平实现抑制蒽环类药物DOX诱导的心肌细胞凋亡，从而缓解心肌细胞毒性作用，实现预防和/或治疗心肌细胞毒性的效果，可用于制备预防和/或治疗心肌损伤相关疾病的药物。
Description
本发明涉及生物碱化合物的医药用途领域，具体涉及一种生物碱化合物在制备预防和/或治疗心脏损伤的产品中的用途。
沙棘(拉丁学名：Hippophae rhamnoides Linn.)，是一种胡颓子科、沙棘属落叶性灌木，其特性是耐旱、抗风沙，可以在盐碱化土地上生存，因此被广泛用于水土保持。中国西北部大量种植沙棘，用于沙漠绿化。
沙棘营养丰富，多种维生素、黄酮类化合物、三萜类化合物、油和脂肪酸、酚类、挥发油类、微量元素、磷脂类、5-羟色胺等活性物质和人体所需的各种氨基酸和蛋白质。
沙棘种籽常用来榨油制成沙棘油，沙棘油中含有206种对人体有益的活性物质，其中有46种生物活性物质，含有大量的维生素E、维生素A、黄酮等。榨油后会产生大量的沙棘籽粕，往往会被当作废料丢弃，或生产成干粉当作饲料，价格非常低廉。倘若能更多的开发出沙棘籽粕的利用价值，将具有极大的经济意义。
另外，沙棘中含有的丰富活性物质，仍有许多未被分离、鉴定，若能对沙棘中新的化学成分及其药理作用进行更加深入、细微的研究与活性机制探讨，则有望开发出更多可治疗疾病且安全有效的天然植物来源药物。
发明内容
目前，许多药物在治疗过程中会带来心肌毒性的副作用，尤其是在恶性肿瘤的化学疗法中，所使用的细胞抑制剂会引起严重的心脏毒性，对患者的预后和康复产生了不良影响。
据报道，蒽环类药物普遍具有心脏毒性，此类药物由于具有较好的抗肿瘤活性，在临床中被广泛应用。蒽环类药物包括多柔比星、柔红霉素、阿克拉霉素、表柔比星、吡柔比星、伊达比星和米托蒽醌等，其中多柔比星(曾用名阿霉素)是临床上常用的广谱抗肿瘤药物之一，在治疗恶性肿瘤方面都取得了很好的疗效，自60年代初以来被广泛地应用于实体瘤、白血病、淋巴瘤、乳腺癌等肿瘤治疗，对心肌组织具有较高亲和力，其抗肿瘤的主要作用机制是其蒽环平面可以 直接嵌入DNA碱基对之间，干扰转录过程，阻止mRNA的合成既抑制DNA的合成又抑制RNA的合成，因此对细胞周期各阶段均有作用，属于细胞周期非特异性药物，但它的蓄积和剂量依赖性的心肌细胞毒性是从药物研发到临床用途以来一直困扰肿瘤治疗实践的主要问题，表现在其治疗剂量大于550mg/m
2时诱发充血性心力衰竭发病率高达11％～30％，而致死率高达50％～60％。阿霉素所致心肌病的机制并不同于其抗肿瘤的作用机制，但其确切机制至今仍不完全明了。然而，许多研究表明阿霉素可致心肌细胞氧化应激、钙超载、线粒体损伤，抑制心肌细胞特异性基因表达等，从而诱导心肌细胞凋亡、坏死、心肌纤维化，降低心肌收缩力，并最终导致心室重塑和充血性心力衰竭。
因此，开发能够减少心脏毒性物质对心脏的损伤、抗心脏毒性的物质具有重要的意义。
针对上述问题，本发明提供从沙棘籽粕中提取得到的生物碱天然化合物Ⅰ(4-[(E)-p-coumaroylamino]butan-1-ol)在制备治疗和/或预防心脏损伤的产品中的用途，所述化合物Ⅰ能够用于预防和/或治疗心脏损伤，通过下调p-JNK和/或Cleaved-Caspase-3的表达水平实现抑制蒽环类药物DOX诱导的心肌细胞凋亡，缓解心肌细胞毒性作用，从而实现预防和/或治疗心肌细胞毒性的效果，可用于制备预防和/或治疗心肌损伤相关疾病的产品。
本发明提供的生物碱化合物Ⅰ在制备预防和/或治疗心脏损伤的产品中的用途，所述化合物Ⅰ的结构式如下：
进一步地，所述心脏损伤选自心肌毒性和/或心肌细胞凋亡。
本发明用途中所述的心脏损伤是蒽环类药物所致；
进一步地，所述蒽环类药物选自多柔比星、柔红霉素、阿克拉霉素、表柔比星、吡柔比星、伊达比星、米托蒽醌的一种或几种，优选为多柔比星。
进一步地，所述产品为延缓和/或抑制心肌细胞凋亡的产品。
进一步地，所述产品为下调Cleaved-Caspase-3和/或p-JNK表达水平的产品。
进一步地，所述产品为Cleaved-Caspase-3抑制剂和/或p-JNK抑制剂。
所述Cleaved-Caspase-3抑制剂是指可以使体内Cleaved-Caspase-3含量降低的产品；所述p-JNK抑制剂是指可以使体内p-JNK含量降低的产品。
进一步地，所述产品的剂型选自片剂、颗粒剂、胶囊剂、栓剂、丸剂、溶液、混悬剂，优选片剂、溶液；进一步地，所述溶液选自注射液。
进一步地，在本发明的具体实施方式中，所述片剂的原料中，每250mg片剂包括如下重量份组分：化合物Ⅰ5～20份、乳糖100～200份、淀粉10～25份、微晶纤维素50～80份、硬脂酸镁1～10份、滑石粉1～10份；进一步为化合物Ⅰ10份、乳糖150份、淀粉15份、微晶纤维素65份、硬脂酸镁5、滑石粉5份。
进一步地，在本发明的具体实施方式中，所述溶液的原料中，每毫升溶液包括如下重量份组分：化合物Ⅰ0.2～1份、葡萄糖30～70份、氯化钠6～12份、水900～1000份；进一步为化合物Ⅰ0.5份、葡萄糖50份、氯化钠9份、水940.5份。
本发明还提供了一种生物碱化合物Ⅰ与蒽环类药物在制备抗肿瘤的联合用药中的用途。
本发明所述的生物碱化合物Ⅰ可与药学上可接受的辅料制成联合制剂，在使用具有心脏毒性副作用的药物的治疗期间同时、分开或分阶段使用。本发明所述联合用药，可以是将生物碱化合物Ⅰ与蒽环类药物混合制备成单一的复方制剂，也可以是将生物碱化合物Ⅰ与蒽环类药物分别制备成两种制剂，再组合。分别制成两种制剂时，生物碱化合物Ⅰ与蒽环类药物的两种制剂可以同时施用或独立施用。所述独立施用时两种制剂施用的次数和顺序不限，包括但不限于可以是先施用生物碱化合物Ⅰ，间隔一段时间后施用蒽环类药物制剂；或者先施用蒽环类药物制剂，间隔一段时间后施用生物碱化合物Ⅰ制剂；或先施用生物碱化合物Ⅰ制剂，间隔一段时间后施用蒽环类药物制剂，间隔一段时间后再施用生物碱化合物Ⅰ制剂。
本发明具有如下有益效果：
本发明对从沙棘籽粕中提取到的生物碱化合物Ⅰ进行活性研究，结果表明，本发明生物碱化合物Ⅰ能够抑制多柔比星(DOX)引起的心肌细胞毒性作用，并通过下调p-JNK/Cleaved-Caspase-3表达水平实现抑制DOX诱导心肌细胞凋 亡，从而抑制多柔比星(DOX)引起的心肌细胞毒性，可用于制备预防和/或治疗心脏毒性物质所引起的心脏损伤的产品。
图1为生物碱化合物Ⅰ对H9c2心肌细胞的毒性影响；
图2为生物碱化合物Ⅰ对DOX诱导H9c2心肌细胞毒性的影响；
图3为生物碱化合物Ⅰ对DOX诱导的H9c2心肌细胞Caspase-3活化的影响；
图4为生物碱化合物Ⅰ对DOX诱导的H9c2心肌细胞p-JNK/JNK的影响。
其中，图3和图4中SJ-1为生物碱化合物Ⅰ；与Con组相比，#P<0.05，##P<0.01，###P<0.001；与DOX模型组相比，*P<0.05，**P<0.01，***P<0.001；Mean±SD,n＝3。
下面对本发明的技术方案进行清楚、完整的描述，显然，所描述的实施例是本发明的一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明实施例中的实验方法，如无特殊说明，均为常规方法，所用的试验材料，如无特殊说明，均为自常规生化试剂公司购买得到，实施例中所涉及的数据均为平均值。
本发明所述生物碱化合物Ⅰ的结构式如下：
实施例1 化合物Ⅰ对H9c2心肌毒性模型中心肌细胞凋亡的抑制作用试验
1.生物碱化合物Ⅰ对H9c2心肌细胞的毒性影响
将H9c2细胞用不同浓度(0.1μM、1μM、5μM、10μM、20μM、40μM、80μM、160μM)的生物碱化合物Ⅰ孵育24h后，采用MTT比色法评价生物碱化合物对心肌细胞的毒性影响。
2.生物碱化合物Ⅰ对DOX诱导H9c2心肌细胞毒性的影响
(1)预先用生物碱化合物Ⅰ孵育H9c2细胞1h，再加入2.5μM的多柔比星(DOX)培养24h后，采用MTT比色法筛选生物碱化合物Ⅰ对DOX诱导心肌细胞凋亡活性，并确定最佳作用浓度范围。
(2)将不同受试沙棘生物碱作用H9c2心肌细胞1h后，用2.5μM的DOX处理24h后提取蛋白质，裂解、刮取、收集细胞裂解液，12000g离心15min，收集上清液弃沉淀，-80℃保存，并采用BCA法对蛋白定量，备用；SDS-PAGE电泳(Step1：80V，30min；Step2：120V，180min)，5％浓缩胶；转膜，PVDF膜，30min，80mA；封闭及杂交，5％脱脂奶粉封闭1h，一抗孵育过夜，二抗室温轻摇孵育1～2h；显影，ECL试剂显影，凝胶成像系统观察细胞内Caspase-3和p-JNK/JNK蛋白表达情况。
测试结果如图1所示，吲哚生物碱化合物Ⅰ在一定浓度范围内与Con组相比无统计学差异(0.1～40μM)，但当其达到80μM时，与Con组相比具有显著性差异性，说明超过在此浓度可能会对H9c2细胞活力产生一定毒性作用。
图2结果表明，不同浓度范围的生物碱化合物Ⅰ组与DOX模型组相比较均表现出抑制DOX诱导心肌细胞毒性，且呈现一定的浓度依赖性，浓度在5～80μM范围内与模型组相比具有显著差异性或极显著差异性。
如图3结果表明，DOX模型组与Con组相比能够极显著增加Cleaved-Caspase-3表达水平，生物碱化合物Ⅰ低、中、高剂量组(10μM、20μM和40μM)与DOX模型组相比，均能不同程度地降低由DOX引起的Cleaved-Caspase-3水平升高，且存在明显的浓度依赖性关系。
如图4结果表明，DOX模型组与Con组相比能够极显著增加p-JNK表达水平。生物碱化合物低剂量组(10μM)与DOX模型组的p-JNK表达水平不存在统计学差异，但是中剂量组(20μM)和高剂量组(40μM)具有极显著差异性，且存在明显的浓度依赖性关系。由此说明，生物碱化合物可以下调DOX诱导的心肌细胞凋亡模型中p-JNK表达水平，结合其对Cleaved-Caspase-3表达水平的影响分析可知，本发明提供的生物碱化合物可以下调p-JNK/Cleaved-Caspase-3表达水平实现抑制DOX诱导心肌细胞凋亡而缓解心肌细胞毒性作用。
综上所述，通过给药测试物质，本发明生物碱化合物Ⅰ可明显抑制心肌毒性作用诱导的细胞凋亡，并涉及下调p-JNK/Cleaved-Caspase-3表达水平实现预防 和/或治疗效果。
本发明生物碱化合物Ⅰ适于用作哺乳动物，特别是人体的药物，能够用于预防和/或治疗心脏中毒剂量的药物所产生的损伤影响和/或其他化学物质引起的心脏损伤状况，特别是心脏的衰退和改变，如蒽环类药物的心肌毒性、心肌纤维化等。
本发明生物碱化合物Ⅰ可作为药物，特别是心脏毒性副作用的药物的治疗过程中，用作辅助治疗，可视治疗状态的类型、所使用的物质和给药形式，采用静脉注射、口服等形式进行使用，使用量可各不相同且可加以变化。
实施例2
含有化合物Ⅰ的片剂
以下组分生产每一片剂：
经过混合、制粒、总混和压片制成250mg片剂。
实施例3
含有化合物Ⅰ的注射液
生产每1ml具有如下组分的注射液：
将上述固体物质溶解于纯净水中，并将溶液无菌灌装于1ml的安瓿瓶中。
以上所述仅为本发明的实施例，并非因此限制本发明的保护范围，凡是利用本发明的说明书所作的等效流程或等效结构的变换，或直接、或间接运用在其他相关的技术领域，均应同理包括在本发明的保护范围之内。
Claims (10)
- 生物碱化合物Ⅰ在制备预防和/或治疗心脏损伤的产品中的用途，所述化合物Ⅰ的结构式如下：
- 根据权利要求1所述的用途，其特征在于，所述心脏损伤选自心肌毒性和/或心肌细胞凋亡。
- 根据权利要求1所述用途，其特征在于，所述心脏损伤是蒽环类药物所致；进一步地，所述蒽环类药物选自多柔比星、柔红霉素、阿克拉霉素、表柔比星、吡柔比星、伊达比星、米托蒽醌的一种或几种，优选为多柔比星。
- 根据权利要求1～3任一项所述的用途，其特征在于，所述产品为延缓和/或抑制心肌细胞凋亡的产品。
- 根据权利要求1～3任一项所述的用途，其特征在于，所述产品为下调Cleaved-Caspase-3和/或p-JNK表达水平的产品。
- 根据权利要求5所述的用途，其特征在于，所述产品为Cleaved-Caspase-3抑制剂和/或p-JNK抑制剂。
- 根据权利要求1所述用途，其特征在于，所述产品的剂型选自片剂、颗粒剂、胶囊剂、栓剂、丸剂、溶液、混悬剂，优选片剂、溶液；进一步地，所述溶液选自注射液。
- 根据权利要求7所述用途，其特征在于，所述片剂的原料中，每250mg片剂包括如下重量份组分：化合物Ⅰ5～20份、乳糖100～200份、淀粉10～25份、微晶纤维素50～80份、硬脂酸镁1～10份、滑石粉1～10份；进一步为化合物Ⅰ10份、乳糖150份、淀粉15份、微晶纤维素65份、硬脂酸镁5、滑石粉5份。
- 根据权利要求7所述用途，其特征在于，所述溶液的原料中，每毫升溶液包括如下重量份组分：化合物Ⅰ0.2～1份、葡萄糖30～70份、氯化钠6～12份、水900～1000份；进一步为化合物Ⅰ0.5份、葡萄糖50份、氯化钠9份、水940.5份。
- 生物碱化合物Ⅰ与蒽环类药物在制备抗肿瘤的联合用药中的用途。
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| CN1356981A (zh) * | 1999-04-13 | 2002-07-03 | 尼科克斯公司 | 药用化合物 |
| CN113209065A (zh) * | 2021-03-29 | 2021-08-06 | 中国科学院西北高原生物研究所 | 生物碱化合物在制备预防和/或治疗心脏损伤的产品中的用途 |
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| DE2328391A1 (de) * | 1972-06-19 | 1974-01-10 | Degussa | Trialkoxycinnamoylaminocarbonsaeuren |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1356981A (zh) * | 1999-04-13 | 2002-07-03 | 尼科克斯公司 | 药用化合物 |
| CN113209065A (zh) * | 2021-03-29 | 2021-08-06 | 中国科学院西北高原生物研究所 | 生物碱化合物在制备预防和/或治疗心脏损伤的产品中的用途 |
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| DESHAN LI, WANG ZONGBAO;KANG KAI;REN GUIPING;YU DAN: "Mechanism study of FGF-21 relieving doxorubicin-induced myocardial inflammation and apoptosis in rats/LI", DONGBEI NONGYE DAXUE XUEBAO - JOURNAL OF NORTHEAST AGRICULTURAL UNIVERSITY, DONGBEI NONGYE DAXUE, CN, vol. 5112005, no. 2, 31 December 2020 (2020-12-31), CN , pages 41 - 50, XP055973722, ISSN: 1005-9369, DOI: 10.19720/j.cnki.issn.1005-9369.2020.12.005 * |
| OUYANG JIAN, ZHOU WEN-NA, LI GANG, WANG XIAO-YAN, DING CHEN-XU, YO U-RUI, SUO, WANG HONG-LUN: "Three New Alkaloids from Hippophae rhamnoides L Li in nn n.subsp. sinensis R Ro ou us si i", HELVETICA CHIMICA ACTA, vol. 98, no. 9, 1 January 2015 (2015-01-01), pages 1287 - 1291, XP055973581 * |
| YAN XIAOLI, TANG JIAJING, DOS SANTOS PASSOS CAROLINA, NURISSO ALESSANDRA, SIMÕES-PIRES CLAUDIA AVELLO, JI MEI, LOU HONGXIANG, FAN : "Characterization of Lignanamides from Hemp ( Cannabis sativa L.) Seed and Their Antioxidant and Acetylcholinesterase Inhibitory Activities", JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 63, no. 49, 16 December 2015 (2015-12-16), US , pages 10611 - 10619, XP055973582, ISSN: 0021-8561, DOI: 10.1021/acs.jafc.5b05282 * |
| ZHOU YUEFANG, WANG SHANSHAN, LOU HONGXIANG, FAN PEIHONG: "Chemical constituents of hemp (Cannabis sativa L.) seed with potential anti-neuroinflammatory activity", PHYTOCHEMISTRY LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 23, 1 February 2018 (2018-02-01), AMSTERDAM, NL , pages 57 - 61, XP055973579, ISSN: 1874-3900, DOI: 10.1016/j.phytol.2017.11.013 * |
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| Publication number | Publication date |
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| CN113209065B (zh) | 2023-06-20 |
| CN113209065A (zh) | 2021-08-06 |
| US20240016765A1 (en) | 2024-01-18 |
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