CN117257805B - 核苷类逆转录酶抑制剂在制备抗血管钙化药物中的应用 - Google Patents
核苷类逆转录酶抑制剂在制备抗血管钙化药物中的应用 Download PDFInfo
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- CN117257805B CN117257805B CN202311497090.5A CN202311497090A CN117257805B CN 117257805 B CN117257805 B CN 117257805B CN 202311497090 A CN202311497090 A CN 202311497090A CN 117257805 B CN117257805 B CN 117257805B
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- reverse transcriptase
- nucleoside reverse
- vascular calcification
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Abstract
本发明公开了核苷类逆转录酶抑制剂在制备抗血管钙化药物中的应用；所述核苷类逆转录酶抑制剂为拉米夫定或司他夫定；本发明发现拉米夫定或司他夫定具有抑制血管钙化及其进展的作用，为血管钙化的治疗提供了新的思路；而且拉米夫定或司他夫定具有较好的药物安全性和较强的抗血管钙化作用，均为已知的小分子化合物，能溶于水或DMSO，稳定性良好，细胞毒性低，可以作为抗血管钙化及相关性疾病防治的候选药物。
Description
技术领域
本发明属于生物医药技术领域，具体涉及核苷类逆转录酶抑制剂在制备抗血管钙化药物中的应用。
背景技术
血管钙化是钙磷以羟基磷灰石的形式在血管壁发生异位沉积的病理现象，类似于骨的形成过程。血管不同层面的钙磷沉积有着不同的病理学表现，血管内膜钙化发生在动脉粥样硬化损伤区域，而中膜钙化主要发生于衰老、糖尿病和终末期肾病中。既往认为血管钙化是一个被动的过程，越来越多的证据表明血管钙化类似于骨的形成，是一个可高度调控的过程。血管钙化发生机制复杂，氧化应激反应、炎症反应、细胞凋亡、基质囊泡产生、血管损伤、钙磷水平过高、钙化抑制因子减少、成骨/软骨诱导因子刺激及血管平滑肌细胞表型转变等因素都可促使细胞外基质发生矿物质沉积，导致血管钙化。
血管钙化导致血管壁僵硬性增加、顺应性降低，进而引起心肌缺血、左心室肥大和心力衰竭，促进血栓形成、斑块破裂，是心脑血管疾病高发病率和高死亡率的重要因素，严重影响人群的生存质量和寿命。同样，一项基于冠脉钙化评分与心血管疾病累积死亡率的研究也暗示了血管钙化是心血管疾病死亡率的关键危险因素。然而，目前关于血管钙化的诊治手段却十分受限。因此，深入探索血管钙化的发病机制，寻找预防或延缓血管钙化发生发展的高效药物具有重要的临床意义。
核苷酸类逆转录酶抑制剂是被批准用于治疗艾滋病和乙型肝炎感染的药物，具有抑制病毒逆转录转录的作用。然而核苷酸类逆转录酶抑制剂是否在血管钙化过程也发挥重要的调控作用尚不明确；因此，深入探索核苷酸类逆转录酶抑制剂对血管钙化的调控作用具有重大意义。
发明内容
本发明的目的在于提供核苷类逆转录酶抑制剂拉米夫定、司他夫定在制备抗血管钙化药物中的应用。
本发明所采取的技术方案是：
本发明提供核苷类逆转录酶抑制剂或其药学上可接受的盐在制备预防和/或治疗血管钙化的药物中的应用。
优选地，所述核苷类逆转录酶抑制剂为拉米夫定或司他夫定。
优选地，所述核苷类逆转录酶抑制剂或其药学上可接受的盐抑制血管平滑肌细胞钙化。
优选地，所述核苷类逆转录酶抑制剂或其药学上可接受的盐抑制主动脉钙化。
优选地，所述药学上可接受的盐包括但不限于：可药用的酸加成盐，如：无机酸例如盐酸、氢溴酸、磷酸、偏磷酸、硝酸和硫酸的盐，以及有机酸例如乙酸、苯磺酸、苯甲酸、柠檬酸、乙磺酸、富马酸、萄糖酸、羟乙酸、羟乙磺酸、乳酸、乳糖酸、马来酸、苹果酸、甲磺酸、琥珀酸、对甲苯磺酸和酒石酸的盐；可药用碱的盐是铵盐、碱金属盐(例如钠盐和钾盐)和碱土金属盐(例如镁盐和钙盐)以及氨基丁三醇(2-氨基-2-羟基甲基-1，3-丙二醇)、二乙醇胺、赖氨酸或乙二胺的盐。
优选地，所述药物含有有效剂量的核苷类逆转录酶抑制剂或其药学上可接受的盐。
在本发明中，所述拉米夫定或其药学上可接受的盐在10～100μM浓度下显著抑制细胞发生血管钙化；所述司他夫定或其药学上可接受的盐在5～100μM浓度下显著抑制细胞发生血管钙化。
优选地，所述拉米夫定或其药学上可接受的盐的浓度为20～50μM。
优选地，所述司他夫定或其药学上可接受的盐的浓度为10～50μM。
优选地，本发明核苷类逆转录酶抑制剂或其药学上可接受的盐的每天的合适剂量范围为0.001-100mg/kg体重；上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
在本发明中，在对动物用药时，所述拉米夫定或其药学上可接受的盐的每日给药剂量为50～100 mg/kg小鼠，和/或，给药时间为8～15天。
优选地，所述血管钙化为动脉粥样硬化、衰老、糖尿病、慢性肾病、高血压、血管病变伴发或引起的血管钙化。
优选地，所述药物还包括至少一种其他具有预防和/或治疗血管钙化功能的成分。
优选地，所述药物还包括药学上可接受的辅料。
优选地，所述药学上可接受的辅料包括：稀释剂、黏合剂、润湿剂、润滑剂、崩解剂、溶剂、乳化剂、助溶剂、增溶剂、防腐剂、pH调节剂、渗透压调节剂、表面活性剂、包衣材料、抗氧剂、抑菌剂或缓冲剂中的至少一种。
优选地，所述药物的剂型包括混悬剂、颗粒剂、胶囊剂、散剂、片剂、乳剂、溶液剂、滴丸剂、注射剂、口服剂、栓剂、灌肠剂、气雾剂、贴剂或滴剂中的至少一种。
优选地，所述药物的给药途径包括静脉注射、腹腔注射、肌肉注射、皮下注射、口服给药、舌下给药、鼻腔给药、雾化给药或经皮给药中的至少一种。
本发明的有益效果是：
本发明发现核苷类逆转录酶抑制剂（拉米夫定或司他夫定）具有抑制血管钙化及其进展的作用，为血管钙化的治疗提供了新的思路；而且拉米夫定或司他夫定具有较好的药物安全性和较强的抗血管钙化作用，也均为已知的小分子化合物，能溶于水或DMSO，稳定性良好，可以作为抗血管钙化及相关性疾病防治的候选药物，具有良好的应用前景。
附图说明
图1为实施不同浓度BCH-189对高磷诱导血管平滑肌细胞钙化作用的茜素红染色结果。
图2为实施不同浓度BCH-189对高磷诱导血管平滑肌细胞钙化作用的钙含量测定的结果。
图3为实施不同浓度d4T对高磷诱导血管平滑肌细胞钙化作用的茜素红染色结果。
图4为实施不同浓度d4T对高磷诱导血管平滑肌细胞钙化作用的钙含量测定的结果。
图5为对维生素D3模型小鼠的血管钙化实施BCH-189干预的大体茜素红染色结果。
图6为对维生素D3模型小鼠的血管钙化实施BCH-189干预的小鼠动脉环进行Runx2IHC染色结果。
其中*P<0.05，**P<0.01，***P<0.001，ns:无显著差异。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述，以充分地理解本发明的目的、特征和效果。显然，所描述的实施例只是本发明的一部分实施例，而不是全部实施例，基于本发明的实施例，本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例，均属于本发明保护的范围。
人类血管平滑肌细胞VSMCs均购自赛百慷（上海）生物技术股份有限公司；磷酸氢二钠购自西格玛广州甄皓贸易有限公司；核苷类逆转录酶抑制剂（拉米夫定、司他夫定均购自MCE广州市齐云生物技术有限公司；蓖麻油聚氧乙烯醚(货号C804845-250ml)、无水葡萄糖购自上海麦克林生化科技股份有限公司公司；钙含量试剂盒购自南京建成生物工程研究所；维生素D3购自生工生物工程（上海）股份有限公司，货号A600988-0001；茜素红染料购自雷根广州市鹏辰生物科技有限公司；
拉米夫定（Lamivudine，BCH-189）的化学式如式（I）所示：
（I）；
司他夫定（Stavudine，d4T）的化学式如式（II）所示：
（II）。
实施例1 核苷类逆转录酶抑制剂（BCH-189/d4T）抑制血管钙化
1、本实施例用磷诱导血管平滑肌细胞发生血管钙化，并分别给予核苷类逆转录酶抑制剂（BCH-189）干预7天后进行茜素红染色，以评估核苷类逆转录酶抑制剂（BCH-189）对血管钙化的抑制作用。具体操作包括：
1）6-12代人血管平滑肌细胞以1 x 105/孔，铺12孔板，每孔加1ml DMEM完全培养基。铺板后第1天给予3.0mM磷诱导钙化，同时给予1μM/5μM/10μM/25μM浓度的BCH-189进行干预，隔日更换DMEM完全培养基并再次给予3.0mM磷诱导钙化，同时给予1μM/5μM/10μM/25μM浓度的BCH-189进行干预，第7日进行茜素红染色。
2）6-12代人血管平滑肌细胞以1 x 105/孔，铺12孔板，每孔加1ml DMEM完全培养基。铺板后第1天给予3.0 mM磷诱导钙化，同时给予1μM/5μM/10μM/25μM 浓度的d4T进行干预，隔日更换DMEM完全培养基并再次给予3.0 mM磷诱导钙化，同时给予1μM/5μM/10μM/25μM浓度的d4T进行干预，第7日进行茜素红染色。
2、为了进一步阐明核苷类逆转录酶抑制剂（BCH-189/d4T）抑制血管钙化的作用，应用磷诱导血管平滑肌细胞发生血管钙化，并分别给予核苷类逆转录酶抑制剂（BCH-189/d4T）干预7天后进行钙含量测定。具体操作包括：
1）6-12代人血管平滑肌细胞以1 x 105/孔，铺12孔板，每孔加1ml DMEM完全培养基。铺板后第1天给予3.0 mM磷诱导钙化，同时给予1μM/5μM/10μM/25μM浓度的BCH-189进行干预，隔日更换DMEM完全培养基并再次给予3.0 mM磷诱导钙化，同时给予1μM/5μM/10μM/25μM 浓度的BCH-189 进行干预，第7日进行钙含量测定。
2）6-12代人血管平滑肌细胞以1 x 105/孔，铺12孔板，每孔加1ml DMEM完全培养基。铺板后第1天给予3.0 mM磷诱导钙化，同时给予1μM/5μM/10μM/25μM浓度的d4T进行干预，隔日更换DMEM完全培养基并再次给予3.0 mM磷诱导钙化，同时给予1μM/5μM/10μM/25μM浓度的d4T进行干预，第7日进行钙含量测定。
茜素红染色结果表明，核苷类逆转录酶抑制剂（BCH-189/d4T）可以显著抑制血管钙化（图1和图3）。进一步的钙含量测定结果也同样证明了核苷类逆转录酶抑制剂（BCH-189/d4T）具有抑制血管钙化的作用（图2和图4）。
综合以上结果可见，核苷类逆转录酶抑制剂（BCH-189/d4T）能有效抑制血管钙化的发生，可作为抗血管钙化的药物。
实施例2 核苷类逆转录酶抑制剂（BCH-189）抑制小鼠发生血管钙化
1、本实施例用维生素D3诱导小鼠发生血管钙化，其中所用的维生素D3为蓖麻油聚氧乙烯醚包裹的维生素D3；制备方法为：①先用200μL无水乙醇溶解66mg维生素D3，②将1.4mL蓖麻油聚氧乙烯醚加入维生素D3乙醇溶液中混匀并，室温静置15min。③取750mg葡萄糖粉末溶解于18.4mL灭菌ddH2O配制葡萄糖水溶液，并室温放置15min；④将上述两种溶液混合摇匀后于4℃保存（VitD3储存液浓度:132000IU/mL）。配液全程保持无菌，若试剂无法保证是无菌级，应在溶液混合后再用滤器过滤。给药动物诱导小鼠发生血管钙化，同时给予核苷类逆转录酶抑制剂（BCH-189）干预10天后对小鼠主动脉进行茜素红染色，以评估核苷类逆转录酶抑制剂（BCH-189）对小鼠血管钙化的抑制作用。
具体操作为：
将8周龄体重相近（20g-25g）的C57BL/6雄性小鼠随机分为空白组（n=10）、维生素D3组（n=10）、维生素D3+BCH-189组（n=10），维生素D3模型小鼠用维生素D3溶液从Day1-3进行腹腔注射，剂量为500IU/kg/天，每天同时间一次性注射；维生素D3+BCH-189组则给予素D3的基础上，从Day1进行腹腔注射BCH-189 70 mg/kg，每天一次，于Day10处死小鼠，并取小鼠主动脉进行茜素红染色。
茜素红染色结果显示，维生素D3成功诱导小鼠发生血管钙化，而核苷类逆转录酶抑制剂（BCH-189）可以显著抑制小鼠血管钙化的进展（图5）。
2、为进一步验证核苷类逆转录酶抑制剂（BCH-189）抑制小鼠血管钙化的发生发展，应用维生素D3诱导小鼠发生血管钙化，并给予核苷类逆转录酶抑制剂（BCH-189）干预10天后，对小鼠主动脉环分别进行成骨表型Runx2的免疫组化（IHC）染色，以进一步评估核苷类逆转录酶抑制剂（BCH-189）对小鼠血管钙化的抑制作用。具体操作如下：
将8周龄体重相近（20g-25g）的C57BL/6雄性小鼠随机分为空白组（n=10）、维生素D3组（n=10）、维生素D3+BCH-189组（n=10），维生素D3模型小鼠用维生素D3溶液从Day1-3进行腹腔注射，剂量为500IU/kg/天，每天同时间一次性注射；维生素D3+BCH-189组则给予素D3的基础上，从Day1进行腹腔注射BCH-189 70 mg/kg，每天一次，于Day10处死小鼠，并取小鼠主动脉环IHC染色，结果显示，核苷类逆转录酶抑制剂（BCH-189）可以显著抑制小鼠发生血管钙化（图6）。
综合以上结果可见，核苷类逆转录酶抑制剂（BCH-189）能有效抑制小鼠血管钙化的发生，可作为抗血管钙化的药物。
上述具体实施方式对本发明作了详细说明，但是本发明不限于上述实施例，在所属技术领域普通技术人员所具备的知识范围内，还可以在不脱离本发明宗旨的前提下作出各种变化。此外，在不冲突的情况下，本发明的实施例及实施例中的特征可以相互组合。
Claims (8)
1.核苷类逆转录酶抑制剂或其药学上可接受的盐作为唯一活性成分在制备治疗血管钙化的药物中的应用；所述核苷类逆转录酶抑制剂为拉米夫定或司他夫定。
2.根据权利要求1所述的应用，其特征在于，所述核苷类逆转录酶抑制剂或其药学上可接受的盐抑制血管平滑肌细胞钙化。
3.根据权利要求1所述的应用，其特征在于，所述核苷类逆转录酶抑制剂或其药学上可接受的盐抑制主动脉钙化。
4.根据权利要求1所述的应用，其特征在于，所述药物含有有效剂量的核苷类逆转录酶抑制剂或其药学上可接受的盐。
5.根据权利要求1～4任一项所述的应用，其特征在于，所述药物还包括药学上可接受的辅料。
6.根据权利要求5所述的应用，其特征在于，所述药学上可接受的辅料包括：稀释剂、黏合剂、润湿剂、润滑剂、崩解剂、溶剂、乳化剂、助溶剂、增溶剂、防腐剂、pH调节剂、渗透压调节剂、表面活性剂、包衣材料、抗氧剂、抑菌剂或缓冲剂中的至少一种。
7.根据权利要求1～4任一项所述的应用，其特征在于，所述药物的剂型包括混悬剂、颗粒剂、胶囊剂、散剂、片剂、乳剂、溶液剂、滴丸剂、注射剂、栓剂、灌肠剂、气雾剂、贴剂或滴剂中的至少一种。
8.根据权利要求1～4任一项所述的应用，其特征在于，所述药物的给药途径包括静脉注射、腹腔注射、肌肉注射、口服给药、舌下给药、鼻腔给药、雾化给药或经皮给药中的至少一种。
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| CA2480758A1 (en) * | 2002-04-12 | 2003-10-23 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
| WO2011088126A2 (en) * | 2010-01-13 | 2011-07-21 | Eiger Biopharmaceuticals, Inc. | Treatment of viral infection with prenyltransferase inhibitors |
| CN106565785A (zh) * | 2016-11-09 | 2017-04-19 | 周雨恬 | 一种具有抗hbv/hiv活性的核苷氨基磷酸酯类化合物及其盐和用途 |
| CN115837023A (zh) * | 2023-02-20 | 2023-03-24 | 中山大学附属第八医院（深圳福田） | 1-甲基烟酰胺在制备抗血管钙化药物中的应用 |
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| CA2480758A1 (en) * | 2002-04-12 | 2003-10-23 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
| WO2011088126A2 (en) * | 2010-01-13 | 2011-07-21 | Eiger Biopharmaceuticals, Inc. | Treatment of viral infection with prenyltransferase inhibitors |
| CN106565785A (zh) * | 2016-11-09 | 2017-04-19 | 周雨恬 | 一种具有抗hbv/hiv活性的核苷氨基磷酸酯类化合物及其盐和用途 |
| CN115837023A (zh) * | 2023-02-20 | 2023-03-24 | 中山大学附属第八医院（深圳福田） | 1-甲基烟酰胺在制备抗血管钙化药物中的应用 |
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