CN106237333A - 紫堇达明的医药用途 - Google Patents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
本发明涉及医药技术领域，具体涉及异喹啉类生物碱紫堇达明(l‑corydalmine，l‑CDL)用于与麻醉性镇痛药组方制备治疗镇痛相关药物的用途。
Description
技术领域
本发明涉及医药技术领域，具体涉及异喹啉类生物碱紫堇达明复方的医药用途。
背景技术
麻醉性镇痛药是以吗啡、杜冷丁、芬太尼为代表的阿片类镇痛药，此类药物镇痛作用强，主要用于手术、外伤、晚期癌症剧烈疼痛者。耐受性指长期用药后中枢神经系统对其敏感性降低，需要增加剂量才能达到原来的药效。阿片类镇痛药反复使用后，使用者会产生耐受和依赖，可分为身体依赖性和精神依赖性。
左旋四氢帕马丁(l-tetrahydropalmatine，l-THP，罗通定)与紫堇达明(l-corydalmine，l-CDL)都是中药延胡索中的有效生物碱成分之一。罗通定列入中国药典，已经在临床安全使用了40多年，用于治疗慢性疼痛、焦虑、失眠；无成瘾性[1-2]。l-THP在多种模型上对甲基苯丙胺，可卡因等诱导的成瘾有抑制作用[3-9]。l-CDL结构与l-THP相似，都具有多巴胺受体D2、D3受体拮抗与5-羟色胺受体(5-HT1A)激动的性质[10-11]。研究发现l-THP在人血浆中含量最高的代谢产物是10-去甲基硫酸结合物，即l-CDL(紫堇达明)的硫酸结合物。其它产物是3-去甲基硫酸结合物。人尿中，含量最高的产物也是l-CDL的硫酸结合物，说明l-THP在体内主要代谢成l-CDL发挥作用。
发明内容
发明人发现，异喹啉类生物碱紫堇达明(l-CDL)与麻醉性镇痛药组方可用于增强镇痛效果，降低麻醉性镇痛药剂量，抑制强效镇痛药的耐受、成瘾及戒断症状。
本申请涉及l-CDL与麻醉性强镇痛药配伍用于镇痛以及镇静、抗焦虑。
在一个方面，本发明提供了异喹啉类生物碱紫堇达明(l-corydalmine，l-CDL)或其药学上可接受的盐与麻醉性镇痛剂结合用于制备治疗镇痛药物的用途。
在一个实施方式中，所述麻醉性镇痛剂为阿片类，优选为吗啡、杜冷丁、芬太尼、舒芬太尼、瑞芬太尼或其盐。
在一个实施方式中，所述异喹啉类生物碱紫堇达明(l-CDL)与所述麻醉性镇痛剂单独或共同地配制为临床上可接受的任何剂型形，包括口服或消化道外给药的各种剂。例如，片剂、胶囊、软胶囊、液体胶囊、颗粒剂、滴丸剂、糖浆剂、干混悬剂、口服溶液、口服混悬液、口腔崩解片、口腔速溶膜、缓释片、控释片、缓释胶囊、控释胶囊、肠溶片、肠溶胶囊、水针剂、冻干粉针剂、无菌粉针剂、输液、滴眼剂、滴鼻剂、喷鼻剂、肺吸入剂、经皮贴剂、搽剂、软膏剂、乳膏剂、栓剂、皮下植入剂、长效注射剂或微针制剂。
在一个实施方式中，所述异喹啉类生物碱紫堇达明(l-CDL)和所述麻醉性镇痛剂相继地或同时地施用。
在另一个方面，本发明涉及异喹啉类生物碱紫堇达明(l-corydalmine，l-CDL)或其药学上可接受的盐与麻醉性镇痛剂的药物组合，其用于制备治疗镇痛药物。
在一个实施方式中，所述麻醉性镇痛剂为阿片类，优选为吗啡、杜冷丁、芬太尼、舒芬太尼、瑞芬太尼或其盐。
在一个实施方式中，所述异喹啉类生物碱紫堇达明(l-CDL)与所述麻醉性镇痛剂单独或共同地配制为临床上可接受的任何剂型形式，包括口服或消化道外给药的各种剂型。
l-CDL与麻醉性镇痛药组方的优势在于：
两种镇痛机制不同的药物伍用可以增强镇痛效果，减少用药剂量，延长麻醉性强镇痛药物耐受性产生的时间，降低依赖性，减少不良反应。
附图简要说明
图1显示了l-CDL与吗啡镇痛作用的量效和时效关系曲线。
图2A、图2B显示了吗啡与l-CDL联用的效果。
图3显示了l-CDL抑制吗啡急性耐受
图4显示了l-CDL抑制吗啡慢性耐受。
详细描述
l-CDL本身具有镇痛作用，但是与吗啡类镇痛药不同，吗啡镇痛作用机制可能是通过激动脊髓胶质区、丘脑内侧、脑室及导水管周围灰质等部位的阿片受体，主要是μ受体，模拟内源性阿片肽对痛觉的调制功能而产生镇痛作用。
l-CDL的镇痛作用不同于阿片类镇痛药，可能与抑制脑干网状结构上行激活系统、阻滞脑内多巴胺受体的功能有关。
l-CDL拮抗多巴胺D2、D3受体激动，具有抗成瘾作用。
药物依赖(成瘾)机制主要涉及多巴胺奖赏系统。新型毒品能抑制多巴胺的代谢和摄取，促进多巴胺合成，升高奖赏脑区伏隔核多巴胺水平，增强多巴胺系统的功能，产生奖赏效应和精神依赖。因此多巴胺系统成为成瘾的治疗靶点之一，寻找高效低副作用的多巴胺受体拮抗剂成为治疗成瘾的研究目标。近年来研究显示l-THP在治疗成瘾方面具有良好的前景。l-THP减弱大鼠体内由可卡因、海洛因引起的自身给药行为，同时可抑制复吸的形成。l-THP可抑制甲基苯丙胺、可卡因，羟考酮、吗啡引起的条件性位置偏爱效应(CPP)的形成和表达，促进CPP效应消退。l-THP能剂量依赖性抑制小鼠甲基苯丙胺、羟考酮诱导的行为敏化的形成、发展和表达。l-THP自身不形成大鼠甲基苯丙胺辨别效应，但能影响甲基苯丙胺辨别行为的重建，阻断甲基苯丙胺辨别行为，表明l-THP可抑制甲基苯丙胺精神依赖性的形成。以上研究显示，l-THP对动物成瘾行为的形成、维持乃至复吸均有抑制作用。
l-SPD的生物利用度很低，且生产成本高，不适合工业化生产。l-CDL具有较高的生物利用度，口服生物利用度可达50％。
目前已经打通l-CDL化学合成路线，制备工艺简便、经济、可控，适宜于工业化生产。
实施例1 小鼠镇痛实验
小鼠热板镇痛药实验方法按文献记载；
小鼠热板镇痛仪购自(DM.7-YLS-21A)北京达美达科技有限公司；
昆明雌性小鼠，体重18-22克，购于北京维通利华公司。
将小鼠置于温度55℃±0.5℃的金属热板上，测定其疼痛反应(“舔后足”现象)的出现时间，共测定2次，每次间隔5min。若出现疼痛反应的时间在10s至30s之间，则视为合格。按照简化随机原则分组，每组10只。小鼠腹腔注射给药，在给药15，30，45，60min后分别使用热板法测定疼痛反应出现时间(痛阈)，若置于热板上60s内仍未出现疼痛反应，则均视为60s。
最大镇痛率(the percentage of maximum possible analgesic effect，％MPAE)＝用药后热痛反应时间-用药前平均热痛反应时间/用药前平均热痛反应时间×100％
小鼠热板实验显示，l-CDL在0.5、1、2.0mg/kg剂量的最大镇痛百分比分别为22.5％，52.0％和78.6％，而对照组为3.2％，l-CDL 2.0mg/kg时的镇痛效应与吗啡5mg/kg时相当(吗啡为70.8％)，而且镇痛时间显著长于吗啡(图1)。
实施例2.l-CDL与吗啡伍用可延长麻醉性镇痛药的镇痛时间
l-CDL可以显著延长吗啡镇痛时间，使用吗啡90分钟后，其镇痛作用下降至11.2％，而分别与l-CDL 1mg/kg,2mg/kg合用后，90分钟后仍具有显著的镇痛效果(79.7％和97.2％)，而且与吗啡配伍使用5小时后，镇痛效应仍可达到51.6％和52.5％。
l-CDL 1.0mg/kg能延长吗啡镇痛时间并使吗啡镇痛半数有效剂量ED50值从4.67mg/kg降至3.14mg/kg，说明l-CDL与吗啡伍用可以增强吗啡的镇痛效果，延长吗啡镇痛并且可以降低吗啡用药剂量。结果见图2A和图2B。
实施例3.l-CDL抑制吗啡产生的急性耐受性
临床医生为了缓解癌症、手术、外伤等患者的持续性疼痛，通常需要连续使用吗啡、杜冷丁、芬太尼等强效镇痛药物，我们的研究结果显示，大鼠每1小时间隔给予吗啡，9小时后，吗啡镇痛效果急剧下降，仅为51.9％，说明吗啡产生急性耐受。
l-CDL与吗啡合用可剂量依赖地抑制吗啡镇痛效应的下降，镇痛效应分别为90.1％，96.6％和100％。在24和48小时，l-CDL与吗啡伍用仍然具有较好的镇痛效果(分别为59.9％，60.1％，60.0％)。(参见图3)
实施例4.l-CDL抑制吗啡产生的慢性耐受
小鼠热板实验结果证明连续给予吗啡后，吗啡镇痛作用百分率逐日下降，服用吗啡第一天的镇痛效应为100％，第8天则降低为24.7％，说明吗啡长期应用产生慢性耐受。吗啡与l-CDL合用后在第8天镇痛效应分别为59.5％，80.7％和83.4％，说明l-CDL能抑制吗啡慢性耐受的形成，维持较好，较长时间的镇痛效果。结果见图4。
Claims (10)
1.下式的异喹啉类生物碱紫堇达明(l-corydalmine，l-CDL)或其药学上可接受的盐与麻醉性镇痛剂结合用于制备治疗镇痛药物的用途：
紫堇达明(R，S):R1＝R2＝OCH3，R3＝OCH3，R4＝OH；。
2.根据权利要求1所述的用途，其中所述麻醉性镇痛剂为阿片类，优选为吗啡、杜冷丁、芬太尼、舒芬太尼、瑞芬太尼或其盐。
3.根据权利要求1所述的用途，其中所述异喹啉类生物碱紫堇达明(l-CDL)与所述麻醉性镇痛剂单独或共同地配制为临床上可接受的任何剂型形式。
4.根据权利要求3所述的用途，其中所述临床上可接受的剂型形式包括口服或消化道外给药的各种剂型。
5.根据权利要求3所述的用途，其中剂型是片剂、胶囊、软胶囊、液体胶囊、颗粒剂、滴丸剂、糖浆剂、干混悬剂、口服溶液、口服混悬液、口腔崩解片、口腔速溶膜、缓释片、控释片、缓释胶囊、控释胶囊、肠溶片、肠溶胶囊、水针剂、冻干粉针剂、无菌粉针剂、输液、滴眼剂、滴鼻剂、喷鼻剂、肺吸入剂、经皮贴剂、搽剂、软膏剂、乳膏剂、栓剂、皮下植入剂、长效注射剂或微针制剂。
6.根据权利要求1所述的用途，其中所述异喹啉类生物碱紫堇达明(l-CDL)和所述麻醉性镇痛剂相继地或同时地施用。
7.下式的异喹啉类生物碱紫堇达明(l-corydalmine，l-CDL)或其药学上可接受的盐与麻醉性镇痛剂的药物组合，其用于制备治疗镇痛药物：
紫堇达明(R，S):R1＝R2＝OCH3，R3＝OCH3，R4＝OH；。
8.根据权利要求7所述的药物组合，其中所述麻醉性镇痛剂为阿片类，优选为吗啡、杜冷丁、芬太尼、舒芬太尼、瑞芬太尼或其盐。
9.根据权利要求7所述的药物组合，其中所述异喹啉类生物碱紫堇达明(l-CDL)与所述麻醉性镇痛剂单独或共同地配制为临床上可接受的任何剂型形式。
10.根据权利要求9所述的用途，其中所述临床上可接受的剂型形式包括口服或消化道外给药的各种剂型。
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| CN111788201A (zh) * | 2018-11-29 | 2020-10-16 | 杨征 | 紫堇达明的结晶盐 |
| CN111788201B (zh) * | 2018-11-29 | 2021-12-28 | 杨征 | 紫堇达明的结晶盐 |
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