CN117045773A - 药物组合物在治疗疼痛上的应用 - Google Patents
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
本发明涉及一种用于镇痛的药物组合物,所述组合物包含眼镜蛇神经毒素和右莰醇,所述疼痛为急性疼痛或慢性疼痛,所述组合物在治疗疼痛上能产生协同镇痛作用。
Description
技术领域
本发明涉及一种组合物在制备治疗患者疼痛药物中的用途。
背景技术
疼痛一直是一种严重影响人类生活质量的临床症状,有时甚至会使人面对死亡的威胁。平常生活中我们一般多见的有神经性头痛,肿瘤或炎症性疼痛,创伤性疼痛等,虽然临床上有治疗疼痛的药物,但是它们都具有非常严重的副作用,不仅经常使用会使患者产生严重的临床毒副作用,甚至有时还不能产生满意的镇痛疗效,所以目前的疼痛治疗的药物痛并没有能够真正达到满足患者临床需求的水准。
眼镜蛇神经毒素也是医务工作者正在使用的一种治疗疼痛的药品,如“科博肽”,它们有着较好的镇痛疗效且无严重副反应,同时由于眼镜蛇神经毒素的镇痛作用是通过与神经突触后的烟碱型乙酰胆碱受体结合而阻断外周及中枢疼痛信号的专递[1,2],故它对一系列疼痛都有效。但是由于神经毒素在最初的几个小时内镇痛作用相对效弱,故在用药开始时间段效果不是十分理想[3,4,5],部分患者感觉镇痛疗效仍然有欠缺,没有达到满意的镇痛疗效,故眼镜蛇神经毒素的镇痛疗效仍有待于进一步提高。
发明内容
本发明涉及一种组合物在制备治疗患者疼痛药物中的应用,其特征在于,所述的组合物包含眼镜蛇神经毒素(Naja neurotoxin)和右莰醇(Dexborneol,也称右旋莰醇)。针对眼镜蛇神经毒素在最初的几个小时内镇痛作用相对效弱的临床特征,本发明提供了一种能与眼镜蛇神经毒素产生协同镇痛作用的治疗疼痛的药物组合物。我们在研究中发现,眼镜蛇神经毒素和右莰醇能产生协同镇痛作用,这种协同镇痛作用要强于单独使用眼镜蛇神经毒素所产生的镇痛作用,而且眼镜蛇神经毒素加右莰醇的协同镇痛作也要强于眼镜蛇神经毒素加冰片所产生的镇痛作用。
在一些实施方案中,所述组合物中眼镜蛇神经毒素和右莰醇的重量比可以为0.02:1~4.0:1,在一些实施方案中,所述组合物中眼镜蛇神经毒素和右莰醇的重量比为0.02:1~0.1:1、0.02:1~0.2:1、0.02:1~0.3:1、0.02:1~0.4:1、0.02:1~0.5:1、0.02:1~0.6:1、0.02:1~0.7:1、0.02:1~0.8:1、0.02:1~0.9:1、0.02:1~1.0:1、0.02:1~2.0:1、0.02:1~3.0:1、0.02:1~4.0:1、优选为0.05:1~1.0:1。
化学突触传递是神经信号传递的主要形式,乙酰胆碱是人体内分布最广泛的神经化学物质,是一种神经递质,通常由胆碱能神经细胞利用胆碱和乙酸盐在辅酶A和胆碱乙酰化酶作用下形成。合成后的乙酰胆碱最后储存在神经细胞突触囊泡内,当神经冲动传播到神经末梢时,末梢以细胞吐囊泡方式"量子释放"乙酰胆碱,作用于突触后膜相应的受体,引起兴奋或抑制性反应,引起受体膜产生动作电位,完成神经传导过程。
研究者们对眼镜蛇神经毒素的镇痛机理作了深入的研究,结果显示眼镜蛇神经毒素可以通过与突触后乙酰胆碱受体结合来抑制疼痛信号在外周及中枢神经中的传导[1,2]。突触是指一个神经元的冲动传到另一个神经元或传到另一细胞间的相互接触的结构,突触是神经元之间在功能上发生联系的部位,也是信息传递的关键部位。眼镜蛇神经毒素中的突触后神经毒素或α-神经毒素,这类毒素竞争性的与位于突触后膜的神经神经接头处的烟碱型乙酰胆碱受体结合,阻断神经递质乙酰胆碱的传导。所以眼镜蛇神经毒素(α-神经毒素)是烟碱乙酰胆碱受体(nAChR)的拮抗剂,在结构上,它们具有共同的三指的结构,故也被称为三指毒素,活性部位靠近中指末端,这种三指结构是一种多功能的结构,以拮抗和缓慢可逆的方式与神经元的烟碱型乙酰胆碱受体结合,阻断神经递质乙酰胆碱的传导。[6,7,8,9,10,11]。所以眼镜蛇神经毒素,包括短链或长链神经毒素,通过与突触后乙酰胆碱受体结合来抑制疼痛信号在神经中传导的共性和他们具有共同的三指蛋白结构对烟碱型乙酰胆碱受体的拮抗和调节有关,这种共同的功能结构导致了它们在治疗疗效上的共同性和一致性,这也是眼镜蛇神经毒素能够镇痛的共同作用机理。
在一些实施方案中,所用的眼镜蛇短链或长链神经毒素来自于中华眼镜蛇神经毒素或孟加拉眼镜蛇神经毒素,它们的成熟肽氨基酸序列具有高度的同源性,(FASTA)序列分别如下:
SEQ ID No.1
lechnqqssq tptttgcsgg etncykkrwr dhrgyrterg cgcpsvkngi einccttdrc nn
SEQ ID No.2
lechnqqssq tptttgcsgg etncykkrwr dhrgyrterg cgcpivkngi esnccttdrc nn
SEQ ID No.3
lechnqqssq apttktcsge tncykkwwsd hrgtiiergc gcpkvkpgvn lnccrtdrcn n
SEQ ID No.4
lechnqqsiq tptttgcsgg etncykkrwr dhrgyrterg cgcpsvkngi einccttdrc nn
SEQ ID No.5
mktllltllvvtivcldlgy tlechnqqss qtptttgcsg getncykkrw rdhrgyrtergcgcpsvkng ieinccttdr cnn
SEQ ID No.6
mktllltllvvtivcldlgy tlechnqqss qtptttgcsg getncykkrw rdhrgyrtergcgcpsvkng ieinccttdr cnn
具体实施方式
以下实施例详细说明发明的技术方案,但本发明的保护范围包括但不限于此。
实施例
眼镜蛇神经毒素+右莰醇组合物的镇痛作用与其它神经毒素制剂及生理盐水镇痛作用的比较1.制剂的制备
方法一
把右莰醇和丙二醇充分搅拌,使之完全溶解;把眼镜蛇神经毒素溶解在纯净水中,然后把上述2种液态充分混合,制成眼镜蛇神经毒素和右莰醇混合溶液,用作肌注或滴鼻。眼镜蛇神经毒素和冰片混合溶液用同样方法制备,用作肌注或滴鼻。
方法二
把右莰醇用羟丙基β环糊精包裹,把眼镜蛇神经毒素溶解在纯净水中,然后把包裹后的眼镜蛇神经毒素溶于眼镜蛇神经毒素水溶液中,用作肌注或滴鼻。眼镜蛇神经毒素和冰片混合溶液用同样方法制备,用作肌注或滴鼻。
2.小鼠热板试验(肌注)
雌性小鼠30~35克,分为4组,每组10个,分别为生理盐水组、眼镜蛇神经毒素组、眼镜蛇神经毒素组+右莰醇组、眼镜蛇神经毒素+冰片组,所用的眼镜蛇神经毒素为“科博肽”,具体剂量如表1所示。将以上4组小鼠进行肌肉注射后将小鼠放于恒热的金属板上(55度),热刺激小鼠足部产生疼痛反应(舔后足),记录小鼠从放于热板上至出现疼痛反应的潜伏期。
表1肌注大鼠添足潜伏期(秒)±标准差
在以上时间段,25ug/kg眼镜蛇神经毒素+25ug/kg右莰醇的镇痛作用均强于25ug/kg眼镜蛇神经毒素+25ug/kg冰片或25ug/kg眼镜蛇神经毒素单药,且有显著性差异,*代表P<0.05。
3.小鼠热板试验(滴鼻)
雌性小鼠30~35克,分为4组,每组10个,分别为生理盐水组、眼镜蛇神经毒素组、眼镜蛇神经毒素组+右莰醇组、眼镜蛇神经毒素+冰片组,所用的眼镜蛇神经毒素为“科博肽”,具体剂量如表1所示。对以上4组小鼠进行滴鼻后将小鼠放于恒热的金属板上(55度),热刺激小鼠足部产生疼痛反应(舔后足),记录小鼠从放于热板上至出现疼痛反应的潜伏期,同样显示,在以上时间段,25ug/kg眼镜蛇神经毒素+25ug/kg右莰醇的镇痛作用均强于其他3种制剂。
Reference:
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5.朱天新,袁彩君,任晚琼.眼镜蛇突触后神经毒素的规模化制备及其镇痛作用的研究[J].华西药学杂志,2007,22(3):247~249。
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Structure,function and evolution ofthree-finger toxins:mini proteinswith multiple targets.Toxicon,2010,56:855-67
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Inhibition of the Nicotinic Acetylcholine Receptors by Cobra Venomα-Neurotoxins:Is Therea Perspective in Lung Cancer Treatment?PLoS One 6(6)e20695.2011。
Claims (10)
1.一种药物组合物在治疗疼痛上的应用,所述组合物含有治疗有效剂量的眼镜蛇神经毒素(Neurotoxin)和右莰醇(Dexborneol,及药物可接受的辅料。
2.根据权利要求(1)所述的用途,其特征在于,所述组合物中眼镜蛇神经毒素和右莰醇的重量比可以为0.02:1~4.0:1,在一些实施方案中,所述组合物中眼镜蛇神经毒素和右莰醇的重量比为0.02:1~0.1:1、0.02:1~0.2:1、0.02:1~0.3:1、0.02:1~0.4:1、0.02:1~0.5:1、0.02:1~0.6:1、0.02:1~0.7:1、0.02:1~0.8:1、0.02:1~0.9:1、0.02:1~1.0:1、0.02:1~2.0:1、0.02:1~3.0:1、0.02:1~4.0:1、优选为0.05:1~1:1。
3.根据权利要求(1)所述的用途,其特征在于,所述组合物中眼镜蛇神经毒素和右莰醇的重量比为1:1。
4.根据权利要求(1)所述的用途,其特征在于,所述组合物中的眼镜蛇神经毒素可来自于眼镜蛇科的蛇短链或长链神经毒素,优选,它们来自于中华眼镜蛇或孟加拉眼镜蛇的神经毒素。
5.根据权利要求(1)所述的用途,其进一步特征在于,所述组合物中眼镜蛇神经毒素是具有SEQ ID No.1-SEQ ID No.6所示的成熟蛋白氨基酸序列的眼镜蛇神经毒素;或分别与SEQ ID No.1-SEQ ID No.6中的眼镜蛇神经毒素具有90%或以上同源性的成熟蛋白,该成熟蛋白的功能与SEQ ID No.
1-SEQ ID No.6所示的氨基酸序列的眼镜蛇神经毒素的功能相同或相似。
6.根据权利要求(1)所述的用途,其特征在于,所述组合物中的眼镜蛇神经毒素制剂选自科博肽注射液、Nyloxin、cobraxin和peperon中的至少一种。
7.根据权利要求(1)所述的用途,其特征在于,所述疼痛为急性疼痛或慢性疼痛,包括神经性疼痛、类风湿关节炎及关节损伤引起的疼痛、癌症疼痛、手术后疼痛、牙痛、痛经、肾痛、胆绞痛、腰背痛及烧伤后疼痛。
8.根据权利要求(1)所述的用途,其特征在于,所述组合物中的使用方法包括静脉注射、肌肉注射、皮下注射、关节腔内注射、口服、舌下、鼻腔、直肠、真皮内、腹膜内或鞘內给药或经皮给药。
9.根据权利要求(1)所述的用途,其特征在于,所述组合物中的眼镜蛇神经毒素剂量包括从1μg/Kg到350μg/kg/每次。
10.根据权利要求(1)所述的用途,其特征在于,所述组合物中药学上可接受的辅料选自丙二醇、羟丙基β环糊精、土温80、乙醇。
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